Orientation selectivity in infancy: behavioural evidence for temporal sensitivity.
One-month-old infants were tested with a habituation-recovery paradigm to determine whether they could discriminate phase-shifting grating patterns that switched between two orientations, three or eight times a second, from grating patterns that only shifted in phase. The infants were found to discriminate patterns switching orientation at the lower temporal rate of 3 reversals s-1, but not 8 reversals s-1. This finding supports the idea that orientation-selective mechanisms improve in their temporal sensitivity during early infancy. Where they can be compared, the results from behavioural and electrophysiological studies agree as to the course of this development.


PSPC1-interchanged interactions with PTK6 and β-catenin synergize oncogenic subcellular translocations and tumor progression.
Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide due to metastasis. Paraspeckle component 1 (PSPC1) upregulation has been identified as an HCC pro-metastatic activator associated with poor patient prognosis, but with a lack of targeting strategy. Here, we report that PSPC1, a nuclear substrate of PTK6, sequesters PTK6 in the nucleus and loses its metastasis driving capability. Conversely, PSPC1 upregulation or PSPC1-Y523F mutation promotes epithelial-mesenchymal transition, stemness, and metastasis via cytoplasmic translocation of active PTK6 and nuclear translocation of β-catenin, which interacts with PSPC1 to augment Wnt3a autocrine signaling. The aberrant nucleocytoplasmic shuttling of active PTK6/β-catenin is reversed by expressing the PSPC1 C-terminal interacting domain (PSPC1-CT131), thereby suppressing PSPC1/PTK6/β-catenin-activated metastasis to prolong the survival of HCC orthotopic mice. Thus, PSPC1 is the contextual determinant of the oncogenic switch of PTK6/β-catenin subcellular localizations, and PSPC1-CT131 functions as a dual inhibitor of PSPC1 and PTK6 with potential for improving cancer therapy.


Forced, not voluntary, exercise improves motor function in Parkinson's disease patients.
Animal studies indicate forced exercise (FE) improves overall motor function in Parkinsonian rodents. Global improvements in motor function following voluntary exercise (VE) are not widely reported in human Parkinson's disease (PD) patients. The aim of this study was to compare the effects of VE and FE on PD symptoms, motor function, and bimanual dexterity. Ten patients with mild to moderate PD were randomly assigned to complete 8 weeks of FE or VE. With the assistance of a trainer, patients in the FE group pedaled at a rate 30% greater than their preferred voluntary rate, whereas patients in the VE group pedaled at their preferred rate. Aerobic intensity for both groups was identical, 60% to 80% of their individualized training heart rate. Aerobic fitness improved for both groups. Following FE, Unified Parkinson's Disease Rating Scale (UPDRS) motor scores improved 35%, whereas patients completing VE did not exhibit any improvement. The control and coordination of grasping forces during the performance of a functional bimanual dexterity task improved significantly for patients in the FE group, whereas no changes in motor performance were observed following VE. Improvements in clinical measures of rigidity and bradykinesia and biomechanical measures of bimanual dexterity were maintained 4 weeks after FE cessation. Aerobic fitness can be improved in PD patients following both VE and FE interventions. However, only FE results in significant improvements in motor function and bimanual dexterity. Biomechanical data indicate that FE leads to a shift in motor control strategy, from feedback to a greater reliance on feedforward processes, which suggests FE may be altering central motor control processes.


The effectiveness of narrative versus informational smoking education on smoking beliefs, attitudes and intentions of low-educated adolescents.
This study tests the effectiveness of narrative versus informational smoking education on smoking beliefs, attitudes and intentions of low-educated adolescents. A field experiment with three waves of data collection was conducted. Participants (N = 256) were students who attend lower secondary education. At the first and third waves, they completed a questionnaire. At the second wave, 50.8% of the participants read a smoking education booklet in narrative form and 49.2% read a booklet in informational form. After reading, all participants also completed a questionnaire at wave 2. Beliefs about negative consequences of smoking, attitudes towards smoking and intentions to smoke were measured. Repeated measures analyses with time as a within-subjects factor and condition as a between-subjects factor showed that beliefs about smoking were more negative at Wave 2 compared to Wave 1, irrespective of condition. However, attitudes towards smoking were more positive at Wave 3 compared to Wave 1 when participants had read the narrative version. These results show that narrative smoking education is not more effective than informational smoking education for low-educated adolescents and can even have an unintended effect for this target group by making attitudes towards smoking more positive.


Enhanced vulnerability of human proteins towards disease-associated inactivation through divergent evolution.
Human proteins are vulnerable towards disease-associated single amino acid replacements affecting protein stability and function. Interestingly, a few studies have shown that consensus amino acids from mammals or vertebrates can enhance protein stability when incorporated into human proteins. Here, we investigate yet unexplored relationships between the high vulnerability of human proteins towards disease-associated inactivation and recent evolutionary site-specific divergence of stabilizing amino acids. Using phylogenetic, structural and experimental analyses, we show that divergence from the consensus amino acids at several sites during mammalian evolution has caused local protein destabilization in two human proteins linked to disease: cancer-associated NQO1 and alanine:glyoxylate aminotransferase, mutated in primary hyperoxaluria type I. We demonstrate that a single consensus mutation (H80R) acts as a disease suppressor on the most common cancer-associated polymorphism in NQO1 (P187S). The H80R mutation reactivates P187S by enhancing FAD binding affinity through local and dynamic stabilization of its binding site. Furthermore, we show how a second suppressor mutation (E247Q) cooperates with H80R in protecting the P187S polymorphism towards inactivation through long-range allosteric communication within the structural ensemble of the protein. Our results support that recent divergence of consensus amino acids may have occurred with neutral effects on many functional and regulatory traits of wild-type human proteins. However, divergence at certain sites may have increased the propensity of some human proteins towards inactivation due to disease-associated mutations and polymorphisms. Consensus mutations also emerge as a potential strategy to identify structural hot-spots in proteins as targets for pharmacological rescue in loss-of-function genetic diseases.


New Perspective on Impact of Folic Acid Supplementation during Pregnancy on Neurodevelopment/Autism in the Offspring Children - A Systematic Review.
It has been conclusively established that folic acid supplementation prior to and during early pregnancy (up to 12 weeks of gestation) can prevent neural tube defects (NTDs). We hypothesized that folate effects may extend from neuro-structural defects to alterations in neuro-behavioural and emotional skills including autism spectrum disorders (ASDs) and other developmental disorders. The objective of this review was to comprehensively evaluate evidence on the impact of folic acid on neurodevelopment other than NTDs. We conducted an online search of relevant literature compiled by the National Library of Medicine from Medline and EMBASE (searched on Dec 31, 2014: http://www.ncbi.nlm.nih.gov/entrez/query/fcgi and http://www.elsevier.com/online-tools/embase). We first created 3 files (search restricted to English literature) using the following key words: 1) folate or folic acid (171322 papers identified by this search); 2) maternal or pregnancy or pregnant or gestation or gestational or prenatal or antenatal or periconception or periconceptional (1349219 papers identified by this search); and 3) autism or autism spectrum disorders or developmental delay or development or neurodevelopment or mental or cognitive or language or personal-social or gross motor or fine motor or behaviour or intellectual or intelligence or Bayley Scale (8268145 papers identified by this search). We then merged the 3 files and reviewed the papers that addressed these three issues simultaneously. A total of 22 original papers that examined the association between folic acid supplementation in human pregnancy and neurodevelopment/autism were identified after the screening, with 15 studies showing a beneficial effect of folic acid supplementation on neurodevelopment/autism, 6 studies showed no statistically significant difference, while one study showed a harmful effect in > 5 mg folic acid supplementation/day during pregnancy. Folic acid supplementation in pregnancy may have beneficial effects on the neurodevelopment of children beyond its proven effect on NTDs.


The premacular bursa's shape revealed in vivo by swept-source optical coherence tomography.
To resolve the controversy surrounding the shape and relationship of posterior vitreous spaces by characterizing the connections between the premacular bursa, the area of Martegiani, and Cloquet's canal. Comprehensive posterior vitreous maps were created using swept-source optical coherence tomography (SS OCT) in a cross-sectional study. The posterior vitreous of 102 eyes of 51 volunteers 21 to 54 years of age without ocular pathologic features was imaged using SS OCT. The DRI OCT-1 Atlantis 3D SS OCT (Topcon Medical Systems, Oakland, NJ) was used to acquire scans of the posterior vitreous over an 18×18-mm area. Posterior vitreous spaces and their relationships were identified. The premacular bursa was identified in all 102 eyes and was found to extend superiorly beyond our scanning ability at a variable angle. No discernible superior borders could be identified. Instead, a connection of the bursa with the preoptic area of Martegiani or its extension, Cloquet's canal, was found in 101 of 102 eyes. This connection occurred at a variable distance from the optic nerve, where it formed a flat and broad superior channel. The skyward direction of this channel was found to be gravity dependent in all 14 eyes of the 7 subjects examined in various head positions. Although SS OCT was able to identify vitreous degeneration, the above changes were present in 28 eyes even without any discernible vitreous degeneration. The premacular bursa, also called the posterior precortical vitreous pocket, was found to continue superiorly beyond the posterior pole without a detectable border. The bursa fused broadly with the extension of the preoptic area of Martegiani, namely Cloquet's canal, or the hyaloidal tract of Eisner. These findings suggest that there is a direct anteroposterior connection between the retrolental and premacular and preoptic spaces already existent in the eyes of young adults before the occurrence of vitreous degeneration. This observation may have important implications with respect to the movement of intrinsic and extrinsic mediators between the anterior and posterior segments.


The angiogenic "vascular endothelial growth factor/flk-1(KDR) receptor" pathway in patients with endometrial carcinoma: prognostic and therapeutic implications.
Vascular endothelial growth factor (VEGF) is an important endothelial cell mitogen associated with increased angiogenesis and aggressive tumor behavior. Its stimulating effect on endothelial cells basically is dependent on the presence of specific VEGF receptors, such as the flk-1(KDR) receptor. This study investigates the roles of VEGF and of a functionally intact angiogenic pathway, "VEGF/flk-1(KDR)," in patients with endometrial carcinoma and their significance in prognosis and therapy. A series of 121 endometrial carcinomas were studied. The expression of VEGF by endometrial tumor cells was assessed using the monoclonal antibody (MoAb) VG1. VEGF/KDR complexes on tumor endothelium or activated microvessel density (aMVD) were identified using the MoAb 11B5. In addition, the standard microvessel density (sMVD) was assessed with anti-CD31. In all tumors, the alkaline phosphatase/antialkaline phosphatase technique was employed. A Fisher exact test or an unpaired, two-tailed t test was used for testing correlations between categoric tumor variables, whereas a log-rank test was used to determine statistical differences between life tables. A Cox proportional hazards model was used to assess the effect of tumor variables on overall survival. Cytoplasmic VEGF expression in > 50% of tumor cells was associated significantly with aMVD (P < 0.0001) and with sMVD (P < 0.003). In univariate survival analysis, VEGF (P = 0.0002), aMVD (P = 0.001), and sMVD (P = 0.0009) were significant prognostic variables. Equally important were the histologic parameters tumor type (P = 0.03), tumor grade (P = 0.003), and disease stage (P < 0.0001). In multivariate analysis, disease stage was the most important independent prognostic factor (P < 0.0001), followed by VEGF/KDR (P < 0.01), and VEGF (P < 0.04). Furthermore, VEGF and VEGF/KDR were the only independent prognostic variables for patients with Stage I endometrioid adenocarcinoma. sMVD and the angiogenic factor VEGF are important indicators of a poor prognosis in patients with endometrial carcinoma. VEGF/KDR complexes define a subgroup of patients with endometrial carcinoma with an even worse prognosis.


Pathways from performance monitoring to negative symptoms and functional outcomes in psychotic disorders.
Performance monitoring entails rapid error detection to maintain task performance. Impaired performance monitoring is a candidate pathophysiological process in psychotic disorders, which may explain the broader deficit in executive function and its known associations with negative symptoms and poor functioning. The current study models cross-sectional pathways bridging neurophysiological measures of performance monitoring with executive function, symptoms, and functioning. Data were from the 20-year assessment of the Suffolk County Mental Health Project. Individuals with psychotic disorders (N = 181) were originally recruited from inpatient psychiatric facilities. Data were also collected from a geographically and demographically matched group with no psychosis history (N = 242). Neural measures were the error-related negativity (ERN) and error positivity (Pe). Structural equation modeling tested mediation pathways. Blunted ERN and Pe in the clinical cohort related to impaired executive function (r = 0.26-0.35), negative symptom severity (r = 0.17-0.25), and poor real-world functioning (r = 0.17-0.19). Associations with executive function were consistent across groups. Multiple potential pathways were identified in the clinical cohort: reduced ERN to inexpressivity was mediated by executive function (β = 0.10); reduced Pe to global functioning was mediated by executive function and avolition (β = 0.10). This supports a transdiagnostic model of psychotic disorders by which poor performance monitoring contributes to impaired executive function, which contributes to negative symptoms and poor real-world functioning. If supported by future longitudinal research, these pathways could inform the development of targeted interventions to address cognitive and functional deficits that are central to psychotic disorders.


Performance of Microbiome Sequence Inference Methods in Environments with Varying Biomass.
Microbiome community composition plays an important role in human health, and while most research to date has focused on high-microbial-biomass communities, low-biomass communities are also important. However, contamination and technical noise make determining the true community signal difficult when biomass levels are low, and the influence of varying biomass on sequence processing methods has received little attention. Here, we benchmarked six methods that infer community composition from 16S rRNA sequence reads, using samples of varying biomass. We included two operational taxonomic unit (OTU) clustering algorithms, one entropy-based method, and three more-recent amplicon sequence variant (ASV) methods. We first compared inference results from high-biomass mock communities to assess baseline performance. We then benchmarked the methods on a dilution series made from a single mock community-samples that varied only in biomass. ASVs/OTUs inferred by each method were classified as representing expected community, technical noise, or contamination. With the high-biomass data, we found that the ASV methods had good sensitivity and precision, whereas the other methods suffered in one area or in both. Inferred contamination was present only in small proportions. With the dilution series, contamination represented an increasing proportion of the data from the inferred communities, regardless of the inference method used. However, correlation between inferred contaminants and sample biomass was strongest for the ASV methods and weakest for the OTU methods. Thus, no inference method on its own can distinguish true community sequences from contaminant sequences, but ASV methods provide the most accurate characterization of community and contaminants. IMPORTANCE Microbial communities have important ramifications for human health, but determining their impact requires accurate characterization. Current technology makes microbiome sequence data more accessible than ever. However, popular software methods for analyzing these data are based on algorithms developed alongside older sequencing technology and smaller data sets and thus may not be adequate for modern, high-throughput data sets. Additionally, samples from environments where microbes are scarce present additional challenges to community characterization relative to high-biomass environments, an issue that is often ignored. We found that a new class of microbiome sequence processing tools, called amplicon sequence variant (ASV) methods, outperformed conventional methods. In samples representing low-biomass communities, where sample contamination becomes a significant confounding factor, the improved accuracy of ASV methods may allow more-robust computational identification of contaminants.


Microsatellite isolation, linkage group identification and determination of recombination frequency in the peach-potato aphid, Myzus persicae (Sulzer) (Hemiptera: Aphididae).
Fifteen polymorphic microsatellite markers were used to establish linkage groups and relative rates of recombination in male and female Myzus persicae (Sulzer) (Hemiptera: Aphididae) (peach-potato aphid). We cloned nine markers from M. persicae and for these we report primer sequences and levels of allelic diversity and heterozygosity in four Australian M. persicae populations. Of the remaining six loci, four loci, also cloned from M. persicae, were obtained from G. Malarky (Natural History Museum, London) and two loci from Sitobion miscanthi were used. Additionally, the primer sequences of locus M77, a locus monomorphic in M. persicae but polymorphic in the closely related Myzus antirrhinii, are presented. Eleven of the 15 polymorphic markers were autosomal and four were X-linked. A linkage analysis was performed on a European pedigree of aphids containing five families with between seven and 11 offspring each. There was no linkage between any loci in females. In males, several pairwise comparisons yielded no recombinant offspring. With the exception of locus M40, these observations were supported in a linkage analysis performed on larger families produced from Australian M. persicae crosses. Locus M40 showed segregation consistent with involvement in a translocation between autosomes 1 and 3 in European samples but not in the Australian samples. From the Australian crosses we report an absence of recombination in males but high recombination rates in females. One X chromosome and four autosomal linkage groups were identified and tentatively assigned to chromosomes. The relevance of achiasmate meiosis to the evolution of sex is discussed.


Post-exposure passive immunisation for preventing measles.
Measles outbreaks continue to occur in countries with high vaccination coverage. Passive immunisation is generally considered to prevent measles in someone who is not immune and has been exposed to infection. Estimates of effectiveness have varied and no minimum effective dose has been determined. To assess the effectiveness and safety of intramuscular injection or intravenous infusion of immunoglobulins (passive immunisation) for preventing measles when administered to exposed susceptible people before the onset of symptoms. We searched CENTRAL (2013, Issue 7), MEDLINE (1946 to July week 5, 2013), CINAHL (1981 to August 2013) and EMBASE (1974 to August 2013). We included randomised controlled trials (RCTs), quasi-RCTs and prospective, controlled (cohort) studies if: participants were susceptible and exposed to measles, polyclonal immunoglobulins derived from human sera or plasma were administered intramuscularly or intravenously as the only intervention in at least one group and the number of subsequent measles cases was measured. We excluded studies of other sources of immunoglobulins. Two authors independently extracted data and critically appraised the included studies. We attempted to contact study authors for missing information. We described the results of studies not included in meta-analyses. We included one RCT, two quasi-RCTs and 10 cohort studies (3925 participants). No studies were rated as low risk of bias for all criteria. Critical appraisal was constrained by a lack of information in most studies. The overall quality of the evidence was moderate.Seven studies (1432 participants) assessed cases of measles after immunoglobulin versus no treatment. Heterogeneity was explained by subgrouping according to the blood product used as an approximation of dose of immunoglobulin. When given within seven days of exposure, immunoglobulins were effective at preventing measles: gamma globulin (risk ratio (RR) 0.17, 95% confidence interval (CI) 0.08 to 0.36), convalescent serum (RR 0.21, 95% CI 0.15 to 0.29 to RR 0.49, 95% CI 0.44 to 0.54) and adult serum (RR 0.52, 95% CI 0.45 to 0.59). The differences in the effectiveness of different blood products were supported by studies not included in the meta-analysis and by two studies (702 participants) that found gamma globulin more effective than serum (RR 0.56, 95% CI 0.46 to 0.69).Based on three studies (893 participants) immunoglobulin was effective at preventing death due to measles compared to no treatment (RR 0.24, 95% CI 0.13 to 0.44).Two studies included measles vaccine alone among the intervention groups. Meta-analysis could not be undertaken. Both studies suggested the vaccine was more effective than gamma globulin.No serious adverse events were observed in any of the included studies, although reporting of adverse events was poor overall. Non-serious adverse events included transient fever, rash, muscle stiffness, local redness and induration. Passive immunisation within seven days of exposure is effective at preventing measles, with the risk for non-immune people up to 83% less than if no treatment is given. Given an attack rate of 45 per 1000 (per the control group of the most recent included study), gamma globulin compared to no treatment has an absolute risk reduction (ARR) of 37 per 1000 and a number needed to treat to benefit (NNTB) of 27. Given an attack rate of 759 per 1000 (per the attack rate of the other included study assessing gamma globulin), the ARR of gamma globulin compared to no treatment is 629 and the NNTB is two.It seems the dose of immunoglobulin administered impacts on effectiveness. A minimum effective dose of measles-specific antibodies could not be identified.Passive immunisation is effective at preventing deaths from measles, reducing the risk by 76% compared to no treatment. Whether the benefits of passive immunisation vary among subgroups of non-immune exposed people could not be determined.Due to a paucity of evidence comparing vaccine to passive immunisation, no firm conclusions can be drawn regarding relative effectiveness.The included studies were not specifically designed to detect adverse events.Future research should consider the effectiveness of passive immunisation for preventing measles in high-risk populations such as pregnant women, immunocompromised people and infants. Further efforts should be made to determine the minimum effective dose of measles-specific antibodies for post-exposure prophylaxis and the relative effectiveness of vaccine compared to immunoglobulin.


Pediatric Dental Appointments No-show: Rates and Reasons.
To determine the frequency and reasons of missed and canceled pediatric dental appointments and identifying the factors associated with it among the patients visiting the pediatric dental clinic of the dental college in Navi Mumbai, Maharashtra, India. To assess the parents' perception regarding the treatment of their children and to explore the merit of different management strategies regarding the missed appointments. Self-administered questionnaires were handed over to the parents in the waiting area, whose children were undergoing treatment in the pediatric dental clinic. Questionnaire included questions pertaining to the sociodemo-graphic characteristics, methods of remembering appointments, and satisfaction with the overall past clinic experience. Of the 294 surveyed sample, 52.0% stated that they have missed an appointment. Highest percentage of the patients had missed due to parents' forgetfulness and patient's exams; 52.0% relied on their memory to remember their appointments, and 44.5% used their diaries and mobiles as a means of reminders. For canceling an appointment, most of them stated that patient was unwell and parents' commitments toward other work led to an increase in rates of no-shows. Socioeconomic status and the methods of remembering the appointment date were found to be significantly correlated with missing an appointment among the surveyed sample (p < 0.05); 48.3% said that they would want a call from the dentist a day prior to their appointment as a reminder. Around one half of the patients attending the pediatric dental clinic missed their appointments. Patients most likely to fail to keep an appointment was the one who was young, remembered appointment via memory, came from a high socioeconomic class, most of them were males, and had previously broken appointments, while patients preferred receiving a call from the dentist as a reminder aide. Missing appointment creates a series of problems. Firstly, it deprives another patient the opportunity of getting treated. Secondly, it contributes to the development of long waiting list for dental services. Thirdly, it affects the patient's treatment time and may cause increase in the dental emergencies leading to a disruption in the doctor-patient relationship and behavioral management problems.How to cite this article: Bhatia R, Vora EC, Panda A. Pediatric Dental Appointments No-show: Rates and Reasons. Int J Clin Pediatr Dent 2018;11(3):171-176.


The Effect of World Trade Center Exposure on the Timing of Diagnoses of Obstructive Airway Disease, Chronic Rhinosinusitis, and Gastroesophageal Reflux Disease.
In a cohort of rescue/recovery workers exposed to the dust that resulted from the collapse of the World Trade Center (WTC), we assessed how a diagnosis of obstructive airways disease (OAD) affected the likelihood of a subsequent diagnosis of chronic rhinosinusitis (CRS) or gastroesophageal reflux disease (GERD). We also assessed whether OAD acted as a mediator of the association between exposure to the WTC rescue/recovery effort and CRS and GERD diagnoses. In this prospective cohort study, we analyzed Fire Department of the City of New York physician diagnoses of OAD, CRS, and GERD that were first documented between September 11, 2001, and September 10, 2011, among 8,968 WTC-exposed firefighters. We used piecewise exponential survival models to evaluate whether OAD was a risk factor for either CRS or GERD and to assess OAD as a possible mediator. An OAD diagnosis significantly increased the risks for subsequent CRS [relative rate (RR), 4.24; 95% CI, 3.78-4.76] and GERD (RR, 3.21; 95% CI, 2.93-3.52) diagnoses. Further, 21% of the WTC exposure effect (high vs. low intensity) on GERD and 13% of the effect (high vs. low intensity) on CRS were mediated by a prior OAD diagnosis. Individuals with an OAD diagnosis had elevated risks for subsequent diagnoses of CRS or GERD. Part of the effect of WTC exposure on CRS and GERD diagnoses is mediated by prior diagnoses of OAD; this mediation effect of OAD may reflect biological pathways or healthcare utilization practices.


Tissue-mimicking phantoms for photoacoustic and ultrasonic imaging.
In both photoacoustic (PA) and ultrasonic (US) imaging, overall image quality is influenced by the optical and acoustical properties of the medium. Consequently, with the increased use of combined PA and US (PAUS) imaging in preclinical and clinical applications, the ability to provide phantoms that are capable of mimicking desired properties of soft tissues is critical. To this end, gelatin-based phantoms were constructed with various additives to provide realistic acoustic and optical properties. Forty-micron, spherical silica particles were used to induce acoustic scattering, Intralipid(®) 20% IV fat emulsion was employed to enhance optical scattering and ultrasonic attenuation, while India Ink, Direct Red 81, and Evans blue dyes were utilized to achieve optical absorption typical of soft tissues. The following parameters were then measured in each phantom formulation: speed of sound, acoustic attenuation (from 6 to 22 MHz), acoustic backscatter coefficient (from 6 to 22 MHz), optical absorption (from 400 nm to 1300 nm), and optical scattering (from 400 nm to 1300 nm). Results from these measurements were then compared to similar measurements, which are offered by the literature, for various soft tissue types. Based on these comparisons, it was shown that a reasonably accurate tissue-mimicking phantom could be constructed using a gelatin base with the aforementioned additives. Thus, it is possible to construct a phantom that mimics specific tissue acoustical and/or optical properties for the purpose of PAUS imaging studies.


Basal cells as stem cells of the mouse trachea and human airway epithelium.
The pseudostratified epithelium of the mouse trachea and human airways contains a population of basal cells expressing Trp-63 (p63) and cytokeratins 5 (Krt5) and Krt14. Using a KRT5-CreER(T2) transgenic mouse line for lineage tracing, we show that basal cells generate differentiated cells during postnatal growth and in the adult during both steady state and epithelial repair. We have fractionated mouse basal cells by FACS and identified 627 genes preferentially expressed in a basal subpopulation vs. non-BCs. Analysis reveals potential mechanisms regulating basal cells and allows comparison with other epithelial stem cells. To study basal cell behaviors, we describe a simple in vitro clonal sphere-forming assay in which mouse basal cells self-renew and generate luminal cells, including differentiated ciliated cells, in the absence of stroma. The transcriptional profile identified 2 cell-surface markers, ITGA6 and NGFR, which can be used in combination to purify human lung basal cells by FACS. Like those from the mouse trachea, human airway basal cells both self-renew and generate luminal daughters in the sphere-forming assay.


Digital communication support and Alzheimer's disease.
Communication is one of the areas where people with dementia and their caregivers experience most challenges. The purpose of this study is to contribute to the understanding of possibilities and pitfalls of using personalized communication applications installed on tablet computers to support communication for people with dementia and their conversational partners. The study is based on video recordings of a woman, 52 years old, with Alzheimer's disease interacting with her husband in their home. The couple was recorded interacting with and without a tablet computer including a personalized communication application. The results from the present study reveal both significant possibilities and potential difficulties in introducing a digital communication device to people with dementia and their conversational partners. For the woman in the present study, the amount of interactive actions and the number of communicative actions seem to increase with the use of the communication application. The results also indicate that problems associated with dementia are foregrounded in interaction where the tablet computer is used.


Symbolic time series analysis of fNIRS signals in brain development assessment.
Assessing an infant's brain development remains a challenge for neuroscientists and pediatricians despite great technological advances. As a non-invasive neuroimaging tool, functional near-infrared spectroscopy (fNIRS) has great advantages in monitoring an infant's brain activity. To explore the dynamic features of hemodynamic changes in infants, in-pattern exponent (IPE), anti-pattern exponent (APE), as well as permutation cross-mutual information (PCMI) based on symbolic dynamics are proposed to measure the phase differences and coupling strength in oxyhemoglobin (HbO) and deoxyhemoglobin (Hb) signals from fNIRS. First, simulated sinusoidal oscillation signals and four coupled nonlinear systems were employed for performance assessments. Hilbert transform based measurements of hemoglobin phase oxygenation and deoxygenation (hPod) and phase-locking index of hPod (hPodL) were calculated for comparison. Then, the IPE, APE and PCMI indices from resting state fNIRS data of preterm, term infants and adults were calculated to estimate the phase difference and coupling of HbO and Hb. All indices' performance was assessed by the degree of monotonicity (DoM). The box plots and coefficients of variation (CV) were employed to assess the measurements and robustness in the results. In the simulation analysis, IPE and APE can distinguish the phase difference of two sinusoidal oscillation signals. Both hPodL and PCMI can track the strength of two coupled nonlinear systems. Compared to hPodL, the PCMI had higher DoM indices in measuring the coupling of two nonlinear systems. In the fNIRS data analysis, similar to hPod, the IPE and APE can distinguish preterm, term infants, and adults in 0.01-0.05 Hz, 0.05-0.1 Hz, and 0.01-0.1 Hz frequency bands, respectively. PCMI more effectively distinguished the term and preterm infants than hPodL in the 0.05-0.1 Hz frequency band. As symbolic time series measures, the IPE and APE were able to detect the brain developmental changes in subjects of different ages. PCMI can assess the resting-state HbO and Hb coupling changes across different developmental ages, which may reflect the metabolic and neurovascular development. The symbolic-based methodologies are promising measures for fNIRS in estimating the brain development, especially in assessing newborns' brain developmental status.


The changing face of critical care medicine: nurse practitioners in the pediatric intensive care unit.
Over the last 50 years, healthcare has undergone countless changes. Some of the important changes in recent years have been budget cuts, decreased resident work hours, and increased patient acuity. The need for additional clinical expertise at the bedside has resulted in nurse practitioners becoming an integral part of the healthcare delivery team. To date, little has been published regarding the role of the nurse practitioners in intensive care units. This article outlines how one pediatric hospital has successfully utilized nurse practitioners in the intensive care unit.


Fat intake, diet variety and health promotion.
Different epidemiological studies indicated that the optimization of diet and nutrition combined with healthy life style can decrease the risk and even lead to amelioration of various noncommunicable diseases. Promising food-based dietary guidelines have been recommended in order to improve the nutritional and health status. One of the most popular recommendations is related to the amount (less fat and fat-rich foods) and type of the dietary fat component (less saturated, more polyunsaturated fatty acids, lower n-6:n-3 ratio). An overview on the nutrient intake among different age groups in Austria shows that the general consumption of some food groups--especially those rich in carbohydrates--is too low and that the intake of fat is far beyond the recommended amount of 30% of total energy (E%). The results of the 24-hour recall made among Austrian adults (n = 2,585) showed that about 18% of this population group had a fat intake of 30-35 E%, whereas 60% had an intake higher than 35 E%. Only 24% of the female and male adults had a fat intake lower than 30 E%. A result of this high proportion of fat--in the form of foods rich in fat--in the average total energy consumption is a too low intake of carbohydrates, and foods rich in carbohydrates, respectively. An increasing fat intake is associated with an increasing intake of some nutrients such as vitamin A, E, calcium and zinc, but a decreasing intake of other nutrients like vitamin C, folate, carotenoids and others. The diversity of foods consumed during a day increases with decreasing amount of fat in the diet of adults. People with a high amount of fat in their daily diet show a lower intake of vegetables and fruit, cereal products, carotenoids, folates and dietary fibers, but a higher intake of meat and meat products, milk and milk products, sweets and flummeries as well as saturated fatty acids (SFA) and cholesterol. Of course, a higher variety of food items in the daily diet should not be associated with a higher energy intake. Thus, foods with a high nutrient density (vegetables, fruits, low-fat milk products, whole grain cereals, legumes etc.) are recommended. Finally, it has to be annotated that a high diversity in the daily diet with reduced fat and SFA intake allows a sufficient nutrient intake and is an important approach for health promotion.


Homology modelling and molecular dynamics simulations: comparative studies of human aquaporin-1.
The structures of the mammalian water transport protein Aqp1 and of its bacterial homologue GlpF enables us to test whether homology models can be used to explore relationships between structure, dynamics and function in mammalian transport proteins. Molecular dynamics simulations (totalling almost 40 ns) were performed starting from: the X-ray structure of Aqp1; a homology model of Aqp1 based on the GlpF structure; and intermediate resolution structures of Aqp1 derived from electron microscopy. Comparisons of protein RMSDs vs. time suggest that the homology models are of comparable conformational stability to the X-ray structure, whereas the intermediate resolution structures exhibit significant conformation drift. For simulations based on the X-ray structure and on homology models, the flexibility profile vs. residue number correlates well with the crystallographic B-values for each residue. In the simulations based on intermediate resolution structures, mobility of the highly conserved NPA loops is substantially higher than in the simulations based on the X-ray structure or the homology models. Pore radius profiles remained relatively constant in the X-ray and homology model simulations but showed substantial fluctuations (reflecting the higher NPA loop mobility) in the intermediate resolution simulations. The orientation of the dipoles of water molecules within the pore is of key importance in maintaining low proton permeability through Aqp1. This property seems to be quite robust to the starting model used in the simulation. These simulations suggest that homology models based on bacterial homologues may be used to derive functionally relevant information on the structural dynamics of mammalian transport proteins.


Validation of the Greek Cypriot Translation of the Triarchic Psychopathy Measure.
Psychopathy is conceived of as a pathological constellation of personality traits, manifested in aberrant behavioral, interpersonal, and emotional tendencies. This study examined within a Greek-speaking nonclinical sample (N = 419) associations between differing phenotypic dimensions of psychopathy (boldness, meanness, disinhibition) assessed via the Triarchic Psychopathy Measure (TriPM) and self-report criterion measures of psychopathology, personality, and history of abuse and neglect. Consistent with predictions of the triarchic model of psychopathy, evidence was found for distinct correlates of the 3 phenotypic dimensions. Boldness was associated with both adaptive (immunity to anxiety/distress, fearlessness, low hostility) and maladaptive tendencies (grandiose manipulative traits, Machiavellian features including desire for control/status, and verbal aggression). Meanness was related to callous and unemotional traits, features of Machiavellianism (e.g., amoral manipulation and distrust of others), physical aggression, and absence of positive parenting. Disinhibition, by contrast, was characterized by anxiety and distress, exposure to violence, and retrospective accounts of abuse history, along with impulsive, irresponsible, and hostile tendencies. These findings indicate that the Greek-Cypriot translation of the TriPM effectively assesses the constructs of the triarchic model and extend what we know about their empirical correlates.


Variants of OTOF and PJVK genes in Chinese patients with auditory neuropathy spectrum disorder.
Mutations in OTOF and PJVK genes cause DFNB9 and DFNB59 types of hearing loss, respectively. The patients carrying pathogenic mutations in either of these genes may show the typical phenotype of auditory neuropathy spectrum disorder (ANSD). The aim of the present study was to identify OTOF and PJVK mutations in sporadic ANSD patients. A total of 76 unrelated Chinese non-syndromic ANSD patients were sequenced on the gene OTOF and PJVK exon by exon. Variants were valued in 105 controls with normal hearing to verify the carrying rate. We identified one pathogenic mutation (c.1194T>A) and three novel, possibly pathogenic, variants (c.3570+2T>C, c.4023+1 G>A, and c.1102G>A) in the OTOF gene, and one novel, possibly pathogenic, variant (c.548G>A) in PJVK. Moreover, we found three novel missense mutations within the exons of OTOF. As we identified 4 and 1 possible pathogenic variants of the OTOF gene and the PJVK gene, respectively, we believe that screening in these genes are important in sporadic ANSD patients. The pathogenicity of these novel mutations needs further study because of their single heterozygous nature. Knowledge on the mutation spectra of these genes in Chinese would be beneficial in understanding the genetic character of this worldwide disease.


Gradient Relationship between Increased Mean Corpuscular Volume and Mortality Associated with Cerebral Ischemic Stroke and Ischemic Heart Disease: A Longitudinal Study on 66,294 Taiwanese.
The gradient relationship between mean corpuscular volume (MCV) and mortality due to ischemic vascular disease has not been researched using a large-scale population-based study. This study evaluated the association between MCV and death attributable to cerebrovascular disease (CVD) and cardiovascular disease (CAD) in a large population- and community-based Taiwanese cohort. A longitudinal study with a 9-year follow-up was conducted to evaluate individuals aged 20 years or older who had participated in the Keelung (the northernmost city in Taiwan) community-based integrated screening (abbreviated as KCIS) program since September 1999. The mortality rates associated with CVD and CAD were classified across a range of different MCV levels. Increased MCV levels were associated with an increased risk of CVD/CAD-related death (adjusted hazard ratio [aHR] = 1.42, trend test P = 0.0119). Marginally statistically significant associations were noted for specific deaths from ischemic heart disease (aHR = 1.44, trend test P = 0.0992) and cerebral ischemic stroke (aHR = 1.66, trend test P = 0.0667), respectively, but no significant gradient relationship was noted for death from cerebral hemorrhage stroke (aHR = 1.23, trend test, P = 0.6278). A gradient relationship between baseline MCV level and CVD/CAD-related death was noted, but whether such gradient relationships existed for two specific deaths and how these relationships may be confounded by extraneous factors that were not considered here should be investigated in the future.


High field metabolic rates of wild harbour porpoises.
Reliable estimates of field metabolic rates (FMRs) in wild animals are essential for quantifying their ecological roles, as well as for evaluating fitness consequences of anthropogenic disturbances. Yet, standard methods for measuring FMR are difficult to use on free-ranging cetaceans whose FMR may deviate substantially from scaling predictions using terrestrial mammals. Harbour porpoises (Phocoena phocoena) are among the smallest marine mammals, and yet they live in cold, high-latitude waters where their high surface-to-volume ratio suggests high FMRs to stay warm. However, published FMR estimates of harbour porpoises are contradictory, with some studies claiming high FMRs and others concluding that the energetic requirements of porpoises resemble those of similar-sized terrestrial mammals. Here, we address this controversy using data from a combination of captive and wild porpoises to estimate the FMR of wild porpoises. We show that FMRs of harbour porpoises are up to two times greater than for similar-sized terrestrial mammals, supporting the hypothesis that small, carnivorous marine mammals in cold water have elevated FMRs. Despite the potential cost of thermoregulation in colder water, harbour porpoise FMRs are stable over seasonally changing water temperatures. Varying heat loss seems to be managed via cyclical fluctuations in energy intake, which serve to build up a blubber layer that largely offsets the extra costs of thermoregulation during winter. Such high FMRs are consistent with the recently reported high feeding rates of wild porpoises and highlight concerns about the potential impact of human activities on individual fitness and population dynamics.


Grafts of Olfactory Stem Cells Restore Breathing and Motor Functions after Rat Spinal Cord Injury.
The transplantation of olfactory ecto-mesenchymal stem cells (OEMSCs) could be a helpful therapeutic strategy for spinal cord repair. Using an acute rat model of high cervical contusion that provokes a persistent hemidiaphragmatic and foreleg paralysis, we evaluated the therapeutic effect of a delayed syngeneic transplantation (two days post-contusion) of OEMSCs within the injured spinal cord. Respiratory function was assessed using diaphragmatic electromyography and neuroelectrophysiological recordings of phrenic nerves (innervating the diaphragm). Locomotor function was evaluated using the ladder-walking locomotor test. Cellular reorganization in the injured area was also studied using immunohistochemical and microscopic techniques. We report a substantial improvement in breathing movements, in activities of the ipsilateral phrenic nerve and ipsilateral diaphragm, and also in locomotor abilities four months post-transplantation with nasal OEMSCs. Moreover, in the grafted spinal cord, axonal disorganization and inflammation were reduced. Some grafted stem cells adopted a neuronal phenotype, and axonal sparing was observed in the injury site. The therapeutic effect on the supraspinal command is presumably because of both neuronal replacements and beneficial paracrine effects on the injury area. Our study provides evidence that nasal OEMSCs could be a first step in clinical application, particularly in patients with reduced breathing/locomotor movements.


Potent Immune Modulation by MEDI6383, an Engineered Human OX40 Ligand IgG4P Fc Fusion Protein.
Ligation of OX40 (CD134, TNFRSF4) on activated T cells by its natural ligand (OX40L, CD252, TNFSF4) enhances cellular survival, proliferation, and effector functions such as cytokine release and cellular cytotoxicity. We engineered a recombinant human OX40L IgG4P Fc fusion protein termed MEDI6383 that assembles into a hexameric structure and exerts potent agonist activity following engagement of OX40. MEDI6383 displayed solution-phase agonist activity that was enhanced when the fusion protein was clustered by Fc gamma receptors (FcγRs) on the surface of adjacent cells. The resulting costimulation of OX40 on T cells induced NFκB promoter activity in OX40-expressing T cells and induced Th1-type cytokine production, proliferation, and resistance to regulatory T cell (Treg)-mediated suppression. MEDI6383 enhanced the cytolytic activity of tumor-reactive T cells and reduced tumor growth in the context of an alloreactive human T cell:tumor cell admix model in immunocompromised mice. Consistent with the role of OX40 costimulation in the expansion of memory T cells, MEDI6383 administered to healthy nonhuman primates elicited peripheral blood CD4 and CD8 central and effector memory T-cell proliferation as well as B-cell proliferation. Together, these results suggest that OX40 agonism has the potential to enhance antitumor immunity in human malignancies. Mol Cancer Ther; 17(5); 1024-38. ©2018 AACR.


Risk of human exposure to vector ticks (Acari: Ixodidae) in a heavily used recreational area in northern California.
The risk of humans encountering vector ticks along hiking trails or in picnic grounds in a Lyme disease-endemic area was evaluated in a multipurpose recreational area (Tilden Regional Park) in the populous San Francisco Bay region of California. Four hillside hiking trails (two high-use, two low-use) were sampled by dragging and walking through low vegetation biweekly for one year; four heavily used picnic areas were sampled concurrently by dragging. Adults of three human-biting ticks were enumerated (n = 1,911) along all trials: Dermacentor occidentalis (63.6% of total), Ixodes pacificus (26.2%), and D. variabilis (0.2%). Subadults (n = 1,669) of D. occidentalis (0.06% of total) and two nonhuman-biters, D. albipictus (70.3%) and Haemaphysalis leporispalustris (29.7%), also were collected. Dragging yielded many more adult ticks than walking year-round for all trials. These methods were significantly correlated during periods of peak tick abundance, but the associations were not sufficiently strong or consistent to allow prediction of captures for either method based on the other. Adult ticks were distributed largely in clusters along the uphill sides of trails. Several adult ticks collected adjacent to trails were found to contain spirochetes identified with polyclonal antibodies as Borrelia burgdorferi (D. occidentalis, 0 of 861; D. variabilis, 2 of 126 [1.6%]; I. pacificus, 1 of 609 [0.2%]). Picnic areas produced low numbers of adult D. occidentalis and I. pacificus, which prohibited testing them for spirochetes. Two measures for evaluating risk were calculated, the encounter distance (= mean number of meters traveled before encountering a vector tick by either dragging or walking) and the mean number of spirochete-infected ticks encountered by these methods per kilometer of trial. These measures revealed that the risk of exposure to spirochete-infected adult ticks along trails was low year-round irrespective of usage, and risk was even lower in picnic areas. Future studies evaluating human exposure to vector ticks in recreational areas should incorporate, whenever possible, testing for multiple pathogens because most ixodid ticks that commonly bite people in the United States are capable of transmitting two or more microbial disease agents.


Scaling Lean in primary care: impacts on system performance.
We examined a wide range of performance outcomes after Lean methodology-a leading strategy to enhance efficiency and patient value-was implemented and scaled across all primary care clinics in a nonprofit, ambulatory care delivery system. Using a stepped wedge approach, we assessed changes associated with the phased introduction of Lean-based redesigns across 46 primary care departments in 17 different clinic locations. Longitudinal analysis of operational metrics included: workflow efficiency, physician productivity, operating expenses, clinical quality, and satisfaction among patients, physicians, and staff. We used interrupted time series analysis with generalized linear mixed models to estimate Lean impacts over time. Projected outcomes in the absence of changes (ie, counterfactuals) were compared with observed outcomes after Lean redesigns were implemented, and mean differences were assessed using 95% bias-corrected bootstrap confidence intervals (CIs). We observed systemwide improvements in workflow efficiencies (eg, 95% CI, 5.8-10.4) and physician productivity (95% CI, 3.9-27.2), with no adverse effects on clinical quality. Patient satisfaction increased with respect to access to care (95% CI, 15.2-20.7), handling of personal issues (95% CI, 2.1-6.9), and overall experience of care (95% CI, 11.0-17.0), but decreased with respect to interactions with care providers (95% CI, -13.4 to -5.7). Departmental operating costs decreased, and annual staff and physician satisfaction scores increased particularly among early adopters, with key improvements in employee engagement, connection to purpose, relationships with staff, and physician time spent working. Lean redesigns can benefit primary care patients, physicians, and staff without negatively impacting the quality of clinical care. Study results may lead other delivery system leaders to innovate using Lean techniques and may further enhance support for Lean learning among public and private payers.


Lung pathology due to hRSV infection impairs blood-brain barrier permeability enabling astrocyte infection and a long-lasting inflammation in the CNS.
The human respiratory syncytial virus (hRSV) is the most common infectious agent that affects children before two years of age. hRSV outbreaks cause a significant increase in hospitalizations during the winter season associated with bronchiolitis and pneumonia. Recently, neurologic alterations have been associated with hRSV infection in children, which include seizures, central apnea, and encephalopathy. Also, hRSV RNA has been detected in cerebrospinal fluids (CSF) from patients with neurological symptoms after hRSV infection. Additionally, previous studies have shown that hRSV can be detected in the lungs and brains of mice exposed to the virus, yet the potential effects of hRSV infection within the central nervous system (CNS) remain unknown. Here, using a murine model for hRSV infection, we show a significant behavior alteration in these animals, up to two months after the virus exposure, as shown in marble-burying tests. hRSV infection also produced the expression of cytokines within the brain, such as IL-4, IL-10, and CCL2. We found that hRSV infection alters the permeability of the blood-brain barrier (BBB) in mice, allowing the trespassing of macromolecules and leading to increased infiltration of immune cells into the CNS together with an increased expression of pro-inflammatory cytokines in the brain. Finally, we show that hRSV infects murine astrocytes both, in vitro and in vivo. We identified the presence of hRSV in the brain cortex where it colocalizes with vWF, MAP-2, Iba-1, and GFAP, which are considered markers for endothelial cells, neurons, microglia, and astrocyte, respectively. hRSV-infected murine astrocytes displayed increased production of nitric oxide (NO) and TNF-α. Our results suggest that hRSV infection alters the BBB permeability to macromolecules and immune cells and induces CNS inflammation, which can contribute to the behavioral alterations shown by infected mice. A better understanding of the neuropathy caused by hRSV could help to reduce the potential detrimental effects on the CNS in hRSV-infected patients.


Effects of human recombinant PEDF protein and PEDF-derived peptide 34-mer on choroidal neovascularization.
Pigment epithelium-derived factor (PEDF) is a serpin with antiangiogenic properties. Previously, the authors showed that PEDF injected into the subconjunctiva reaches the choroid. Here, they examined the effects of PEDF polypeptide fragments on vessel sprouting and on choroidal neovascularization (CNV) after subconjunctival administration. Recombinant human PEDF (rhuPEDF) was cleaved at its serpin-exposed loop by limited chymotrypsin proteolysis. Synthetic PEDF peptides 34-mer (Asp(44)-Asn(77)) and 44-mer (Val(78)-Thr(121)) were used. Ex vivo chick aortic vessel sprouting assays were performed. CNV was induced in rats by laser injury of Bruch's membrane. Daily subconjunctival injections (0.01-10 pmol/d protein) were performed for 5 days starting at day of injury or at the seventh day after injury. New vessel volumes were quantified using optical sections of choroid/RPE flat-mounts labeled with isolectin-Ib4. PEDF distribution was evaluated by immunofluorescence of choroid/RPE/retina cross-sections. Full-length rhuPEDF, cleaved rhuPEDF, or peptide 34-mer exhibited ex vivo antiangiogenic activity, but peptide 44-mer was inefficient. PEDF immunostaining around CNV lesions diminished after laser injury. Subconjunctival administration of rhuPEDF or 34-mer at 0.1 pmol/d decreased CNV lesion volumes by 52% and 47%, respectively, whereas those of 44-mer were similar to vehicle injections. Doses of 0.1 and 1 pmol/d rhuPEDF decreased fully developed CNV complex volumes by 45% and 50%, respectively, compared with vehicle injections. A functional region for the inhibition of vessel sprouting and CNV resides within the 34-mer region of PEDF. Furthermore, subconjunctival administration of optimal range dosages of rhuPEDF or 34-mer can suppress and regress rat CNV lesions, demonstrating that these agents reach the choroid/RPE complex as functionally active molecules.


Pigs with Severe Combined Immunodeficiency Are Impaired in Controlling Influenza A Virus Infection.
Influenza A viruses (IAV) infect many host species, including humans and pigs. Severe combined immunodeficiency (SCID) is a condition characterized by a deficiency of T, B, and/or natural killer (NK) cells. Animal models of SCID have great value for biomedical research. Here, we evaluated the pathogenesis and the innate immune response to the 2009 H1N1 pandemic IAV (H1N1pdm09) using a recently identified line of naturally occurring SCID pigs deficient in T and B lymphocytes that still have functional NK cells. SCID pigs challenged with H1N1pdm09 showed milder lung pathology compared to the non-SCID heterozygous carrier pigs. Viral titers in the lungs and nasal swabs of challenged SCID pigs were significantly higher than in carrier pigs 7 days postinfection, despite higher levels of IL-1β and IFN-α in the lungs of SCID pigs. The lower levels of pulmonary pathology were associated with the T and B cell absence in response to infection. The higher viral titers, prolonged shedding, and delayed viral clearance indicated that innate immunity was insufficient for controlling IAV in pigs. This recently identified line of SCID pigs provides a valuable model to understand the immune mechanisms associated with influenza protection and recovery in a natural host.


Qxpak.5: old mixed model solutions for new genomics problems.
Mixed models have a long and fruitful history in statistics. They are pertinent to genomics problems because they are highly versatile, accommodating a wide variety of situations within the same theoretical and algorithmic framework. Qxpak is a package for versatile statistical genomics, specifically designed for sophisticated quantitative trait loci and association analyses. Multiple loci, multiple trait, infinitesimal genetic effects, imprinting, epistasis or sex linked loci can be fitted. The new version (v. 5) allows us, among other new features, to include either relationship matrices obtained with molecular information or user defined matrices that can be read from an input file. This feature can be used for genome selection or - more importantly - to correct for population structure in association studies. In crosses, two parental lines, not necessarily inbred, can be accommodated. This software aims at simplifying statistical genetic analyses implementing a coherent and unified approach by mixed models. It provides a tool that can be used in a wide variety of situations with ample genetic and statistical modeling flexibility. The software, a complete manual and examples are available at http://www.icrea.cat/Web/OtherSectionViewer.aspx?key=485&titol=Software:Qxpak.


Looking inside the black box of community rehabilitation and intermediate care teams in the United Kingdom: an audit of service and staffing.
To generate a picture of the range, configuration and staffing of community and intermediate care services in the United Kingdom (UK) and to ascertain whether any relationships exist between service configuration and staffing models. A service audit tool was sent to members of the Community Therapist's Network (CTN) and to chief executives of primary care and National Health Service trusts in the UK. Data were collected from the CTN and chief executives of primary care trusts (PCTs) and NHS trusts between late 2005 and early 2006. The overall response rate to the two audits was 37% (n = 243), with 77% of these responses (n = 186) useable. Services varied greatly in terms of their organisation and staffing configurations. Skill mix varied according to the location of service delivery, with home-based services utilising more therapy and support staff than inpatient services. Two clusters of service emerged, based on the number of referrals per year, support staff in the team and the level of care provided by the service. There are no clear patterns to the structure and organisation of community and intermediate care services in relation to their purpose, and it remains unclear how different staffing configurations impact on service costs and patient outcomes. The amount of variation observed indicates that there is likely to be considerable variability in service costs and outcomes for the teams. Further evidence is required to determine the impact of different staffing models, and to identify approaches that optimise both effectiveness and efficiency.


Variation in GIGYF2 is not associated with Parkinson disease.
A recent study reported that mutations in a gene on chromosome 2q36-37, GIGYF2, result in Parkinson disease (PD). We have previously reported linkage to this chromosomal region in a sample of multiplex PD families, with the strongest evidence of linkage obtained using the subset of the sample having the strongest family history of disease and meeting the strictest diagnostic criteria. We have tested whether mutations in GIGYF2 may account for the previously observed linkage finding. We sequenced the GIGYF2 coding region in 96 unrelated patients with PD used in our original study that contributed to the chromosome 2q36-37 linkage signal. Subsequently, we genotyped the entire sample of 566 multiplex PD kindreds as well as 1,447 controls to test whether variants in GIGYF2 are causative or increase susceptibility for PD. We detected three novel variants as well as one of the previously reported seven variants in a total of five multiple PD families; however, there was no consistent evidence that these variants segregated with PD in these families. We also did not find a significant increase in risk for PD among those inheriting variants in GIGYF2 (p = 0.28). We believe that variation in a gene other than GIGYF2 accounts for the previously reported linkage finding on chromosome 2q36-37.


Transcriptomic Analysis of the Kuruma Prawn Marsupenaeus japonicus Reveals Possible Peripheral Regulation of the Ovary.
Crustacean reproduction has been hypothesized to be under complex endocrinological regulation by peptide hormones. To further improve our understanding of the mechanisms underlying this complex regulation, knowledge is needed regarding the hormones not only of the central nervous system (CNS) such as the X-organ/sinus gland (XOSG), brain, and thoracic ganglia, but also the peripheral gonadal tissues. For example, in vertebrates, some gonadal peptide hormones including activin, inhibin, follistatin, and relaxin are known to be involved in the reproductive physiology. Therefore, it is highly likely that some peptide factors from the ovary are serving as the signals among peripheral tissues and central nervous tissues in crustaceans. In this work, we sought to find gonadal peptide hormones and peptide hormone receptors by analyzing the transcriptome of the ovary of the kuruma prawn Marsupenaeus japonicus. The generated ovarian transcriptome data led to the identification of five possible peptide hormones, including bursicon-α and -β, the crustacean hyperglycemic hormone (CHH)-like peptide, insulin-like peptide (ILP), and neuroparsin-like peptide (NPLP). Dominant gene expressions for the bursicons were observed in the thoracic ganglia and the ovary, in the CNS for the CHH-like peptide, in the heart for NPLP, and in the ovary for ILP. Since the gene expressions of CHH-like peptide and NPLP were affected by a CHH (Penaeus japonicus sinus gland peptide-I) from XOSG, we produced recombinant peptides for CHH-like peptide and NPLP using Escherichia coli expression system to examine their possible peripheral regulation. As a result, we found that the recombinant NPLP increased vitellogenin gene expression in incubated ovarian tissue fragments. Moreover, contigs encoding putative receptors for insulin-like androgenic gland factor, insulin, neuroparsin, and neuropeptide Y/F, as well as several contigs encoding orphan G-protein coupled receptors and receptor-type guanylyl cyclases were also identified in the ovarian transcriptome. These results suggest that reproductive physiology in crustaceans is regulated by various gonadal peptide hormones, akin to vertebrates.


Efficacy and safety of 5-hydroxytryptophan on depression and apathy in Parkinson's disease: a preliminary finding.
Several studies have indicated that altered serotonergic neurotransmission may contribute to non-motor features commonly associated with Parkinson's disease (PD) such as apathy and depression. 5-hydroxytryptophan (5-HTP) is the intermediate metabolite of L-tryptophan in the production of serotonin. To date, there has been inconsistent research on the use of 5-HTP in PD. The purpose of this study was to compare the effects of 5-HTP with those of placebo on apathy and depressive symptoms in patients with PD. A single-center, randomized, double-blind placebo-controlled cross-over trial was employed; 25 individuals were subsequently enrolled into the study. Patients received placebo and 50 mg of 5-HTP daily over a period of 4 weeks. For the assessment of efficacy on depressive and apathy symptoms the Beck Depression Inventory-II (BDI-II), Hamilton Depression Rating Scale (HDRS) and Apathy Scale (AS) were respectively administered at screening, baseline and weeks 4, 8, 12 and 16. Primary efficacy outcomes were the comparison of 5-HTP to placebo in mean change from baseline to weeks 4, 8, 12 and 16 in total score on the AS, BDI-II and HDRS. Repeated-measures analysis revealed a significant improvement of depressive symptoms during the 50-mg 5-HTP treatment compared with placebo as assessed by the HDRS. No effect of 5-HTP was seen on apathy symptoms assessed by the AS. This study provides preliminary evidence of clinical benefit of 5-HTP for treating depressive symptoms in PD. Larger studies with a longer treatment duration are needed to corroborate these early findings.


Printed Thin Magnetic Films Based on Diblock Copolymer and Magnetic Nanoparticles.
Printing techniques have been well established for large-scale production and have developed to be effective in controlling the morphology and thickness of the film. In this work, printing is employed to fabricate magnetic thin films composed of polystyrene coated maghemite nanoparticles (γ-Fe2O3 NPs) and polystyrene-block-poly(methyl methacrylate) (PS-b-PMMA) diblock copolymer. By applying an external magnetic field during the print coating step, oriented structures with a high content of nanoscale magnetic particles are created. The morphology of the magnetic films and the arrangement of NPs within the polymer matrix are characterized with real and reciprocal space techniques. Due to the applied magnetic field, the magnetic NPs self-assemble into microscale sized wires with controlled widths and separation distances, endowing hybrid films with a characteristic magnetic anisotropy. At the nanoscale level, due to the PS coating, the NPs disperse as single particles at low NP concentrations. The NPs self-assemble into nanosized clusters inside the PS domains when the NP concentration increases. Due to a high loading of uniformly dispersed magnetic NPs across the whole printed film, a strong sensitivity to an external magnetic field is achieved. The enhanced superparamagnetic property of the printed films renders them promising candidate materials for future magnetic sensor applications.


Assessment of bronchial and pulmonary blood supply in non-small cell lung cancer subtypes using computed tomography perfusion.
The aim of this study was to investigate the dual blood supply of non-small cell lung cancer (NSCLC) and its association with tumor subtype, size, and stage, using computed tomography perfusion (CTP). A total of 54 patients (median age, 65 years; range, 42-79 years; 15 women, 39 men) with suspected lung cancer underwent a CTP scan of the lung tumor. Pulmonary and bronchial vasculature regions of interest were used to calculate independently CTP parameters (blood flow [BF], blood volume [BV], and mean transit time [MTT]) of the tumor tissue. The mean and maximum pulmonary and bronchial perfusion indexes (PImean and PImax) were calculated. The tumoral volume and the largest tumoral diameter were assessed. Differences in CTP parameters and indexes among NSCLC subtypes, tumor stages and tumor dimensions were analyzed using non-parametric tests. According to biopsy, 37 patients had NSCLC (22 adenocarcinomas [ACs], 8 squamous cell carcinomas [SCCs], 7 large-cell carcinomas [LCC]). The mean bronchial BF/pulmonary BF, bronchial BV/pulmonary BV, and bronchial MTT/pulmonary MTT was 41.2 ± 30.0/36.9 ± 24.2 mL/100 mL/min, 11.4 ± 9.7/10.4 ± 9.4 mL/100 mL, and 11.4 ± 4.3/14.9 ± 4.4 seconds, respectively. In general, higher bronchial BF than pulmonary BF was observed in NSCLC (P = 0.014). Using a tumoral volume cutoff of 3.5 cm, a significant difference in pulmonary PImax was found (P = 0.028). There was a significantly higher mean pulmonary BF in LCCs and SCCs compared with ACs (P = 0.018 and P = 0.044, respectively), whereas the mean bronchial BF was only significantly higher in LCCs compared with ACs (P = 0.024). Correspondingly, the PImax was significantly higher in LCCs and SCCs than in ACs (P = 0.001 for both). Differences between bronchial and pulmonary PImean and PImax among T stages and Union Internationale Contre le Cancer stages were not statistically significant (P values ranging from 0.691 to 0.753). The known dual blood supply of NSCLC, which depends on tumor size and histological subtype, is reflected in CTP parameters, with parameters depending both on tumor size and histological subtype. This has to be accounted for when analyzing NSCLC with CTP.


Dextromethorphan protects against cerebral injury following transient focal ischemia in rabbits.
We investigated dextromethorphan, both a dextrorotatory opioid derivative and a clinically tested N-methyl-D-aspartate (NMDA) receptor antagonist, in a rabbit model of transient focal cerebral ischemia. Fourteen rabbits were randomly assigned to treatment with a 20 mg/kg i.v. loading dose followed by a 10 mg/kg/hr infusion of 0.4% dextromethorphan in normal saline or with an equivalent volume of normal saline alone. One hour after treatment, the rabbits underwent a 1-hour occlusion of the left internal carotid and anterior cerebral arteries followed by 4 hours of reperfusion. The seven dextromethorphan-treated rabbits showed a significant decrease in the area of neocortical severe ischemic neuronal damage (10.5%) compared with the seven normal saline-treated controls (49.6%, p less than 0.001). The dextromethorphan-treated rabbits also demonstrated significantly smaller areas of cortical edema (10.2%) on magnetic resonance imaging than the controls (38.6%, p less than 0.01). Analysis of somatosensory evoked potentials revealed recovery of the ipsilateral amplitude to contralateral values within 5 minutes of reperfusion in the dextromethorphan-treated rabbits but not in the controls (p less than 0.01). In our rabbit model of transient focal cerebral ischemia, dextromethorphan appears to protect the brain against ischemic neuronal damage and edema, as well as to promote neurophysiologic recovery. This clinically available drug should be further investigated as having potential therapeutic value in the treatment of stroke.


Challenges of genetic testing in adolescents with cardiac arrhythmia syndromes.
The ability to sequence individual genomes is leading to the identification of an increasing number of genetic risk factors for serious diseases. Knowledge of these risk factors can often provide significant medical and psychological benefit, but also raises complex ethical and social issues. This paper focuses on one area of rapid progress: the identification of mutations causing long QT syndrome and other cardiac channel disorders, which can explain some previously unexplained deaths in infants (SIDS) and children and adults (SUDS) and prevent others from occurring. This genetic knowledge, discovered posthumously in many cases, has implications for clinical care for surviving family members who might carry the same mutations. The information obtained from genetic testing, in the context of personal and family history, can guide individually tailored interventions that reduce risk and save lives. At the same time, obtaining and disclosing genetic information raises difficult issues about confidentiality and decision making within families. We draw on the experience of the Montefiore-Einstein Center for Cardiogenetics, which has played a leading role in the genetic diagnosis and clinical management of cardiac channel diseases, to explore some of the challenging ethical questions arising in affected families with adolescent children. We focus on the related issues of (1) family confidentiality, privacy and disclosure and (2) adolescent decision making about genetic risk, and argue for the value of interdisciplinary dialogue with affected families in resolving these issues.


Antioxidant status, lipid peroxidation and nitric oxide in fibromyalgia: etiologic and therapeutic concerns.
We proposed to assess the oxidant/antioxidant status, lipid peroxidation and nitric oxide (NO) in untreated fibromyalgia (FM) patients and controls. The effect of amitriptyline (A, 20 mg daily) and sertraline (S, 100 mg daily) treatment on patients' superoxide dismutase (SOD), xanthine oxidase (XO), adenosine deaminase (ADA) enzyme activities, thiobarbituric acid reactive substances (TBARS) and NO levels was investigated. Thirty female patients with primary FM and age-matched 16 healthy female controls were included. Patients received an 8-week course of treatment with either A or S. FM patients had higher serum levels of TBARS (particularly malondialdehyde) and lower levels of nitrite compared to controls whereas enzyme activities were similar. A and S significantly improved Fibromyalgia Impact Questionnaire (FIQ) pain scores, Hamilton anxiety and depression rating scales. But neither A nor S had significant effects on measured oxidative stress parameters, except SOD activity that was significantly reduced after S treatment. Total myalgic scores negatively correlated with XO activity, and depression scales negatively correlated with levels of TBARS. Our results indicate that patients with FM are under oxidative stress. These findings represent a rationale for further research assessing the effect of free radical scavengers or antioxidant agents like vitamins and omega-3 fatty acids on peripheral and central mechanisms in FM.


Validation of the actical activity monitor in middle-aged and older adults.
This study was designed to validate the Actical activity monitor in middle-aged and older adults of varying body composition to develop accelerometer thresholds to distinguish between light and moderate intensity physical activity (PA). Nonobese 45 to 64 yr (N = 29), obese 45 to 64 yr (N = 21), and ≥65 yr (N = 23; varying body composition) participants completed laboratory-based sitting, household, and locomotive activities while wearing an Actical monitor and a portable metabolic measurement system. Nonlinear regression analysis was used to identify activity count (AC) cut-points to differentiate between light intensity (<3 METs) and moderate intensity (≥3METs) PA. Using group-specific algorithms, AC cut points for 3 METs were 1634, 1107, and 431 for the obese 45 to 64 yr group, nonobese 45 to 64 yr group, and ≥65 yr group, respectively. However, sensitivity and specificity analysis revealed that an AC cut-point of 1065 yielded similar accuracy for detecting an activity as less than or greater than 3 METs, regardless of age and body composition. For the Actical activity monitor, an AC cut-point of 1065 can be used to determine light and moderate intensity PA in people ≥45 years of age.


Wax on, wax off: nest soil facilitates indirect transfer of recognition cues between ant nestmates.
Social animals use recognition cues to discriminate between group members and non-members. These recognition cues may be conceptualized as a label, which is compared to a neural representation of acceptable cue combinations termed the template. In ants and other social insects, the label consists of a waxy layer of colony-specific hydrocarbons on the body surface. Genetic and environmental differences between colony members may confound recognition and social cohesion, so many species perform behaviors that homogenize the odor label, such as mouth-to-mouth feeding and allogrooming. Here, we test for another mechanism of cue exchange: indirect transfer of cuticular hydrocarbons via the nest material. Using a combination of chemical analysis and behavioral experiments with Camponotus aethiops ants, we show that nest soil indirectly transfers hydrocarbons between ants and affects recognition behavior. We also found evidence that olfactory cues on the nest soil influence nestmate recognition, but this effect was not observed in all colonies. These results demonstrate that cuticular hydrocarbons deposited on the nest soil are important in creating uniformity in the odor label and may also contribute to the template.


Redescription of Microsporidium takedai (Awakura, 1974) as Kabatana takedai (Awakura, 1974) comb. n.
Ultrastructural study of the microsporidian Microsporidium takedai from the muscles of masu salmon Oncorhynchus masou proved that this species can be assigned to the genus Kabatana Lom, Dyková and Tonguthai, 2000. The parasites develop within disintegrated sarcoplasm without any delimiting boundary or cyst. Cylindrical multinucleate meronts proliferate by serial constrictions into uninucleate stages which repeat the process. Eventually, the uninucleate stages transform into uninucleate sporonts, which divide once to produce sporoblasts, thus functioning as sporoblast mother cells. Spores, with a subterminally located anchoring disc and 3 to 4 turns of the polar tube coil, average 3.3 by 1.9 microm in size. The exospore is divided into small fields; the endospore frequently makes small invaginations into the spore inside. Phylogenetic analysis using SSU rDNA sequence consistently placed Kabatana takedai in a group consisting of Microgemma sp., Spraguea lophii and Glugea americanus. The K. takedai could easily be separated from the other species in the same group by 2 inserts in the SSU rDNA sequence.


Public support for policies to improve population and planetary health: A population-based online experiment assessing impact of communicating evidence of multiple versus single benefits.
Effective interventions for reducing the consumption of products that harm population and planetary health often lack public support, impeding implementation. Communicating evidence of policies' effectiveness can increase public support but there is uncertainty about the most effective ways of communicating this evidence. Some policies have multiple benefits such as both improving health and the environment. This study assesses whether communicating evidence of multiple versus single benefits of a policy increases its support. Participants (n = 4616) nationally representative of the British population were randomised to one of 24 groups in an online experiment with a 4 × 3 × 2 between-subjects factorial design. The messages that participants viewed differed according to the evidence they communicated (no message, effectiveness for changing behaviour, effectiveness for changing behaviour + one policy benefit, effectiveness for changing behaviour + three policy benefits), type of policy (taxation, availability) and the target behaviour (consumption of energy-dense food, alcohol, or meat). The primary outcome was policy support. In a full factorial ANOVA, there was a significant main effect of communicating evidence of effectiveness on policy support, which was similar across policies and behaviours. Communicating three benefits increased support relative to communicating one benefit (d = 0.15; p = 0.01). Communicating one benefit increased support compared to providing evidence for changing behaviour alone (d = 0.13; p = 0.004) or no message (d = 0.11 p = 0.022). Communicating evidence of a policy's benefits increases support for policy action across different behaviours and policies. Presenting multiple benefits of policies enhances public support.


Large-scale proteomics analysis of the human kinome.
Members of the human protein kinase superfamily are the major regulatory enzymes involved in the activity control of eukaryotic signal transduction pathways. As protein kinases reside at the nodes of phosphorylation-based signal transmission, comprehensive analysis of their cellular expression and site-specific phosphorylation can provide important insights into the architecture and functionality of signaling networks. However, in global proteome studies, low cellular abundance of protein kinases often results in rather minor peptide species that are occluded by a vast excess of peptides from other cellular proteins. These analytical limitations create a rationale for kinome-wide enrichment of protein kinases prior to mass spectrometry analysis. Here, we employed stable isotope labeling by amino acids in cell culture (SILAC) to compare the binding characteristics of three kinase-selective affinity resins by quantitative mass spectrometry. The evaluated pre-fractionation tools possessed pyrido[2,3-d]pyrimidine-based kinase inhibitors as immobilized capture ligands and retained considerable subsets of the human kinome. Based on these results, an affinity resin displaying the broadly selective kinase ligand VI16832 was employed to quantify the relative expression of more than 170 protein kinases across three different, SILAC-encoded cancer cell lines. These experiments demonstrated the feasibility of comparative kinome profiling in a compact experimental format. Interestingly, we found high levels of cytoplasmic and low levels of receptor tyrosine kinases in MV4-11 leukemia cells compared with the adherent cancer lines HCT116 and MDA-MB-435S. The VI16832 resin was further exploited to pre-fractionate kinases for targeted phosphoproteomics analysis, which revealed about 1200 distinct phosphorylation sites on more than 200 protein kinases. This hitherto largest survey of site-specific phosphorylation across the kinome significantly expands the basis for functional follow-up studies on protein kinase regulation. In conclusion, the straightforward experimental procedures described here enable different implementations of kinase-selective proteomics with considerable potential for future signal transduction and kinase drug target analysis.


Risk of leptomeningeal disease in patients treated with stereotactic radiosurgery targeting the postoperative resection cavity for brain metastases.
We sought to determine the risk of leptomeningeal disease (LMD) in patients treated with stereotactic radiosurgery (SRS) targeting the postsurgical resection cavity of a brain metastasis, deferring whole-brain radiation therapy (WBRT) in all patients. We retrospectively reviewed 175 brain metastasis resection cavities in 165 patients treated from 1998 to 2011 with postoperative SRS. The cumulative incidence rates, with death as a competing risk, of LMD, local failure (LF), and distant brain parenchymal failure (DF) were estimated. Variables associated with LMD were evaluated, including LF, DF, posterior fossa location, resection type (en-bloc vs piecemeal or unknown), and histology (lung, colon, breast, melanoma, gynecologic, other). With a median follow-up of 12 months (range, 1-157 months), median overall survival was 17 months. Twenty-one of 165 patients (13%) developed LMD at a median of 5 months (range, 2-33 months) following SRS. The 1-year cumulative incidence rates, with death as a competing risk, were 10% (95% confidence interval [CI], 6%-15%) for developing LF, 54% (95% CI, 46%-61%) for DF, and 11% (95% CI, 7%-17%) for LMD. On univariate analysis, only breast cancer histology (hazard ratio, 2.96) was associated with an increased risk of LMD. The 1-year cumulative incidence of LMD was 24% (95% CI, 9%-41%) for breast cancer compared to 9% (95% CI, 5%-14%) for non-breast histology (P=.004). In patients treated with SRS targeting the postoperative cavity following resection, those with breast cancer histology were at higher risk of LMD. It is unknown whether the inclusion of whole-brain irradiation or novel strategies such as preresection SRS would improve this risk or if the rate of LMD is inherently higher with breast histology.


Accuracy of Platelet Counting by Optical and Impedance Methods in Patients with Thrombocytopaenia and Microcytosis.
Obtaining accurate platelet counts in microcytic blood samples is challenging, even with the most reliable automated haematology analysers. The CELL-DYN(™) Sapphire (Abbott Laboratories, Chicago, Illinois, USA) analyser uses both optical density and electronic impedance methods for platelet counting. This study aimed to evaluate the accuracy of optical density and electrical impedance methods in determining true platelet counts in thrombocytopaenic samples with microcytosis as defined by low mean corpuscular volume (MCV) of red blood cells. Additionally, the impact of microcytosis on platelet count accuracy was evaluated. This study was carried out between February and December 2014 at the Haematology Laboratory of the Sultan Qaboos University Hospital in Muscat, Oman. Blood samples were collected and analysed from 189 patients with thrombocytopaenia and MCV values of <76 femtolitres. Platelet counts were tested using both optical and impedance methods. Stained peripheral blood films for each sample were then reviewed as a reference method to confirm platelet counts. The platelet counts estimated by the impedance method were on average 30% higher than those estimated by the optical method (P <0.001). The estimated intraclass correlation coefficient was 0.52 (95% confidence interval: 0.41-0.62), indicating moderate reliability between the methods. The degree of agreement between methods ranged from -85.5 to 24.3 with an estimated bias of -30, suggesting that these methods generate different platelet results. The impedance method significantly overestimated platelet counts in microcytic and thrombocytopaenic blood samples. Further attention is therefore needed to improve the accuracy of platelet counts, particularly for patients with conditions associated with microcytosis.


Estrogen deficiency-induced Ca balance impairment is associated with decrease in expression of epithelial Ca transport proteins in aged female rats.
The study is designed to determine whether estrogen and vitamin D endocrine systems interact to regulate calcium (Ca) balance as well as changes in mRNA expression of epithelial Ca transport proteins involved in intestinal and renal Ca transport in aging animals in response to ovariectomy and low dietary Ca intake. Eleven-month-old female sham or ovariectomized (OVX) rats were divided into four groups and fed with either a low-Ca (LCD; 0.1% Ca, 0.65% P) or a high-Ca (HCD; 1.2% Ca, 0.65% P) diet for 12weeks. Ca balance and mRNA expression of Ca transport proteins in the intestine and kidney from rats were systematically studied. OVX rats fed with LCD resulted in a negative Ca balance. LCD suppressed serum Ca in OVX but not sham rats, resulting in an induction of serum PTH and 1,25(OH)2D3 levels. The surge in serum 1,25(OH)2D3 levels in LCD-fed OVX rats was associated with an increase in mRNA expression of intestinal transient receptor potential cation channel (TRPV6) and calbindin D9k (CaBP9k) as well as renal vitamin D receptor (VDR), but such an induction was unable to restore Ca balance in vivo. In contrast, the negative Ca balance was associated with suppression of intestinal plasma membrane Ca pump (PMCA1b) and renal transient receptor potential cation channel (TRPV5), calbindin D28k (CaBP28k) and PMCA1b mRNA expression in aged OVX rats. Negative Ca balance in aged female OVX rats is associated with estrogen-dependent and vitamin D-independent downregulation of epithelial Ca transport protein mRNA expression.


Lateral light scattering in fibrous media.
Lateral light scattering in fibrous media is investigated by computing the modulation transfer function (MTF) of 22 paper samples using a Monte Carlo model. The simulation tool uses phase functions from infinitely long homogenous cylinders and the directional inhomogeneity of paper is achieved by aligning the cylinders in the plane. The inverse frequency at half maximum of the MTF is compared to both measurements and previous simulations with isotropic and strongly forward single scattering phase functions. It is found that the conical scattering by cylinders enhances the lateral scattering and therefore predicts a larger extent of lateral light scattering than models using rotationally invariant single scattering phase functions. However, it does not fully reach the levels of lateral scattering observed in measurements. It is argued that the hollow lumen of a wood fiber or dependent scattering effects must be considered for a complete description of lateral light scattering in paper.


Enhancing Attraction of African Malaria Vectors to a Synthetic Odor Blend.
The deployment of odor-baited tools for sampling and controlling malaria vectors is limited by a lack of potent synthetic mosquito attractants. A synthetic mixture of chemical compounds referred to as "the Mbita blend" (MB) was shown to attract as many host-seeking malaria mosquitoes as attracted to human subjects. We hypothesized that this effect could be enhanced by adding one or more attractive compounds to the blend. We tested changes in the capability of MB (ammonia + L-lactic acid + tetradecanoic acid +3-methyl-1-butanol + carbon dioxide) to attract host-seeking malaria mosquitoes by addition of selected dilutions of butyl-2-methylbutanoate (1:10,000), 2-pentadecanone (1:100), 1-dodecanol (1:10,000), and butan-1-amine (1:10,000,000). The experiments were conducted in semi-field enclosures and in a village in western Kenya. In semi-field enclosures, the attraction of Anopheles gambiae sensu stricto females to MB-baited traps was not enhanced by adding butyl-2-methylbutanoate. There was, however, an increase in the proportion of An. gambiae caught in traps containing MB augmented with the selected dilutions of butan-1-amine, 2-pentadecanone, and 1-dodecanol. When tested in the village, addition of butan-1-amine to MB enhanced catches of female An. gambiae sensu lato, An. funestus, and Culex mosquitoes. 1-Dodecanol increased attraction of An. gambiae s.l. to the MB, while addition of 2-pentadecanone improved trap catches of An. funestus and Culex mosquitoes. This study demonstrates the possibility of enhancing synthetic odor blends for trapping the malarial mosquitoes An. gambiae s.l. and An. funestus, as well as some culicine species. The findings provide promising results for the optimization and utilization of synthetic attractants for sampling and controlling major disease vectors.


Effects of a thrombin inhibitor, argatroban, on ischemic brain damage in the rat distal middle cerebral artery occlusion model.
To elucidate the role of thrombin in brain damage during focal cerebral ischemia, we investigated the effects of a selective thrombin inhibitor, argatroban, on microthrombi formation, regional cerebral blood flow (rCBF), infarct areas and neurological deficits using a rat thrombotic distal middle cerebral artery (dMCA) occlusion model. The rat dMCA was occluded by a platelet-rich thrombus formed after photochemical reaction between rose bengal and green light. One day after dMCA occlusion, the number of microthrombi were counted. In the separate animals, rCBF was measured by using the iodoantipyrine method 1 day after dMCA occlusion. Three days after dMCA occlusion, behavioral tests were performed and the size of the cerebral infarction was determined. In the present study, argatroban was administered i.p. by continuous infusion after dMCA occlusion. Argatroban (0.3 mg/h/rat) significantly (P < .05) decreased the number of microthrombi 1 day after dMCA occlusion. Argatroban (0.1 and 0.3 mg/h/rat) significantly (P < .01) reversed a decrease in rCBF 1 day after dMCA occlusion. Argatroban (0.3 mg/h/rat) also significantly (P < .01) reduced the size of the cerebral infarction. Administration of argatroban (0.1 and 0.3 mg/h/rat) resulted in a significant improvement in neurological deficits 3 days after dMCA occlusion (P < .01 and P < .05, respectively). Argatroban decreased the size of the cerebral infarction and improved neurological deficits in the rat thrombotic dMCA occlusion model. These effects were thought to be due to the improvement of rCBF and to the reduction in secondary thrombus formation after dMCA occlusion.


Calcium pumps of plasma membrane and cell interior.
Calcium entering the cell from the outside or from intracellular organelles eventually must be returned to the extracellular milieu or to intracellular storage organelles. The two major systems capable of pumping Ca2+ against its large concentration gradient out of the cell or into the sarco/endoplasmatic reticulum are the plasma membrane Ca2+ ATPases (PMCAs) and the sarco/endoplasmic reticulum Ca2+ ATPases (SERCAs), respectively. In mammals, multigene families code for these Ca2+ pumps and additional isoform subtypes are generated via alternative splicing. PMCA and SERCA isoforms show developmental-, tissue- and cell type-specific patterns of expression. Different PMCA and SERCA isoforms are characterized by different regulatory and kinetic properties that likely are optimized for the distinct functional tasks fulfilled by each pump in setting resting cytosolic or intra-organellar Ca2+ levels, and in shaping intracellular Ca2+ signals with spatial and temporal resolution. The loss or malfunction of specific Ca2+ pump isoforms is associated with defects such as deafness, ataxia or heart failure. Understanding the involvement of different Ca2+ pump isoforms in the pathogenesis of disease allows their identification as therapeutic targets for the development of selective strategies to prevent or combat the progression of these disorders.


Pharmacological treatment of depression in women with breast cancer: a systematic review.
The objective of this study is to review the literature on pharmacological treatment of depression in women with breast cancer. According to the PRISMA guidelines, we conducted a systematic review of randomized, controlled clinical trials and open label prospective studies on antidepressants effects on depression in women with breast cancer up to January 14, 2013. In this analysis, a total of 213 studies were identified, and six studies met the inclusion criteria. Of the six studies, three were placebo-controlled randomized controlled clinical trials with fluoxetine, a selective serotonin reuptake inhibitor; and Mianserin—a noradrenergic and specific serotonergic antidepressant. Both studies found that fluoxetine and mianserin significantly improved depressive symptoms and quality of life (QOL) compared with placebo. Conversely, desipramine, a tricyclic antidepressant, and the SSRI, paroxetine, showed no significant effects on depression compared with placebo. A double-blind, parallel group study comparing a tricyclic antidepressant, amitriptyline, and paroxetine showed a significant and comparable improvement in depression and QOL. Two open label, prospective studies found that escitalopram and the norepinephrine reuptake inhibitor, reboxetine, significantly improved depression and QOL compared with baseline values. In conclusion, depression is a clinical problem in patients with breast cancer. Pharmacological treatment with antidepressants may improve depression and QOL. However, the evidence is limited, and the studies are too heterogeneous to recommend one regimen or drug over another. Further antidepressant studies are needed to guide depression treatment in patients with breast cancer.


Pediatric diagnosis not made until adulthood: a case of Wolf-Hirschhorn syndrome.
Wolf-Hirschhorn syndrome is a well-known clinical entity caused by a terminal deletion of the short arm of chromosome 4 (4p-). The diagnosis is usually made in childhood because of the pathognomonic facial dysmorphism, multi-organ involvement and seizures. Epilepsy is a major medical complication during the first years of life, with seizures typically being frequent, although they tend to improve or cease with age. We report on a woman diagnosed with WHS in her thirties by array-CGH. She presents with milder dysmorphic features, recognized by stereophotogrammetry and seizures persistent in adulthood.