Perceptual learning of detection of textures in noise.
We examined whether the effects of practice on visual detection are stimulus specific and whether practice alters response bias. Eighty-four subjects performed yes-no detection of band-limited noise patterns (textures) in two levels of external noise, on two consecutive days. On day 2, one-half of the observers switched to novel textures. Texture contrast was varied on signal-present trials using the method of constant stimuli. The signal was present on 50% of the trials. We measured d', detection thresholds, and two measures of response criterion: a global criterion that was based on sensitivity at all signal levels (Jones et al., 2015) and a local criterion computed at a hit rate of 70% or 80% (Wenger & Rasche, 2006). Performance improved for both groups on day 2, indicating that improvement transferred to novel textures. Increases in d' were associated with a decrease in false alarms across days. The global criterion became less liberal and became more optimal (i.e., less biased) with practice; however, this effect was small and was not statistically significant in all conditions. The local criterion measure also became slightly less liberal with practice in most conditions, becoming more or less optimal depending on the hit rate at which it was computed. Overall, the effects of practice on sensitivity in a visual detection task generalized to novel patterns. In addition, we found that practice had relatively small effects on response criterion, and the precise effects on response bias differed between global and local measures of criterion.


The effect of chlorogenic acid on blood pressure: a systematic review and meta-analysis of randomized clinical trials.
Several dietary supplements are currently marketed for management of hypertension, but the evidence for effectiveness is conflicting. Our objective was to critically appraise and evaluate the evidence for the effectiveness of chlorogenic acids (CGAs) on blood pressure, using data from published randomized clinical trials (RCTs). Electronic searches were conducted in Medline, Embase, Amed, Cinahl and The Cochrane Library. We also hand-searched the bibliographies of all retrieved articles. Two reviewers independently determined the eligibility of studies and extracted the data. The reporting quality of all included studies was assessed by the use of a quality assessment checklist adapted from the Consolidated Standard of Reporting Trials Statement. Disagreements were resolved through discussion. Seven eligible studies were identified, and five including 364 participants were included. There were variations in the reporting quality of the included RCTs. Meta-analysis revealed a statistically significant reduction in systolic blood pressure in favour of CGA (mean difference (MD): -4.31 mm Hg; 95% confidence interval (CI): -5.60 to -3.01; I(2)=65%; P<0.00001). Meta-analysis also showed a significant reduction in diastolic blood pressure favouring CGA (MD: -3.68 mm Hg; 95% CI: -3.91 to -3.45; I(2)=97%; P<0.00001). All studies reported no adverse events. In conclusion, the evidence from published RCTs suggests that CGA intake causes statistically significant reductions in systolic and diastolic blood pressures. The size of the effect is moderate. Few clinical trials have been conducted; they vary in design and methodology and are confined to Asian populations and funded by CGA manufacturers. Large independent trials evaluating the effects of CGA on blood pressure are warranted.


Machine learning and wearable devices of the future.
Machine learning (ML) is increasingly recognized as a useful tool in healthcare applications, including epilepsy. One of the most important applications of ML in epilepsy is seizure detection and prediction, using wearable devices (WDs). However, not all currently available algorithms implemented in WDs are using ML. In this review, we summarize the state of the art of using WDs and ML in epilepsy, and we outline future development in these domains. There is published evidence for reliable detection of epileptic seizures using implanted electroencephalography (EEG) electrodes and wearable, non-EEG devices. Application of ML using the data recorded with WDs from a large number of patients could change radically the way we diagnose and manage patients with epilepsy.


The NSPCC UK Minding the Baby® (MTB) home-visiting programme, supporting young mothers (aged 14-25) in the first 2 years of their baby's life: study protocol for a randomised controlled trial.
Young mothers living in low-income urban settings often are exposed to significant and chronic environmental difficulties including poverty, social isolation and poor education and typically also have to cope with personal histories of abuse and depression. Minding the Baby® (MTB) is an interdisciplinary home-visiting programme developed to support first-time young mothers, which integrates primary care and mental health approaches into a single intensive intervention from the last trimester of pregnancy until the child's second birthday. The primary aim of the intervention is to promote caregiver sensitivity, and, secondarily, to promote both child and maternal socioemotional outcomes. This is a multisite randomised controlled trial (RCT) with a target recruitment of 200 first-time adolescent mothers (under 26 years of age). One hundred participants will be randomised to the MTB group and they will receive the MTB programme in addition to the usual services available in their areas. Those participants not allocated to MTB will receive Treatment as Usual (TAU) only. Researchers will carry out blind assessments at baseline (before the birth of the baby), and outcome assessments around the child's first and second birthdays. The primary outcome will be the quality of maternal sensitivity and the secondary outcomes will focus on attachment security, child cognitive/language development, behavioural problems, postponed childbearing, maternal mental health and incidents of child protection interventions. This study evaluates the Minding the Baby® programme in the UK. In particular, this RCT explores the effectiveness of this integrative approach, which focusses on maternal mental issues as well as parent-infant interaction, parental concerns and developmental outcomes. ISRCTN08678682 (date of registration 3 April 2014).


The Integrator complex controls the termination of transcription at diverse classes of gene targets.
Complexes containing INTS3 and either NABP1 or NABP2 were initially characterized in DNA damage responses, but their biochemical function remained unknown. Using affinity purifications and HIV Integration targeting-sequencing (HIT-Seq), we find that these complexes are part of the Integrator complex, which binds RNA Polymerase II and regulates specific target genes. Integrator cleaves snRNAs as part of their processing to their mature form in a mechanism that is intimately coupled with transcription termination. However, HIT-Seq reveals that Integrator also binds to the 3' end of replication-dependent histones and promoter proximal regions of genes with polyadenylated transcripts. Depletion of Integrator subunits results in transcription termination failure, disruption of histone mRNA processing, and polyadenylation of snRNAs and histone mRNAs. Furthermore, promoter proximal binding of Integrator negatively regulates expression of genes whose transcripts are normally polyadenylated. Integrator recruitment to all three gene classes is DSIF-dependent, suggesting that Integrator functions as a termination complex at DSIF-dependent RNA Polymerase II pause sites.


Radiological biomarkers for diagnosis in PSP: Where are we and where do we need to be?
PSP is a pathologically defined neurodegenerative tauopathy with a variety of clinical presentations including typical Richardson's syndrome and other variant PSP syndromes. A large body of neuroimaging research has been conducted over the past two decades, with many studies proposing different structural MRI and molecular PET/SPECT biomarkers for PSP. These include measures of brainstem, cortical and striatal atrophy, diffusion weighted and diffusion tensor imaging abnormalities, [18F] fluorodeoxyglucose PET hypometabolism, reductions in striatal dopamine imaging and, most recently, PET imaging with ligands that bind to tau. Our aim was to critically evaluate the degree to which structural and molecular neuroimaging metrics fulfill criteria for diagnostic biomarkers of PSP. We queried the PubMed, Cochrane, Medline, and PSYCInfo databases for original research articles published in English over the past 20 years using postmortem diagnosis or the NINDS-SPSP criteria as the diagnostic standard from 1996 to 2016. We define a five-level theoretical construct for the utility of neuroimaging biomarkers in PSP, with level 1 representing group-level findings, level 2 representing biomarkers with demonstrable individual-level diagnostic utility, level 3 representing biomarkers for early disease, level 4 representing surrogate biomarkers of PSP pathology, and level 5 representing definitive PSP biomarkers of PSP pathology. We discuss the degree to which each of the currently available biomarkers fit into this theoretical construct, consider the role of biomarkers in the diagnosis of Richardson's syndrome, variant PSP syndromes and autopsy confirmed PSP, and emphasize current shortfalls in the field. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.


Characterization of human DNA polymerase delta and its immunochemical relationships with DNA polymerase alpha and epsilon.
DNA polymerase delta was purified from human placenta and its polymerase catalytic subunit identified as a 125-kDa polypeptide by activity staining. This 125-kDa form of DNA polymerase delta resembles that reported from calf thymus (Lee, M. Y. W. T., Tan, C.-K., Downey, K. M., and So, A. G. (1984) Biochemistry 23, 1906-1913) and differs in molecular properties from a previously described form isolated from human placenta (Lee, M. Y. W. T., and Toomey, N. L. (1987) Biochemistry 26, 1076-1085) and now referred to as DNA polymerase epsilon. The properties of DNA polymerase delta were further investigated to determine its relationships with DNA polymerase epsilon. The two enzymes differed in their response to proliferating cell nuclear antigen. Monoclonal antibodies against DNA polymerase delta were raised and used to examine its immunochemical relationships with DNA polymerase alpha and epsilon. These studies provided evidence that all three proteins are structurally distinct but share a common epitope(s). Immunofluorescence microscopy indicates that DNA polymerase delta and possibly also DNA polymerase epsilon are localized to the nucleus.


Increased macrolide resistance of Mycoplasma pneumoniae in France directly detected in clinical specimens by real-time PCR and melting curve analysis.
Mycoplasma pneumoniae is a common aetiological agent of community-acquired respiratory tract infections for which macrolides are the treatment of choice. In France, only two macrolide-resistant isolates were reported in 1999. In contrast, several recent data reported that macrolide-resistant M. pneumoniae isolates have been spreading since 2000 in Japan. Mutations A2058G (Escherichia coli numbering), A2058C, A2059G, A2062G, C2611A and C2611G in domain V of the 23S rRNA gene were associated in vivo or in vitro with this resistance. The aim of this study was to determine whether macrolide resistance of M. pneumoniae is emerging in France. We developed a duplex real-time PCR for the detection of the six 23S rRNA mutations associated with macrolide resistance in M. pneumoniae and a simplex real-time PCR for the identification of the A2058G mutation, the most common one. Both methods rely on fluorescence resonance energy transfer coupled to melting curve analysis and are directly applicable to clinical samples. The duplex real-time PCR assay, first validated on 40 genetically characterized M. pneumoniae strains, was then applied directly on 248 French respiratory tract clinical samples. Among M. pneumoniae-positive specimens collected before 2005, no macrolide-resistant M. pneumoniae isolate was detected. In contrast, among 51 samples collected between 2005 and 2007, five (9.8%) yielded a resistant genotype, suggesting a recent increase in macrolide-resistant M. pneumoniae isolates in France. The epidemiological monitoring of macrolide resistance in this species has become necessary in France and Europe, and will be made easier by using these PCR assays.


Trends in U.S. Burden of Clostridioides difficile Infection and Outcomes.
Efforts to prevent Clostridioides difficile infection continue to expand across the health care spectrum in the United States. Whether these efforts are reducing the national burden of C. difficile infection is unclear. The Emerging Infections Program identified cases of C. difficile infection (stool specimens positive for C. difficile in a person ≥1 year of age with no positive test in the previous 8 weeks) in 10 U.S. sites. We used case and census sampling weights to estimate the national burden of C. difficile infection, first recurrences, hospitalizations, and in-hospital deaths from 2011 through 2017. Health care-associated infections were defined as those with onset in a health care facility or associated with recent admission to a health care facility; all others were classified as community-associated infections. For trend analyses, we used weighted random-intercept models with negative binomial distribution and logistic-regression models to adjust for the higher sensitivity of nucleic acid amplification tests (NAATs) as compared with other test types. The number of cases of C. difficile infection in the 10 U.S. sites was 15,461 in 2011 (10,177 health care-associated and 5284 community-associated cases) and 15,512 in 2017 (7973 health care-associated and 7539 community-associated cases). The estimated national burden of C. difficile infection was 476,400 cases (95% confidence interval [CI], 419,900 to 532,900) in 2011 and 462,100 cases (95% CI, 428,600 to 495,600) in 2017. With accounting for NAAT use, the adjusted estimate of the total burden of C. difficile infection decreased by 24% (95% CI, 6 to 36) from 2011 through 2017; the adjusted estimate of the national burden of health care-associated C. difficile infection decreased by 36% (95% CI, 24 to 54), whereas the adjusted estimate of the national burden of community-associated C. difficile infection was unchanged. The adjusted estimate of the burden of hospitalizations for C. difficile infection decreased by 24% (95% CI, 0 to 48), whereas the adjusted estimates of the burden of first recurrences and in-hospital deaths did not change significantly. The estimated national burden of C. difficile infection and associated hospitalizations decreased from 2011 through 2017, owing to a decline in health care-associated infections. (Funded by the Centers for Disease Control and Prevention.).


Assessment of in vitro interferon-gamma responses from peripheral blood mononuclear cells of cattle infected with Mycoplasma mycoides ssp. mycoides small colony type.
Contagious bovine pleuropneumonia (CBPP) is a lung disease caused by the bacterial pathogen Mycoplasma mycoides ssp. mycoides small colony type (MmmSC). It has been spreading due to a number of factors including poor vaccine efficacy and poor sensitivity of current diagnostic tests. The purpose of this study was to assess interferon gamma (IFN-gamma) release after stimulation of peripheral blood mononuclear cells (PBMC) from experimentally infected cattle. PBMC collected from 15 artificially infected animals were incubated with different concentrations of total MmmSC antigen. After 72h of incubation the IFN-gamma release was measured and found to be elevated in 11 animals. We did not observe a correlation between IFN-gamma release of animals with and without pathomorphological gross lesions. Therefore, our data do not confirm a role for CD4 T-lymphocytes in protection, since there is no correlation between IFN-g secretion (supposed to be mainly derived from CD4 T-cells) and disease severity. Additionally, we applied immunocytochemistry on affected lung tissue and detected no build up of T-lymphocytes (CD4 T-cells, CD8 T-cells) but a high presence of myeloid cells.


Does This Patient Have Posttraumatic Stress Disorder?: Rational Clinical Examination Systematic Review.
Posttraumatic stress disorder (PTSD) is a relatively common mental health condition frequently seen, though often unrecognized, in primary care settings. Identifying and treating PTSD can greatly improve patient health and well-being. To systematically review the utility of self-report screening instruments for PTSD among primary care and high-risk populations. We searched MEDLINE and the National Center for PTSD's Published International Literature on Traumatic Stress (PILOTS) databases for articles published on screening instruments for PTSD published from January 1981 through March 2015. Study quality was rated using Quality Assessment of Diagnostic Accuracy Studies (QUADAS) criteria. Studies of screening instruments for PTSD evaluated using gold standard structured clinical diagnostic interviews that had interview samples of at least 50 individuals. We identified 2522 citations, retrieved 318 for further review, and retained 23 cohort studies that evaluated 15 screening instruments for PTSD. Of the 23 studies, 15 were conducted in primary care settings in the United States (n = 14,707 were screened, n = 5374 given diagnostic interview, n = 814 had PTSD) and 8 were conducted in community settings following probable trauma exposure (ie, natural disaster, terrorism, and military deployment; n = 5302 were screened, n = 4263 given diagnostic interview, n = 393 were known to have PTSD with an additional 50 inferred by rates reported by authors). Two screens, the Primary Care PTSD Screen (PC-PTSD) and the PTSD Checklist were the best performing instruments. The 4-item PC-PTSD has a positive likelihood ratio of 6.9 (95% CI, 5.5-8.8) and a negative likelihood ratio of 0.30 (95% CI, 0.21-0.44) using the same score indicating a positive screen as used by the Department of Veterans Affairs in all of its primary care clinics. The 17-item PTSD Checklist has a positive likelihood ratio of 5.2 (95% CI, 3.6-7.5) and a negative likelihood ratio of 0.33 (95% CI, 0.29-0.37) using scores of around 40 as indicating a positive screen. Using the same score employed by primary care clinics in the Department of Veterans Affairs to indicate a positive screen, the 4-item PC-PTSD has a sensitivity of 0.69 (95% CI, 0.55-0.81), a specificity of 0.92 (95% CI, 0.86-0.95), a positive likelihood ratio of 8.49 (95% CI, 5.56-12.96) and a negative likelihood ratio of 0.34 (95% CI, 0.22-0.48). For the 17-item PTSD Checklist, scores around 40 as indicating a positive screen, have a sensitivity of 0.70 (95% CI, 0.64-0.77), a specificity of 0.90 (95% CI, 0.84-0.93), a positive likelihood ratio of 6.8 (95% CI, 4.7-9.9) and a negative likelihood ratio of 0.33 (95% CI, 0.27-0.40). Two screening instruments, the PC-PTSD and the PTSD Checklist, show reasonable performance characteristics for use in primary care clinics or in community settings with high-risk populations. Both are easy to administer and interpret and can readily be incorporated into a busy practice setting.


Pediatric Ameloblastic Fibroma: A Case Report.
To highlight the potential difficulties in diagnosing neoplastic lesion of the head and neck in children within autism spectrum. Ameloblastic fibromas are a variation of odontogenic tumors that are located in the posterior mandible in 70% of cases. The tumors may be either unilocular or multilocular when observed radiographically. Ameloblastic fibromas tend to have well-defined, scalloped margins radiographically but may also be corticated. In close to 75% of all cases, an impacted tooth is associated with the lesion. Although not confined to patients who are in their first or second decades of life, ameloblastic fibromas most often arise in this population. A 9-year-old male diagnosed with autism presented with tenderness in the left mandible. The parents were able to elucidate the child's problem as tingling rather than pain. The patient was referred for histopathological diagnosis and treatment. After evaluation and biopsy, the lesion was identified as a pediatric ameloblastic fibroma. He subsequently underwent the conservative approach of marsupialization and curettage without complication. Six-month follow-up revealed no evidence of recurrence and normal eruption patterns of the succedaneous teeth in the affected area. In this specific case, the conservative approach to treatment appears to have been appropriate. This may not be the appropriate course for every case; as such, each case will have an individualized approach. Earlier recognition with careful inspection can reduce potential complications. We might be missing early diagnosis of ameloblastic fibroma and other significant orofacial neoplasms in patients who are nonverbal or nondescriptive such as those with autism. Moreover, careful inspection of radiographic and clinical signs cannot be overemphasized.


International Life Sciences Institute (Health and Environmental Sciences Institute, HESI) initiative on moving towards better predictors of drug-induced torsades de pointes.
Knowledge of the cardiac safety of emerging new drugs is an important aspect of assuring the expeditious advancement of the best candidates targeted at unmet medical needs while also assuring the safety of clinical trial subjects or patients. Present methodologies for assessing drug-induced torsades de pointes (TdP) are woefully inadequate in terms of their specificity to select pharmaceutical agents, which are human arrhythmia toxicants. Thus, the critical challenge in the pharmaceutical industry today is to identify experimental models, composite strategies, or biomarkers of cardiac risk that can distinguish a drug, which prolongs cardiac ventricular repolarization, but is not proarrhythmic, from one that prolongs the QT interval and leads to TdP. To that end, the HESI Proarrhythmia Models Project Committee recognized that there was little practical understanding of the relationship between drug effects on cardiac ventricular repolarization and the rare clinical event of TdP. It was on that basis that a workshop was convened in Virginia, USA at which four topics were introduced by invited subject matter experts in the following fields: Molecular and Cellular Biology Underlying TdP, Dynamics of Periodicity, Models of TdP Proarrhythmia, and Key Considerations for Demonstrating Utility of Pre-Clinical Models. Contained in this special issue of the British Journal of Pharmacology are reports from each of the presenters that set out the background and key areas of discussion in each of these topic areas. Based on this information, the scientific community is encouraged to consider the ideas advanced in this workshop and to contribute to these important areas of investigations over the next several years.


Molecular map of the desmosomal plaque.
Recent biochemical and molecular approaches have begun to establish the protein interactions that lead to desmosome assembly. To determine whether these associations occur in native desmosomes we have performed ultrastructural localisation of specific domains of the major desmosomal components and have used the results to construct a molecular map of the desmosomal plaque. Antibodies directed against the amino- and carboxy-terminal domains of desmoplakin, plakoglobin and plakophilin 1, and against the carboxy-terminal domains of desmoglein 3, desmocollin 2a and desmocollin 2b, were used for immunogold labelling of ultrathin cryosections of bovine nasal epidermis. For each antibody, the mean distance of the gold particles, and thus the detected epitope, from the cytoplasmic surface of the plasma membrane was determined quantitatively. Results showed that: (i) plakophilin, although previously shown to bind intermediate filaments in vitro, is localised extremely close to the plasma membrane, rather than in the region where intermediate filaments are seen to insert into the desmosomal plaque; (ii) while the 'a' form of desmocollin overlaps with plakoglobin and desmoplakin, the shorter 'b' form may be spatially separated from them; (iii) desmoglein 3 extends across the entire outer plaque, beyond both desmocollins; (iv) the amino terminus of desmoplakin lies within the outer dense plaque and the carboxy terminus some 40 nm distant in the zone of intermediate filament attachment. This is consistent with a parallel arrangement of desmoplakin in dimers or higher order aggregates and with the predicted length of desmoplakin II, indicating that desmoplakin I may be folded or coiled. Thus several predictions from previous work were borne out by this study, but in other cases our observations yielded unexpected results. These results have significant implications relating to molecular interactions in desmosomes and emphasise the importance of applying multiple and complementary approaches to biological investigations.


Non parametric, self organizing, scalable modeling of spatiotemporal inputs: the sign language paradigm.
Modeling and recognizing spatiotemporal, as opposed to static input, is a challenging task since it incorporates input dynamics as part of the problem. The vast majority of existing methods tackle the problem as an extension of the static counterpart, using dynamics, such as input derivatives, at feature level and adopting artificial intelligence and machine learning techniques originally designed for solving problems that do not specifically address the temporal aspect. The proposed approach deals with temporal and spatial aspects of the spatiotemporal domain in a discriminative as well as coupling manner. Self Organizing Maps (SOM) model the spatial aspect of the problem and Markov models its temporal counterpart. Incorporation of adjacency, both in training and classification, enhances the overall architecture with robustness and adaptability. The proposed scheme is validated both theoretically, through an error propagation study, and experimentally, on the recognition of individual signs, performed by different, native Greek Sign Language users. Results illustrate the architecture's superiority when compared to Hidden Markov Model techniques and variations both in terms of classification performance and computational cost.


Human neuroelectric patterns predict performance accuracy.
In seven right-handed adults, the brain electrical patterns before accurate performance differed from the patterns before inaccurate performance. Activity overlying the left frontal cortex and the motor and parietal cortices contralateral to the performing hand preceded accurate left- or right-hand performance. Additional strong activity overlying midline motor and premotor cortices preceded left-hand performance. These measurements suggest that brief, spatially distributed neural activity patterns, or "preparatory sets," in distinct cognitive, somesthetic-motor, and integrative motor areas of the human brain may be essential precursors of accurate visuomotor performance.


A Modified Behavior Risk Factor Surveillance System to Assess Diabetes Self-management Behaviors and Diabetes Care in Monterrey Mexico: A Cross-sectional Study.
Type 2 diabetes mellitus (T2DM) is one of the leading causes of death from worldwide non-communicable diseases. The prevalence of diabetes in the Mexico (MX)-United States border states exceeds the national rate in both countries. The economic burden of diabetes, due to decreased productivity, disability, and medical costs, is staggering and increases significantly when T2DM-related complications occur. The purpose of this study was to use a modified behavioral risk factor surveillance system (BRFSS) to describe the T2DM self-management behaviors, diabetes care, and health perception of a convenience sample of adults with T2DM in Monterrey, MX. This cross-sectional study design, with convenience sampling, was conducted with a convenience sample (n = 351) of adults in the metropolitan area of Monterrey, MX who self-reported a diagnosis of T2DM. Potential participants were recruited from local supermarkets. Twenty-six diabetes and health-related items were selected from the BRFSS and administered in face-to-face interviews by trained data collectors. Data analysis was conducted using descriptive statistics. The mean age was 47 years, and the mean length of time with T2DM was 12 years. The majority was taking oral medication and 34% required insulin. Daily self-monitoring of feet was performed by 56% of the participants; however, only 8.8% engaged in blood glucose self-monitoring. The mean number of health-care provider visits was 9.09 per year, and glycated hemoglobin level (HbA1c) was assessed 2.6 times per year. Finally, only 40.5% of the participants recalled having a dilated eye exam. We conclude the modified BRFSS survey administered in a face-to-face interview format is an appropriate tool for assessing engagement in T2DM self-management behaviors, diabetes care, and health perception. Extension of the use of this survey in a more rigorous design with a larger scale survey is encouraged.


The role of fitness in the association between fatness and cardiometabolic risk from childhood to adolescence.
Fatness and fitness both influence cardiometabolic risk. The purpose of this study was to investigate whether childhood fatness and increasing fatness from childhood to adolescence are associated with cardiometabolic risk during adolescence and how fitness affects this association. Of 565 adolescents (283 boys and 282 girls) from the TRacking Adolescents Individual Life Survey (TRAILS) data on anthropometric parameters (age 11 and 16), metabolic parameters, and fitness (age 16) were available. Body mass index and skinfolds were used as measures for fatness. Increasing fatness was calculated by subtracting Z-scores for fatness at age 11 from Z-score fatness at age 16. Cardiometabolic risk was calculated as the average of the standardized means of mean arterial pressure, fasting serum triglycerides, high-density lipoprotein-cholesterol, glucose, and waist circumference. Insulin resistance was calculated by homeostasis model assessment-insulin resistance (HOMA-IR). Fitness was estimated as maximal oxygen consumption (VO(2) max) during a shuttle run test. Boys showed a higher clustered cardiometabolic risk when compared to girls (p < 0.01). Childhood fatness (age 11) and increasing fatness were independently associated with cardiometabolic risk during adolescence. In boys, high fitness was related to a reduced effect of increasing fatness on clustered cardiometabolic risk. Childhood fatness, increasing fatness, and fitness were independently associated with HOMA-IR. Moreover, in boys this association was dependent of fatness. Childhood fatness and increasing fatness are associated with increased cardiometabolic risk and HOMA-IR during adolescence, but a good fitness attenuates this association especially in fat boys.


Accelerometer-Measured Sedentary and Physical Activity Time and Their Correlates in European Older Adults: The SITLESS Study.
Sedentary behavior (SB) and physical activity (PA) are important determinants of health in older adults. This study aimed to describe the composition of accelerometer-measured SB and PA in older adults, to explore self-reported context-specific SB, and to assess sociodemographic and functional correlates of engaging in higher levels of SB in participants of a multicenter study including four European countries. One thousand three hundred and sixty community-dwelling older adults from the SITLESS study (61.8% women; 75.3 ± 6.3 years) completed a self-reported SB questionnaire and wore an ActiGraph accelerometer for 7 days. Accelerometer-determined compositional descriptive statistics were calculated. A fixed-effects regression analysis was conducted to assess the sociodemographic (country, age, sex, civil status, education, and medications) and functional (body mass index and gait speed) correlates. Older adults spent 78.8% of waking time in SB, 18.6% in light-intensity PA, and 2.6% in moderate-to-vigorous PA. Accelerometry showed that women engaged in more light-intensity PA and walking and men engaged in higher amounts of moderate-to-vigorous PA. Watching television and reading accounted for 47.2% of waking time. Older age, being a man, single, taking more medications, being obese and overweight, and having a slower gait speed were statistically significant correlates of more sedentary time. The high amount of SB of our participants justifies the need to develop and evaluate interventions to reduce sitting time. A clinically relevant change in gait speed can decrease almost 0.45 percentage points of sedentary time. The distribution of context-specific sedentary activities by country and sex showed minor differences, albeit worth noting.


MabCent: Arctic marine bioprospecting in Norway.
The deep waters surrounding the coastline of the northern parts of Norway represent an exciting biotope for marine exploration. Dark and cold Arctic water generates a hostile environment where the ability to adapt is crucial to survival. These waters are nonetheless bountiful and a diverse plethora of marine organisms thrive in these extreme conditions, many with the help of specialised chemical compounds. In comparison to warmer, perhaps more inviting shallower tropical waters, the Arctic region has not been as thoroughly investigated. MabCent is a Norwegian initiative based in Tromsø that aims to change this. Since 2007, scientists within MabCent have focussed their efforts on the study of marine organisms inhabiting the Arctic waters with the long term goal of novel drug discovery and development. The activities of MabCent are diverse and range from sampling the Arctic ice shelf to the chemical synthesis of promising secondary metabolites discovered during the screening process. The current review will present the MabCent pipeline from isolation to identification of new bioactive marine compounds via an extensive screening process. An overview of the main activities will be given with particular focus on isolation strategies, bioactivity screening and structure determination. Pitfalls, hard earned lessons and the results so far are also discussed.


Evaluation of expression and function of the H+/myo-inositol transporter HMIT.
The phosphoinositide (PIns) signalling pathway regulates a series of neuronal processes, such as neurotransmitter release, that are thought to be altered in mood disorders. Furthermore, mood-stabilising drugs have been shown to inhibit key enzymes that regulate PIns production and alter neuronal growth cone morphology in an inositol-reversible manner. Here, we describe analyses of expression and function of the recently identified H+/myo-inositol transporter (HMIT) investigated as a potential regulator of PIns signalling. We show that HMIT is primarily a neuronal transporter widely expressed in the rat and human brain, with particularly high levels in the hippocampus and cortex, as shown by immunohistochemistry. The transporter is localised at the Golgi apparatus in primary cultured neurones. No HMIT-mediated electrophysiological responses were detected in rat brain neurones or slices; in addition, inositol transport and homeostasis were unaffected in HMIT targeted null-mutant mice. Together, these data do not support a role for HMIT as a neuronal plasma membrane inositol transporter, as previously proposed. However, we observed that HMIT can transport inositol triphosphate, indicating unanticipated intracellular functions for this transporter that may be relevant to mood control.


Uncertainty in velocity measurement based on diode-laser absorption in nonuniform flows.
This work investigates the error caused by nonuniformities along the line-of-sight in velocity measurement using tunable diode-laser absorption spectroscopy (TDLAS). Past work has demonstrated TDLAS as an attractive diagnostic technique for measuring velocity, which is inferred from the Doppler shift of two absorption features using two crossing laser beams. However, because TDLAS is line-of-sight in nature, the obtained velocity is a spatially averaged value along the probing laser beams. As a result, nonuniformities in the flow can cause uncertainty in the velocity measurement. Therefore, it is the goal of this work to quantify the uncertainty caused by various nonuniformities typically encountered in practice, including boundary layer effects, the divergence/convergence of the flow, and the methods used to fit the Doppler shift. Systematic analyses are performed to quantify the uncertainty under various conditions, and case studies are reported to illustrate the usefulness of such analysis in interpreting experimental data obtained from a scramjet facility. We expect this work to be valuable for the design and optimization of TDLAS-based velocimetry, and also for the quantitative interpretation of the measurements.


One Health promotion and the politics of dog management in remote, northern Australian communities.
Community perspectives are rarely sought or integrated into dog management policy and practice. Dog management in remote communities in Australia has focused on reducing the number of dogs, which is often implemented by visiting veterinarians, despite widely-held opinions that fly-in-fly-out services provide only temporary solutions. We conducted participatory research in a group of remote communities in northern Australia to explore how dog-related problems arise and are managed, and explain their impacts from a One Health perspective. Over the course of a year, 53 residents from a range of backgrounds contributed through in-depth interviews with key community service providers, and informal semi-structured discussions with community residents. Free-roaming dogs have broader impacts on canine and human health than previously documented. Dog-keeping norms that enable free-roaming can enhance human and dog wellbeing and intra-family connectivity. This can also cause disengagement and conflict with other residents, leading to resentment and occasionally violence towards dogs. Dog-related problems are underpinned by constraints associated with remote-living, governance and differing sociocultural norms. Focusing on dog population reduction detracts from the welfare benefits and sociocultural value of free-roaming dogs and undermines community-determined management that can overcome constraints to support local values and co-promote canine and human wellbeing.


Mapping of QTL affecting incidence of blood and meat inclusions in egg layers.
Occurrence of blood and meat inclusions is an internal egg quality defect. Mass candling reveals most of the spots, but because brown eggshell hampers selection in brown chicken lines it has not been possible to eliminate the defect by selection. Estimated frequency of blood and meat inclusions in brown layers is about 18% whereas it is 0.5% in white egg layers. Several factors are known to increase the incidence of this fault: genetic background, low level of vitamin A and/or D, stress or infections, for instance. To study the genetic background of the defect, a mapping population of 1599 F2 hens from a cross of White Rock and Rhode Island Red lines was set up. Our histopathological analyses show that blood spots consist of mainly erythrocytes and that meat spots are accumulations of necrotic material. Linkage analysis of 27 chromosomes with 162 microsatellite markers revealed one significant quantitative trait locus (QTL) affecting blood spot and meat spot frequency. We sequenced a fragment of a candidate gene within the region, ZO-2, coding for a tight junction protein. Nine polymorphisms were detected and two of them were included in fine-mapping and association analysis. Fine-mapping defined the QTL result. To further verify the QTL, association analyses were carried out in two independent commercial breeding lines with the marker MCW241 and surrounding SNPs. Association was found mainly in a 0.8 Mb-wide chromosomal area on GGAZ. There was good agreement between the location of the QTL region on chromosome Z and the association results in the commercial breeds analyzed. Variations found in tight junction protein ZO-2 and microRNA gga-mir-1556 may predispose egg layers to blood and meat spot defects. This paper describes the first results of detailed QTL analyses of the blood and meat spots trait(s) in chickens.


A unified framework for managing provenance information in translational research.
A critical aspect of the NIH Translational Research roadmap, which seeks to accelerate the delivery of "bench-side" discoveries to patient's "bedside," is the management of the provenance metadata that keeps track of the origin and history of data resources as they traverse the path from the bench to the bedside and back. A comprehensive provenance framework is essential for researchers to verify the quality of data, reproduce scientific results published in peer-reviewed literature, validate scientific process, and associate trust value with data and results. Traditional approaches to provenance management have focused on only partial sections of the translational research life cycle and they do not incorporate "domain semantics", which is essential to support domain-specific querying and analysis by scientists. We identify a common set of challenges in managing provenance information across the pre-publication and post-publication phases of data in the translational research lifecycle. We define the semantic provenance framework (SPF), underpinned by the Provenir upper-level provenance ontology, to address these challenges in the four stages of provenance metadata:(a) Provenance collection - during data generation(b) Provenance representation - to support interoperability, reasoning, and incorporate domain semantics(c) Provenance storage and propagation - to allow efficient storage and seamless propagation of provenance as the data is transferred across applications(d) Provenance query - to support queries with increasing complexity over large data size and also support knowledge discovery applicationsWe apply the SPF to two exemplar translational research projects, namely the Semantic Problem Solving Environment for Trypanosoma cruzi (T.cruzi SPSE) and the Biomedical Knowledge Repository (BKR) project, to demonstrate its effectiveness. The SPF provides a unified framework to effectively manage provenance of translational research data during pre and post-publication phases. This framework is underpinned by an upper-level provenance ontology called Provenir that is extended to create domain-specific provenance ontologies to facilitate provenance interoperability, seamless propagation of provenance, automated querying, and analysis.


Atypical dopa responsive parkinsonism in a patient with megalencephaly, midbrain Lewy body disease, and some pathological features of Hallervorden-Spatz disease.
A 38 year old patient with megalencephaly, mental retardation, and lifelong tremor developed levodopa responsive parkinsonism in his mid-30s followed by the appearance of dyskinesiae, motor fluctuations, hallucinations, and dementia. Brain MRI showed, as well as other changes, iron deposition in the globus pallidus, substantia nigra, and the pulvinar of the thalamus. Postmortem examination disclosed depigmentation of the substantia nigra pars compacta with neuronal loss, gliosis, and Lewy body formation. Axonal dystrophic spheroids, neuronal loss, calcification, and iron deposition were found in the substantia nigra pars reticulata. Less severe changes without neuronal loss were seen in the globus pallidus. This combination of megalencephaly with neuroaxonal changes predominantly in the pars reticulata and Lewy body degeneration isolated to the substantia nigra pars compacta has not been previously reported.


Prevalence and Risk of Violent Ideation and Behavior in Serious Mental Illnesses: An Analysis of 63,572 Patient Records.
Research has consistently demonstrated that people diagnosed with serious mental illness (SMI) are at increased risk for violent ideation and behavior (VIB) and that this is especially the case for SMI patients with comorbid substance use disorders (SUD). Despite this, what is still largely unknown is the relative prevalence of VIB across diagnostic categories, whether the rates of VIB in SMI groups exceed the rates observed in people with SUD only, and which demographic factors increase the likelihood of VIB under different circumstances for people with SMI. To address these questions, we analyzed the intake records of 63,572 patients diagnosed with SMIs (i.e., schizoaffective disorder, schizophrenia, bipolar disorder, and unipolar depression), substance use disorders, and non-SMI psychiatric disorders. Raw prevalence rates for a combined metric of VIB were established and compared for each group, and a series of logistic regression analyses were performed to estimate how various demographic factors influenced the likelihood of VIB endorsement in each study group. Our results revealed that (a) patients with SMI conditions had higher rates of VIB than both patients with non-SMI psychopathology and those with substance use disorders only; (b) patients with SMI and comorbid substance use pathology were responsible for the majority of VIB within each SMI condition; and (c) men with SMI conditions had higher prevalence rates of VIB than females. In addition, we found that for every SMI diagnosis, comorbid substance use disorders and younger age were related to greater risk for VIB, and where race and gender were found to significantly alter the likelihood of VIB endorsement, African American status and female gender were independently related to greater risk. The implications of these findings and directions for future research are discussed.


Evaluation of the toxicity of iron-ion irradiation in murine bone marrow dendritic cells via increasing the expression of indoleamine 2,3-dioxygenase 1.
High linear energy transfer radiation is known to deposit higher energy in tissues and cause greater toxicity compared to low-LET irradiation. Local immunosuppression is frequently observed after irradiation (IR). Dendritic cells (DCs) play important roles in the initiation and maintenance of the immune response. The dysfunction of DCs contributes to tumor evasion and growth. However, molecular mechanisms underlying the establishment of immune tolerance induced by heavy ion IR through this DC population are poorly understood. Therefore, here we report our findings on the dysfunction of bone marrow-derived dendritic cells (BMDCs) induced by 1 Gy iron ion radiation and promotions of expressions of JNK1/2/3, indoleamine 2,3-dioxygenase 1 (IDO1), p-ERK1/2 and p38/MAPK; and decrease of IDO2, MHC class II, CD40, CD80 expressions and IFN-γ and TNF-α secretion after total-body IR in mice. JNK+IDO1+ BMDCs showed up-expression of p-ERK1/2 and p-p38/MAPK, reduced expression of MHC class II and CD80, and were not able to effectively stimulate allogeneic spleen T cells. The inhibition of IDO1 expressions could partly restore the function of BMDCs. In all, our study shows that elevated JNK and IDO1 expression induced by Fe ion IR could result in dysfunction of BMDCs via p-p38/MAPK and p-ERK1/2 signal pathway, and it may represent a new mechanism in radiation-induced immune tolerance.


Malignant Mixed Germ Cell Tumors of the Ovary: A Series of Rare Cases.
Malignant mixed germ cell tumors of ovary are rare aggressive cancers affecting young adolescent girls. The commonest combination reported in literature is dysgerminoma and endodermal sinus tumors but in our study the most common combination was immature teratoma and endodermal sinus tumor which is exteremely rare. Preservation of future fertility is a concern. Fertility sparing surgery followed by combination chemotherapy is the current treatment of choice but treatment must be individualized depending upon the nature of the tumor. A retrospective study on five patients with these tumors was conducted on patients at Guru Gobind Singh Medical College and Hospital (Punjab, India) between September 2009 to January 2018. Median age of patients was 15.6 years. Histopathological combination was immature teratoma and endodermal sinus tumor (n=3), endodermal sinus tumor and embryonal carcinoma (n=1), and mature and immature teratoma (n=1). Tumor markers AFP, beta HCG and LDH were raised in all except the patient with mature and immature teratoma. All patients underwent surgery followed by combination chemotherapy. Three patients developed metastasis within six months of treatment and died. In the remaining two, no reccurrence was reported till date. Malignant mixed germ cell tumors of ovary are extremely rare tumors and have poor prognosis. Fertility preservation is a concern as these patients are usually young adolescent girls but fertility sparing treatment must be individualized on the basis of tumor type, surgical staging, and availability of combination chemotherapy. Considering high recurrence rate and mortality, total hysterectomy with bilateral salpingo-oophorectomy with complete surgical staging followed by combination chemotherapy should be perfomed at advanced stage and aggressive tumor biology. Preservation of fertility must be held secondary.


Age-related changes in the propensity of dogs to bite.
This retrospective cohort study was aimed at describing the effects of age at acquisition, age, and duration of ownership of dogs on the risk of (1) bites during play and (2) non-play bites to humans. Data were collected on 110 dogs that had bitten during play with a person, 161 dogs that had bitten outside of play and 951 non-biting dogs from veterinary clients in Kingston (KGN), Jamaica and San Francisco (SF), USA. Modified Poisson regression was employed to model the relationships of both types of bites to each variable separately. Effects of the variables on dog bite risk (1) during and (2) outside of play with the dog, differed from each other and by type of bite. Effects varied with the dog's age and age-related associations were strongest in dogs younger than 1 year old. Ages at acquisition of dogs at highest risk for bites during play were substantially lower than those at risk for non-play bites. Ages and durations of ownership of dogs at highest risk for bites during play were also lower than those of dogs at highest risk for non-play bites. The propensity of a dog to bite changes as it ages and relationships between dog bites occurring during and outside of play and the dog's age at acquisition, current age, and duration of ownership, differ from each other.


Can Toxicokinetic and Toxicodynamic Modeling Be Used to Understand and Predict Synergistic Interactions between Chemicals?
Some chemicals are known to enhance the effect of other chemicals beyond what can be predicted with standard mixture models, such as concentration addition and independent action. These chemicals are called synergists. Up until now, no models exist that can predict the joint effect of mixtures including synergists. The aim of the present study is to develop a mechanistic toxicokinetic (TK) and toxicodynamic (TD) model for the synergistic mixture of the azole fungicide, propiconazole (the synergist), and the insecticide, α-cypermethrin, on the mortality of the crustacean Daphnia magna. The study tests the hypothesis that the mechanism of synergy is the azole decreasing the biotransformation rate of α-cypermethrin and validates the predictive ability of the model on another azole with a different potency: prochloraz. The study showed that the synergistic potential of azoles could be explained by their effect on the biotransformation rate but that this effect could only partly be explained by the effect of the two azoles on cytochrome P450 activity, measured on D. magna in vivo. TKTD models of interacting mixtures seem to be a promising tool to test mechanisms of interactions between chemicals. Their predictive ability is, however, still uncertain.


Which components of heart failure programmes are effective? A systematic review and meta-analysis of the outcomes of structured telephone support or telemonitoring as the primary component of chronic heart failure management in 8323 patients: Abridged Cochrane Review.
Telemonitoring (TM) and structured telephone support (STS) have the potential to deliver specialized management to more patients with chronic heart failure (CHF), but their efficacy is still to be proven. The aim of this meta-analysis was to review randomized controlled trials (RCTs) of TM or STS for all-cause mortality and all-cause and CHF-related hospitalizations in patients with CHF, as a non-invasive remote model of a specialized disease-management intervention. We searched all relevant electronic databases and search engines, hand-searched bibliographies of relevant studies, systematic reviews, and meeting abstracts. Two reviewers independently extracted all data. Randomized controlled trials comparing TM or STS to usual care in patients with CHF were included. Studies that included intensified management with additional home or clinic-visits were excluded. Primary outcomes (mortality and hospitalizations) were analysed; secondary outcomes (cost, length of stay, and quality of life) were tabulated. Thirty RCTs of STS and TM were identified (25 peer-reviewed publications (n= 8323) and five abstracts (n= 1482)). Of the 25 peer-reviewed studies, 11 evaluated TM (2710 participants), 16 evaluated STS (5613 participants) with two testing both STS and TM in separate intervention arms compared with usual care. Telemonitoring reduced all-cause mortality {risk ratio (RR) 0.66 [95% confidence interval (CI) 0.54-0.81], P< 0.0001 }and STS showed a similar, but non-significant trend [RR 0.88 (95% CI 0.76-1.01), P= 0.08]. Both TM [RR 0.79 (95% CI 0.67-0.94), P= 0.008], and STS [RR 0.77 (95% CI 0.68-0.87), P< 0.0001] reduced CHF-related hospitalizations. Both interventions improved quality of life, reduced costs, and were acceptable to patients. Improvements in prescribing, patient-knowledge and self-care, and functional class were observed. Telemonitoring and STS both appear effective interventions to improve outcomes in patients with CHF. Systematic Review Number: Cochrane Database of Systematic Reviews. 2008:Issue 3. Art. No.: CD007228. DOI: 10.1002/14651858.CD007228.


Consensus conference: acitretin in combination with UVB or PUVA in the treatment of psoriasis.
Although adjunctive treatment with retinoids in concert with either psoralen-ultraviolet A (PUVA) or ultraviolet B (UVB) phototherapy has been a treatment option for chronic, moderate to severe plaque psoriasis for nearly two decades, acitretin-UV therapy is an underutilized therapeutic modality. According to a recent member survey by the National Psoriasis Foundation, many psoriasis patients are frustrated with available treatment options, which they perceive as ineffective, inconvenient, and/or excessively conservative. Treatment of psoriasis with acitretin in concert with UVB or PUVA is emerging as a viable clinical strategy. Compared with either acitretin or UV light monotherapy alone, the combination regimen enhances efficacy and limits treatment frequency, duration, and cumulative doses. These effects translate into care that is more effective, better tolerated, more convenient, less costly, and, perhaps, safer during long-term treatment than phototherapy alone. Drawing from an extensive literature search and the expertise of its participants, this consensus conference advances clinical recommendations as well as "clinical pearls" for health providers who treat patients with chronic, moderate to severe plaque psoriasis and suggests avenues for future research.


Enhanced tactile encoding and memory recognition in congenital blindness.
Several behavioural studies have shown that early-blind persons possess superior tactile skills. Since neurophysiological data show that early-blind persons recruit visual as well as somatosensory cortex to carry out tactile processing (cross-modal plasticity), blind persons' sharper tactile skills may be related to cortical re-organisation resulting from loss of vision early in their life. To examine the nature of blind individuals' tactile superiority and its implications for cross-modal plasticity, we compared the tactile performance of congenitally totally blind, low-vision and sighted children on raised-line picture identification test and re-test, assessing effects of task familiarity, exploratory strategy and memory recognition. What distinguished the blind from the other children was higher memory recognition and higher tactile encoding associated with efficient exploration. These results suggest that enhanced perceptual encoding and recognition memory may be two cognitive correlates of cross-modal plasticity in congenital blindness.


Modification of Kv2.1 K+ currents by the silent Kv10 subunits.
Human and rat Kv10.1a and b cDNAs encode silent K+ channel pore-forming subunits that modify the electrophysiological properties of Kv2.1. These alternatively spliced variants arise by the usage of an alternative site of splicing in exon 1 producing an 11-amino acid insertion in the linker between the first and second transmembrane domains in Kv10.1b. In human, the Kv10s mRNA were detected by Northern blot in brain kidney lung and pancreas. In brain, they were expressed in cortex, hippocampus, caudate, putamen, amygdala and weakly in substantia nigra. In rat, Kv10.1 products were detected in brain and weakly in testes. In situ hybridization in rat brain shows that Kv10.1 mRNAs are expressed in cortex, olfactory cortical structures, basal ganglia/striatal structures, hippocampus and in many nuclei of the amygdala complex. The CA3 and dentate gyrus of the hippocampus present a gradient that show a progression from high level of expression in the caudo-ventro-medial area to a weak level in the dorso-rostral area. The CA1 and CA2 areas had low levels throughout the hippocampus. Several small nuclei were also labeled in the thalamus, hypothalamus, pons, midbrain, and medulla oblongata. Co-injection of Kv2.1 and Kv10.1a or b mRNAs in Xenopus oocytes produced smaller currents that in the Kv2.1 injected oocytes and a moderate reduction of the inactivation rate without any appreciable change in recovery from inactivation or voltage dependence of activation or inactivation. At higher concentration, Kv10.1a also reduces the activation rate and a more important reduction in the inactivation rate. The gene that encodes for Kv10.1 mRNAs maps to chromosome 2p22.1 in human, 6q12 in rat and 17E4 in mouse, locations consistent with the known systeny for human, rat and mouse chromosomes.


Gene expression profiling distinguishes proneural glioma stem cells from mesenchymal glioma stem cells.
Tumor heterogeneity of high-grade glioma (HGG) is recognized by four clinically relevant subtypes based on core gene signatures. However, molecular signaling in glioma stem cells (GSCs) in individual HGG subtypes is poorly characterized. Previously we identified and characterized two mutually exclusive GSC subtypes with distinct activated signaling pathways and biological phenotypes. One GSC subtype presented with a gene signature resembling Proneural (PN) HGG, whereas the other was similar to Mesenchymal (Mes) HGG. Classical HGG-derived GSCs were sub-classified as either one of these two subtypes. Differential mRNA expression analysis of PN and Mes GSCs identified 5,796 differentially expressed genes, revealing a pronounced correlation with the corresponding PN or Mes HGGs. Mes GSCs displayed more aggressive phenotypes in vitro and as intracranial xenografts in mice. Further, Mes GSCs were markedly resistant to radiation compared with PN GSCs. Expression of ALDH1A3 - one of the most up-regulated Mes representative genes and a universal cancer stem cell marker in non-brain cancers - was associated with self-renewal and a multi-potent stem cell population in Mes but not PN samples. Moreover, inhibition of ALDH1A3 attenuated the growth of Mes but not PN GSCs in vitro. Lastly, radiation treatment of PN GSCs up-regulated Mes-associated markers and down-regulated PN-associated markers, whereas inhibition of ALDH1A3 attenuated an irradiation-induced gain of Mes identity in PN GSCs in vitro. Taken together, our data suggest that two subtypes of GSCs, harboring distinct metabolic signaling pathways, represent intertumoral glioma heterogeneity and highlight previously unidentified roles of ALDH1A3-associated signaling that promotes aberrant proliferation of Mes HGGs and GSCs. Inhibition of ALDH1A3-mediated pathways therefore might provide a promising therapeutic approach for a subset of HGGs with the Mes signature. Here, we describe the gene expression analysis, including pre-processing methods for the data published by Mao and colleagues in PNAS [1], integration of microarray data from this study with The Cancer Genome Atlas (TCGA) glioblastoma data and also with another published study.


Age-specific association of migraine with cryptogenic TIA and stroke: Population-based study.
To determine whether there is an association between previous migraine and cryptogenic TIA or ischemic stroke at older ages. We determined the age-specific associations of history of migraine and Trial of Org 10172 in Acute Stroke Treatment (TOAST) subtype of TIA and ischemic stroke in a population-based cohort study (Oxford Vascular Study; 2002-2012). Among 1,810 eligible patients with TIA or ischemic stroke, 668 (36.9%) had cryptogenic events, of whom 187 (28.0%) had previous migraine. Migraine was more commonly associated with cryptogenic events than with those of known etiology (odds ratio [OR] 1.73, 95% confidence interval [CI] 1.38-2.16, p < 0.0001; cardioembolic 2.00, 1.50-2.66, p < 0.0001; large artery 1.75, 1.20-2.53, p = 0.003; small vessel 1.32, 0.95-1.83, p = 0.096). The association of migraine with cryptogenic events was independent of age, sex, and all measured vascular risk factors (RFs) (adjusted OR 1.68, 1.33-2.13, p < 0.0001) and was strongest at older ages (<55 years, OR 1.11, 0.55-2.23; 55-64 years, 1.48, 0.83-2.63; ≥65 years, 1.81, 1.39-2.36) and in patients without vascular RFs (0 RFs OR 2.62, 1.33-5.15; 1 RF 2.01, 1.35-3.01; 2 RFs 1.80, 1.21-2.68; 3 RFs 1.21, 0.71-2.07; 4 RFs 0.92, 0.28-2.99). Results were consistent for migraine with or without aura and for analyses excluding TIA or stratified by sex or vascular territory of event. In this population-based study of stroke etiology stratified by age, migraine was most strongly associated with cryptogenic TIA and ischemic stroke, particularly at older ages, suggesting a causal role or a shared etiology.


How critical cost analysis can save money in today's NHS: a review of carpal tunnel surgery in a district general hospital.
With today's National Health Service (NHS) facing huge financial pressures the healthcare profession cannot afford to carry on spending at the current rate. Individual clinicians should be encouraged to critically appraise their own practices to bring about a more efficient and cost-effective service. The purpose of this project was to analyse the way that carpal tunnel surgery was being performed within our institution and bring about safe changes to practice that reduce expenditure. By critiquing our practices and applying simple changes based around sound evidence an annual saving of over £15 500 to the department was made. The changes instigated are simple, sustainable and safe to implement while providing improved patient satisfaction. They are also easily transferrable across institutions and to other minor hand surgical procedures to afford even greater ongoing savings to the NHS.


Interleukin-17-producing CD4(+) T cells increase with severity of liver damage in patients with chronic hepatitis B.
Interleukin-17 (IL-17)-producing CD4(+) T cells (Th17)-mediated immune response has been demonstrated to play a critical role in inflammation-associated disease; however, its role in chronic hepatitis B virus (HBV) infection remains unknown. Here we characterized peripheral and intrahepatic Th17 cells and analyzed their association with liver injury in a cohort of HBV-infected patients including 66 with chronic hepatitis B (CHB), 23 with HBV-associated acute-on-chronic liver failure (ACLF), and 30 healthy subjects as controls. The frequency of circulating Th17 cells increased with disease progression from CHB (mean, 4.34%) to ACLF (mean, 5.62%) patients versus healthy controls (mean, 2.42%). Th17 cells were also found to be largely accumulated in the livers of CHB patients. The increases in circulating and intrahepatic Th17 cells positively correlated with plasma viral load, serum alanine aminotransferase levels, and histological activity index. In vitro, IL-17 can promote the activation of myeloid dendritic cells and monocytes and enhance the capacity to produce proinflammatory cytokines IL-1beta, IL-6, tumor necrosis factor (TNF)-alpha, and IL-23 in both CHB patients and healthy subjects. In addition, the concentration of serum Th17-associated cytokines was also increased in CHB and ACLF patients. Th17 cells are highly enriched in both peripheral blood and liver of CHB patients, and exhibit a potential to exacerbate liver damage during chronic HBV infection.


Healthcare quality and safety: a review of policy, practice and research.
Over the last two decades healthcare quality and safety have risen to the fore of health policy and research. This has largely been informed by theoretical and empirical ideas found in the fields of ergonomics and human factors. These have enabled significant advances in our understanding and management of quality and safety. However, a parallel and at time neglected sociological literature on clinical quality and safety is presented as offering additional, complementary, and at times critical insights on the problems of quality and safety. This review explores the development and contributions of both the mainstream and more sociological approaches to safety. It shows that where mainstream approaches often focus on the influence of human and local environment factors in shaping quality, a sociological perspective can deepen knowledge of the wider social, cultural and political factors that contextualise the clinical micro-system. It suggests these different perspectives can easily complement one another, offering a more developed and layered understanding of quality and safety. It also suggests that the sociological literature can bring to light important questions about the limits of the more mainstream approaches and ask critical questions about the role of social inequality, power and control in the framing of quality and safety.


REDUCING LENGTH OF STAY AND IMPROVING QUALITY OF CARE BY IMPLEMENTATION OF INFORMATICS SYSTEM AND CARE BUNDLE IN THE INTENSIVE CARE UNIT.
Clinical situations in intensive care units (ICUs) change rapidly, and many factors may prolong the length of stay (LOS) of patients. The objectives of the study were to examine the effects of implementing an electronic-ICU (e-ICU) and an informatics system in an ICU on the LOS of patients and quality of care. We evaluated the implementation of a technology electronic dashboard-ICU (TED-ICU) system to upload automatically physiological information and clinical data within the critical care unit for providing real-time information to the care team. Furthermore, TED-ICU software automatically performed Sequential Organ Failure Assessment (SOFA) every 48 h. If a patient's SOFA score decreased by more than 2 points, there was an automatic reminder for transferring patients to the general ward. We prospectively collected data for this study from the ICU before and after implementing the e-ICU. In total, 2248 patients were admitted to our ICU during the study period (1147 and 1101 patients before and after TED-ICU implementation, respectively). Demographic characteristics and in-hospital mortality rates did not differ significantly between the two groups, and the LOS decreased from 7.26 to 5.53 days (p < 0.01). Implementing an informatics system (TED-ICU) and care bundle in ICUs can reduce the LOS.


External stenting and disease progression in saphenous vein grafts two years after coronary artery bypass grafting: A multicenter randomized trial.
Little data exist regarding the potential of external stents to mitigate long-term disease progression in saphenous vein grafts. We investigated the effect of external stents on the progression of saphenous vein graft disease. A total of 184 patients undergoing isolated coronary artery bypass grafting, using an internal thoracic artery graft and at least 2 additional saphenous vein grafts, were enrolled in 14 European centers. One saphenous vein graft was randomized to an external stent, and 1 nonstented saphenous vein graft served as the control. The primary end point was the saphenous vein graft Fitzgibbon patency scale assessed by angiography, and the secondary end point was saphenous vein graft intimal hyperplasia assessed by intravascular ultrasound in a prespecified subgroup at 2 years. Angiography was completed in 128 patients and intravascular ultrasound in the entire prespecified cohort (n = 51) at 2 years. Overall patency rates were similar between stented and nonstented saphenous vein grafts (78.3% vs 82.2%, P = .43). However, the Fitzgibbon patency scale was significantly improved in stented versus nonstented saphenous vein grafts, with Fitzgibbon patency scale I, II, and III rates of 66.7% versus 54.9%, 27.8% versus 34.3%, and 5.5% versus 10.8%, respectively (odds ratio, 2.02; P = .03). Fitzgibbon patency scale was inversely related to saphenous vein graft minimal lumen diameter, with Fitzgibbon patency scale I, II, and III saphenous vein grafts having an average minimal lumen diameter of 2.62 mm, 1.98 mm, and 1.32 mm, respectively (P < .05). Externally stented saphenous vein grafts also showed significant reductions in mean intimal hyperplasia area (22.5%; P < .001) and thickness (23.5%; P < .001). Two years after coronary artery bypass grafting, external stenting improves Fitzgibbon patency scales of saphenous vein grafts and significantly reduces intimal hyperplasia area and thickness. Whether this will eventually lead to improved long-term patency is still unknown.


Intake of grains and dietary fiber and prostate cancer aggressiveness by race.
Purpose. To examine the associations among intake of refined grains, whole grains and dietary fiber and aggressiveness of prostate cancer in African Americans (AA, n = 930) and European Americans (EA, n = 993) in a population-based, case-only study (The North Carolina-Louisiana Prostate Cancer Project, PCaP). Methods. Prostate cancer aggressiveness was categorized as high, intermediate or low based on Gleason grade, PSA level and clinical stage. Dietary intake was assessed utilizing the NCI Diet History Questionnaire. Logistic regression (comparing high to intermediate/low aggressive cancers) and polytomous regression with adjustment for potential confounders were used to determine odds of high prostate cancer aggressiveness with intake of refined grains, whole grains and dietary fiber from all sources. Results. An inverse association with aggressive prostate cancer was observed in the 2nd and 3rd tertiles of total fiber intake (OR = 0.70; 95% CI, 0.50-0.97 and OR = 0.61; 95% CI, 0.40-0.93, resp.) as compared to the lowest tertile of intake. In the race-stratified analyses, inverse associations were observed in the 3rd tertile of total fiber intake for EA (OR = 0.44; 95% CI, 0.23-0.87) and the 2nd tertile of intake for AA (OR = 0.57; 95% CI, 0.35-0.95). Conclusions. Dietary fiber intake was inversely associated with aggressive prostate cancer among both AA and EA men.


[ADPKD and intracranial aneurysms: indications for screening, follow-up and clinical management].
Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent hereditary nephropathy and is the fourth most common cause for end-stage renal disease in Europe. ADPKD is a systemic disease; besides the typical renal involvement, characterized by progressive cyst expansion leading to massive enlargement and distortion of the kidney architecture and, ultimately, to end-stage renal disease, multiple extrarenal manifestations can be observed included cysts in other organs, diverticulosis, cardiac valvulopathies, abdominal and inguinal hernias, vascular anomalies. The rupture of an intracranial aneurysm is one of the most serious complications in ADPKD patients. Aim of this review is to provide useful indications for the clinician to define the risk of intracranial aneurysms in ADPKD population, to identify screening criteria (which patients to screen, how often and with which diagnostic methods), to estimate the risk of rupture of intracranial aneurysms, which may require intervention.


Association between incongruence about survivor function and outcomes among stroke survivors and family caregivers.
Stroke survivors and family caregivers often have incongruent appraisals of survivor cognitive, physical, and psychosocial function. Partner incongruence contributes to poor outcomes for survivors and caregivers. This study explored whether partner incongruence: (1) differs by function domain; (2) increases or decreases over time, and; (3) is associated with self-rated health, distress, stress, and depressive symptoms. Structured surveys were administered to 32 survivors and caregivers at approximately 3 (enrollment) and 7 months (follow-up) post-stroke. Paired t-tests were used to examine partners' ratings of survivor function at enrollment and follow-up, and changes in incongruence over time. Partial correlations were used to examine the association between incongruence at enrollment and outcomes at follow-up. Survivors consistently rated their own memory and thinking as significantly better than caregivers rated their memory and thinking. At follow-up, survivors rated their own communication as significantly better than caregivers rated their communication. Incongruence about survivor memory and thinking was associated with survivor distress, as well as caregiver distress, stress, and depressive symptoms. Incongruence about survivor ADLs was associated with caregiver stress and depressive symptoms. Incongruence about survivor social participation was associated with caregiver distress. Findings from this study suggest that survivors and caregivers often have incongruent appraisals of survivor function, that incongruence does not improve naturally over time, and that incongruence may be detrimental for survivor and caregiver outcomes. Further research should be directed at the mitigation of incongruence and strategies to improve outcomes for both survivors and family caregivers.


Evidence for a non-myristoylated pool of the 80 kDa protein kinase C substrate of rat brain.
A protein of 80 kDa apparent molecular mass was found to be specifically myristolylated in rat brain cytosols derived from either whole brain or synaptosomes. The attachment of the fatty acid took place in the absence of protein synthesis, since the cytosols did not incorporate [14C]lysine into protein, nor did cycloheximide affect the incorporation of the myristic acid into the protein. The fatty acid was incorporated into the protein via an acid-labile/alkali-resistant band, and Pronase digestion of the labelled protein showed that the lipid was covalently linked to a glycine residue. Together, these data suggested that the myristic acid was amide-linked to the N-terminal residue of the protein. The protein was identified as one of the major protein kinase C substrates, the MARCKS (myristoylated alanine-rich C kinase substrate) protein, by showing that Ca2+ stimulated its phosphorylation, by its heat stability and by immune precipitation (using an antiserum to the MARCKS protein). Incorporation of myristic acid into intact protein continued for up to 12 h, despite the fact that over this period some degradation of the protein could be demonstrated. In pulse-chase experiments, the pattern of loss of the incorporated fatty acid was similar to that of the protein itself, and therefore the loss of radioactivity probably reflects protein degradation rather than specific de-acylation of the protein. Together, these results suggest that there is a pool of unacylated MARCKS protein in the rat brain.


Effects of the oral Janus kinase inhibitor tofacitinib on patient-reported outcomes in patients with active rheumatoid arthritis: results of two Phase 2 randomised controlled trials.
Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Here we investigated the effects of tofacitinib on patient-reported outcomes (PRO) in patients with active RA. Two, 6-month, double-blind, placebo-controlled Phase 2b studies were performed. The combination study evaluated patients with inadequate response to methotrexate who received tofacitinib 1-15 mg twice daily (BID), 20 mg once daily or placebo, on background methotrexate. In the monotherapy study, patients with inadequate response to disease-modifying anti-rheumatic drugs received tofacitinib 1-15 mg BID, adalimumab 40 mg once every other week or placebo. PROs measured were: Patient's Assessment of Arthritis Pain (PAAP), Patient's Assessment of Disease Activity, HAQ-DI, FACIT-F and SF-36. In the combination study (n=507), significant improvements (p<0.05) versus placebo were observed at Week 12 in PAAP (visual analogue scale) and HAQ-DI for all tofacitinib groups. In the monotherapy study (n=384), significant improvements in PAAP were observed at Week 12 for tofacitinib 5, 10 and 15 mg BID, and in HAQ-DI for tofacitinib 3, 5, 10 and 15 mg BID. Significant improvements versus placebo were seen at Week 2 in PAAP (both studies) and HAQ‑DI (monotherapy study) with tofacitinib, and were maintained throughout each study. In both studies, improvements in several domains of the SF-36 in the tofacitinib groups were observed at Weeks 12 and 24. In patients with active RA, tofacitinib, either in combination with methotrexate or as monotherapy, demonstrated rapid and sustained improvement in pain, physical functioning and health-related quality of life.


Neuropsychiatric symptoms in Alzheimer's disease: past progress and anticipation of the future.
Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) are widespread and disabling. This has been known since Dr. Alois Alzheimer's first case, Frau Auguste D., presented with emotional distress and delusions of infidelity/excessive jealousy, followed by cognitive symptoms. Being cognizant of this, in 2010 the Alzheimer's Association convened a research roundtable on the topic of NPS in AD. A major outcome of the roundtable was the founding of a Professional Interest Area (PIA) within the International Society to Advance Alzheimer's Research and Treatment (ISTAART). The NPS-PIA has prepared a series of documents that are intended to summarize the literature and provide more detailed specific recommendations for NPS research. This overview paper is the first of these living documents that will be updated periodically as the science advances. The overview is followed by syndrome-specific synthetic reviews and recommendations prepared by NPS-PIA workgroups on depression, apathy, sleep, agitation, and psychosis.


Exercise effects on hip bone mineral density in older, post-menopausal breast cancer survivors are age dependent.
We evaluated whether age moderated the effect of impact + resistance exercise on hip BMD in older post-menopausal breast cancer survivors (BCS). Exercise was more beneficial among younger than older women within our sample, suggesting that much older BCS may require different training programs to improve hip health. Previously, we reported that a program of resistance + impact training stopped bone loss at the spine in older, post-menopausal BCS but had no effect on bone mineral density (BMD) at the hip. Aging may blunt the responsiveness of the hip to mechanical loading, so we conducted a secondary data analysis to evaluate whether age moderated the effect of exercise on hip BMD. We analyzed data from our randomized, controlled trial in older (≥ 50 years of age at diagnosis), post-menopausal, post-adjuvant treatment BCS (n = 106) comparing women assigned to impact + resistance exercise (POWIR) or to a control program of low-intensity stretching (FLEX). We examined effect modification by age on BMD at three hip sites (greater trochanter, femoral neck, and total hip) using hierarchical linear modeling adjusting for time since diagnosis and use of adjuvant hormone therapy. Age moderated the effect of exercise on total hip BMD such that younger women in POWIR were more likely to see a positive net benefit than FLEX compared to older women where there was little difference between groups (p = 0.02). The skeletal response to loading at the hip within post-menopausal BCS diminishes with age. Whether more vigorous exercise programs and/or longer training periods are required to favorably change hip health in older BCS will require future study and careful thought about the risks and benefits of tougher training programs.


Airway pressure release ventilation: theory and practice.
Airway pressure release ventilation (APRV) is a relatively new mode of ventilation, that only became commercially available in the United States in the mid-1990s. Airway pressure release ventilation produces tidal ventilation using a method that differs from any other mode. It uses a release of airway pressure from an elevated baseline to simulate expiration. The elevated baseline facilitates oxygenation, and the timed releases aid in carbon dioxide removal. Advantages of APRV include lower airway pressures, lower minute ventilation, minimal adverse effects on cardio-circulatory function, ability to spontaneously breathe throughout the entire ventilatory cycle, decreased sedation use, and near elimination of neuromuscular blockade. Airway pressure release ventilation is consistent with lung protection strategies that strive to limit lung injury associated with mechanical ventilation. Future research will probably support the use of APRV as the primary mode of choice for patients with acute lung injury.


A pilot study of joint stability at the zirconium or titanium abutment/titanium implant interface.
To compare the interfaces of loaded and unloaded zirconium and titanium abutments with titanium implants using scanning electron microscopy (SEM). Zirconium and titanium abutments (n = 5 per group; four test and one control) were torque-tightened into titanium implants secured into metal blocks, and computer-aided design/computer-assisted manufacture-based zirconium oxide copings were fabricated and cemented to the abutments with temporary resin-based cement. Specimens of each restoration were subjected to cyclic axial and lateral loading of 30 N at 2 Hz for 500,000 cycles using a servohydraulic test system; control specimens were left unloaded. Then, the abutment/implant assemblies were embedded in acrylic resin, sectioned longitudinally along the midline, and inspected under SEM with x-ray microanalysis. Loosening or fracture of the copings and implant components was not observed after dynamic loading in both groups. SEM and x-ray microanalysis revealed unexpected microleakage of acrylic resin at the interface. Acrylic resin in the implants tightened to the titanium abutments was limited to the cervical part, and the components displayed scratched and smashed regions, suggesting slight deformation of the implant neck. Microleakage and pooling of acrylic resin were observed approaching the screw joint in loaded implants tightened to zirconia abutments, and the amount of microleakage was greater than in the unloaded control specimens, which had a larger microgap than the titanium abutment/titanium implant interface. Loaded zirconia abutments were associated with wear, scratches, and, in one sample, chipping. Zirconium abutment/titanium implant interface may be susceptible to wear of the abutment coupled with deformation of the implant neck greater than that associated with the conventional titanium abutment/titanium implant interface under dynamic loading.


Bioluminescence imaging as a tool to evaluate germ cells in vitro and transplantation in vivo as fertility preservation of prepubertal male mice.
To determine the feasibility of bioluminescence imaging (BLI) to evaluate the efficiency of germ cell transplantation in vitro and in vivo in fertility preservation for infertile male mice. Transgenic mouse model. University-based teaching hospital. Transgenic mice. Busulfan was used to induce testicular failure in 3-week-old immature FVB/NJNarl wild-type recipient mice. At 8 weeks of age they received hemizygotic germinal cells from 3-week-old immature male FVB/N-Tg (PolII-luc) Ltc strain transgenic donor mice, transplanted into the seminiferous tubules. Isolated germinal cells were suspended in multiwell plates with the bioluminescent substrate d-luciferin in excess to quantify viable germ cells in vitro. Quantitatively in vivo BLI was applied to demonstrate the efficiency and success of transplantation and BLI of live pups born from wild-type in vivo. Live birth pup of FVB/N-Tg (PolII-luc) Ltc transgenic mouse were born and imaged by bioluminescence after mating FVB/NJNarl female wild-type and male wild-type infertile recipient 4-6 months after transplantation of germinal cells of FVB/N-Tg (PolII-luc). The BLI could be applied successfully to this transgenic small animal model. It proved a useful tool for quantifying germ cells in vitro and for assessing the efficacy of germ cell transplantation in vivo.


The nurse in the mirror: Image of the female nurse during the Italian fascist period.
To describe the image of the female Licensed Nurse in Italy as promoted by the Fascist party from 1939-1943 and to understand how gender stereotypes influenced the construction of this image. Mixed methods design. The study started in 2016 and ended in 2019. In the qualitative phase, the primary source was analysis, following Chabod's historical method (2012), while the quantitative phase involved statistical analysis of textual data. All data came from the only nursing category magazine of the time: 'L'Infermiera Italiana' (The Italian Nurse), published from 1939-1943. From 112 articles analysed, the gradual elevation of the nurse emerged, including the partial replacement of 'old' nurses with Graduate Nurses. The analysis shows the maturation in structure, differentiation and specification, together with the birth of a new professional image. The accepted image of the nurse was now a woman of high moral character with religious ideals, but less known for her technical skills, an exception being the Visiting Health Assistant who functioned at a high level in the society. The study shows an articulated, congruent and cohesive set of dimensions through which to review history and to understand the dynamics underlying the structuring of the nurse's professional image. A better understanding of the dynamics behind the development of the professional image will guide present and future actions on gender stereotypes and their negative effects on the safety and quality of nursing care. International synergies and alliances are required.


Identification of three new bovine T-cell receptor delta variable gene subgroups expressed by peripheral blood T cells.
To understand the biology of gammadelta T cells in ruminants, it is necessary to have a comprehensive picture of gammadelta T-cell receptor gene diversity and expression. In this study, three new subgroups of bovine T-cell receptor delta (TRD) variable genes were identified by RT-PCR and sequencing and homology with TRDV genes from other mammals determined. Previously unidentified TRDV subgroup genes described in this study include the bovine homologues of ovine TRDV2, TRDV3, and TRDV4 which were named accordingly. TRDV2 subgroup has two genes (TRDV2-1 and TRDV2-2) while we found the previously identified TRDV1 has at least eight genes corresponding to separate genomic sequences. Nucleotide and amino acid sequences for particular gene subgroups between cattle and sheep were more than 87% identical but identities among TRDV subgroups within a species were much less, with bovine TRDV4 having <45% identity to the other three bovine TRDV gene subgroups. Analysis of circulating bovine gammadelta T cells revealed that genes from all four TRDV subgroups were expressed in combination with TRDJ1, TRDJ3, and TRDC, although TRDV4 was the least represented, and all displayed a variety of CDR3 junctional lengths. Finally, some genes within the TRDV1, TRDV2, and TRDV3 subgroups recombined with TRAV incorporating TRAJs, suggesting dual use.


The myelotoxicity of carboplatin is influenced by the time of its administration.
Previous studies have demonstrated that there are circadian rhythms in susceptibility to a range of commonly used cytotoxic drugs. In this study we have compared the pharmacokinetics and myelotoxicity of carboplatin administered at 18.00 and 06.00 in random order in patients with advanced ovarian carcinoma. Carboplatin treatment at 06.00 is associated with significantly greater thrombocytopenia than at 18.00 (platelet nadir 95,000 versus 180,000, p less than 0.05). There was no pharmacokinetic difference in the patients' handling of ultrafilterable platinum therefore it is possible that there is an intrinsic rhythm of susceptibility of bone marrow to carboplatin.


Neonatal corneal stromal development in the normal and lumican-deficient mouse.
The purpose of this study was to characterize temporally stromal growth and transparency in lumican-deficient and normal neonatal mice. Lumican-deficient mice and CD1 wild-type mice were evaluated by in vivo confocal microscopy through-focusing (CMTF) to quantify stromal and epithelial thickness and corneal light-scattering and by laser scanning CM to determine density of keratocytes from 1 day to 12 weeks after birth. CD1 corneas showed a rapid loss of light-scattering, decreasing by 50% from day 1 to day 12, that paralleled a 60% decrease in density of keratocytes. By contrast, the stroma demonstrated a marked swelling from day 8 to day 12, followed by thinning at day 14. Compared to corneas from CD1 mice, lumican-deficient corneas showed significantly increased (P < 0.05) light-scattering beginning at week 3 that remained elevated above wild-type levels for the duration of the study. Stromal development was also markedly altered, with thinning detected at week 3, followed by no detectable stromal growth for the duration of the study. Density of keratocytes was significantly increased, but the total cell number was similar compared with that in the wild-type cornea, suggesting no effect on keratocyte differentiation. Development of normal neonatal corneal transparency appears related to changes in density of keratocytes. The stroma, however, undergoes a marked swelling and thinning at the time of eyelid opening (days 8-14). In the lumican-deficient mouse, stromal swelling is abolished, indicating that this critical phase in stromal development is lumican dependent and essential for normal stromal growth and maintenance of stromal transparency.


Screening of cellulases for biofuel production: online monitoring of the enzymatic hydrolysis of insoluble cellulose using high-throughput scattered light detection.
A new prospective cellulase assay simultaneously combining high-throughput, online analysis and insoluble cellulosic substrates is described. The hydrolysis of three different insoluble cellulosic substrates, catalysed by a commercial cellulase preparation from Trichoderma reesei (Celluclast), was monitored using the BioLector - allowing online monitoring of scattered light intensities in a continuously shaken microtiter plate. Cellulase activities could be quantitatively assayed using the BioLector. At low cellulase/cellulose ratios, the Michaelis-Menten parameters of the cellulase mixture were mainly affected by the crystallinity index of the cellulose. Here, the apparent maximum cellulase activities inversely correlated with the crystallinity index of the cellulose. At high cellulase/cellulose ratios the particle size of the cellulose, defining the external surface area accessible to the cellulases, was the key determining factor for cellulase activity. The developed technique was also successfully applied to evaluate the pH optimum of cellulases. Moreover, the non-hydrolytic deagglomeration of cellulose particles was investigated, for the first time, using high-throughput scattered light detection. In conclusion, this cellulase assay ideally links high-throughput, online analysis and realistic insoluble cellulosic substrates in one simple system. It will considerably simplify and accelerate fundamental research on cellulase screening.


The Power of the Political in an Urbanizing International.
In this article, I argue that there is a startling resonance between Hans Morgenthau's conception of the political and power and recent analyses of an urbanizing international realm. By making this connection clear, I depart from a mechanistic understanding of politics, which tends to inform both conventional International Relations views and some claims in urban studies pertaining to the rise of global cities as international actors. Turning to Morgenthau's conception of the political and power also has wider implications for International Relations studies of urbanization: it helps explain a tendency toward depoliticization caused by ignoring the conflictual character of the political. The emphasis on the political, on the other hand, serves as a bridge between International Relations and urbanization studies by creating conditions for the repoliticization of urban space. After illustrating the existential manifestation of the political and its violent outfalls, the remainder of this article turns to its relational and dialogical manifestation that points out the shortcomings of reading the political merely as an existential concept in the context of urbanization.


Biological and Chemical Adaptation to Endogenous Hydrogen Peroxide Production in Streptococcus pneumoniae D39.
The catalase-negative, facultative anaerobe Streptococcus pneumoniae D39 is naturally resistant to hydrogen peroxide (H2O2) produced endogenously by pyruvate oxidase (SpxB). Here, we investigate the adaptive response to endogenously produced H2O2. We show that lactate oxidase, which converts lactate to pyruvate, positively impacts pyruvate flux through SpxB and that ΔlctO mutants produce significantly lower H2O2. In addition, both the SpxB pathway and a candidate pyruvate dehydrogenase complex (PDHC) pathway contribute to acetyl coenzyme A (acetyl-CoA) production during aerobic growth, and the pyruvate format lyase (PFL) pathway is the major acetyl-CoA pathway during anaerobic growth. Microarray analysis of the D39 strain cultured under aerobic versus strict anaerobic conditions shows upregulation of spxB, a gene encoding a rhodanese-like protein (locus tag spd0091), tpxD, sodA, piuB, piuD, and an Fe-S protein biogenesis operon under H2O2-producing conditions. Proteome profiling of H2O2-induced sulfenylation reveals that sulfenylation levels correlate with cellular H2O2 production, with endogenous sulfenylation of ≈50 proteins. Deletion of tpxD increases cellular sulfenylation 5-fold and has an inhibitory effect on ATP generation. Two major targets of protein sulfenylation are glyceraldehyde-3-phosphate dehydrogenase (GapA) and SpxB itself, but targets also include pyruvate kinase, LctO, AdhE, and acetate kinase (AckA). Sulfenylation of GapA is inhibitory, while the effect on SpxB activity is negligible. Strikingly, four enzymes of capsular polysaccharide biosynthesis are sulfenylated, as are enzymes associated with nucleotide biosynthesis via ribulose-5-phosphate. We propose that LctO/SpxB-generated H2O2 functions as a signaling molecule to downregulate capsule production and drive altered flux through sugar utilization pathways. IMPORTANCE Adaptation to endogenous oxidative stress is an integral aspect of Streptococcus pneumoniae colonization and virulence. In this work, we identify key transcriptomic and proteomic features of the pneumococcal endogenous oxidative stress response. The thiol peroxidase TpxD plays a critical role in adaptation to endogenous H2O2 and serves to limit protein sulfenylation of glycolytic, capsule, and nucleotide biosynthesis enzymes in S. pneumoniae.


A mechanism for branchial acid excretion in marine fish: identification of multiple Na+/H+ antiporter (NHE) isoforms in gills of two seawater teleosts.
Both Na+/H+ exchange and the electrogenic extrusion of H+ via an H+-ATPase have been postulated to drive acid excretion across the branchial epithelium of fishes. While the H+-ATPase/Na+ channel system appears to be the predominant mechanism in some freshwater species, it may play a reduced role in seawater and brackish-water animals, where high external Na+ concentrations may thermodynamically favor Na+/H+ exchange driven by a Na+/H+ antiporter (NHE). In this study, we used molecular and immunological methods to assess the role of NHE isoforms in the branchial epithelium of the marine long-horned sculpin (Myoxocephalus octodecimspinosus) and the euryhaline killifish (Fundulus heteroclitus). Northern blot analysis of RNA probed with the human NHE-1 BamHI fragment suggested the presence of homologous gill NHE mRNA in sculpin. RT-PCR on gill RNA isolated from sculpin recovering from metabolic acidosis provided evidence for two distinct NHE isoforms; one with 76 % amino acid homology to mammalian NHE-2, and another 92 % homologous to trout erythrocytic beta-NHE. Killifish also have transcripts with 91 % homology to beta-NHE. Immunological detection using monoclonal antibodies for mammalian NHE-1 revealed a protein antigenically similar to this isoform in the gills of both species. Metabolic acidosis caused an approximately 30-fold decrease in expression of the NHE-1-like protein in sculpin. We speculate that beta-NHE in the gills plays the intracellular 'housekeeping' roles described for mammalian NHE-1. During systemic acidosis, apical gill NHE-2 (which is sensitive to external amiloride and low [Na+]) in parallel with a dramatic suppression of basolateral NHE-1 activity enhances net capdelta H+ transfers to the water.