The clinical benefit of epidermal growth factor receptor and human epidermal growth factor receptor 2 targeted agents adding to endocrine therapy in hormone receptor-positive breast cancer.
Studies have suggested that the crosstalk between estrogen receptor and ErbB receptor is involved in endocrine therapy (ET) resistance, which might be overcome by drugs-targeting ErbB receptor. However, the results of clinical studies remain controversial. The aim of this meta-analysis was to evaluate the efficacy and safety of ErbB (mainly epidermal growth factor receptor and human epidermal growth factor receptor 2 [HER2]) inhibitors added to ET for hormone receptor-positive breast cancer patients. Eligible randomized clinical trials on ET with or without ErbB receptor-targeting inhibitors (ERTI) for hormone receptor-positive breast cancer were identified by searching the main electronic databases (up to July 2015). Revman 5.3 was used to analyze the outcomes extracted from the included trials. In the overall population, ERTI failed to show any significant differences on overall response rate (ORR), clinical benefit rate (CBR), and overall survival (OS). However, improvement on progression-free survival (PFS) (hazard ratio [HR] 0.84, 95% confidence interval [CI] = 0.76-0.93, P = 0.0005) was observed. For the HER2+ subgroup, ERTI could significantly improve ORR, CBR, PFS, OS, and time to progression compared to endocrine monotherapy. This improvement cannot be found in the HER2- subgroup. The risk of serious adverse events (SAEs) increased significantly when ERTI was present (RR = 2.09, 95% CI = 1.44-3.02, P < 0.0001). For HR+/HER2+ breast cancer, ERTI added to ET can significantly improve the clinical efficacy with the cost of increasing SAE.


Safety net hospital emergency departments: creating safety valves for non-urgent care.
Hospital emergency departments (EDs) are caring for more patients, including those with non-urgent needs that could be treated in alternative, more cost-effective settings, such as a clinic or physician's office. According to findings from the Center for Studying Health System Change's 2007 site visits to 12 nationally representative metropolitan communities, many emergency departments at safety net hospitals--the public and not-for-profit hospitals that serve large proportions of low-income, uninsured and Medicaid patients--are attempting to meet patients' non-urgent needs more efficiently. Safety net EDs are working to redirect non-urgent patients to their hospitals' outpatient clinics or to community health centers and clinics, with varied results. Efforts to develop additional primary, specialty and dental care in community settings, along with promoting the use of these providers, could stem the use of emergency departments for non-urgent care, while increasing access to care, enhancing quality and containing costs.


Pregnancy is a Risk Factor for Pancreatitis After Endoscopic Retrograde Cholangiopancreatography in a National Cohort Study.
There are limited data on the safety of endoscopic retrograde cholangiopancreatography (ERCP) during pregnancy, only data from observational series (approximately 350 cases) have been published. We aimed to evaluate the safety of ERCP in pregnant women by evaluating a large nationwide database. We performed a retrospective matched-cohort study, collecting data from the National Inpatient Sample from 2008 through 2009. We compared data from pregnant women who underwent ERCP (n = 907) with those from nonpregnant women who underwent ERCP (controls, n = 2721). Complications related to ERCP were measured against the matched controls. Obstetric and fetal complications were measured against the national average of all obstetric admissions. ERCP-associated complications of perforation, infection, and bleeding were infrequent in both cohorts (P > .05). Post-ERCP pancreatitis (PEP) occurred in 12% of pregnant women and in 5% of controls (P < .001). There was a significantly lower rate of PEP in teaching hospitals (9.6%) than in nonteaching hospitals (14.6%; P < .001). The adjusted odds ratio for developing PEP among pregnant women vs controls was 2.8 (95% confidence interval [CI], 2.1-3.8). This risk of PEP was higher among nonteaching hospitals (adjusted odds ratio, 3.5; 95% CI, 2.3-5.2) than teaching hospitals (adjusted odds ratio, 2.5; 95% CI, 1.6-3.9). Pregnancy is an independent risk factor for PEP; PEP and PEP among pregnant women are each more prevalent in community hospitals than teaching centers. Proper precautions therefore should be considered for pregnant women undergoing ERCP, including transfer to a tertiary care center if appropriate.


Differentiating normal from abnormal rates of genital epithelial findings in vaginal microbicide trials.
Candidate vaginal microbicides could cause genital irritation, which in turn could facilitate HIV transmission instead of preventing it. While genital epithelial findings are documented in a standardized manner in most microbicide trials, little is known about background rates and predictors for many types of genital findings. A secondary analysis was conducted using data from a Phase II expanded safety study of the candidate microbicide Carraguard gel (Population Council, NY, USA) in Thailand. Genital findings were identified by visual inspection of the cervix, vaginal walls and external genitalia during pelvic exams prior to gel use (screening and enrollment) and during gel use (at 2 weeks and Months 1-12). Women were interviewed about potential risk factors for genital findings at every visit and tested routinely for sexually transmitted and vaginal infections. A total of 258 genital findings were identified in 152 woman-years of follow-up. Genital findings were positively associated with older age, increased parity, self-report of genital symptoms, positive HSV-2 serology, bacterial vaginosis by Nugent scoring and the presence of a genital finding at baseline. Furthermore, vaginal findings were positively associated with vaginal practices and yeast infections. Genital findings were negatively associated with use of hormonal contraception, inconsistently associated with frequency of sex and applicator use, and not associated with condom use. Several factors that are common in women of reproductive age account for the background rate of genital epithelial findings in this population.


Orally active antischistosomal early leads identified from the open access malaria box.
Worldwide hundreds of millions of schistosomiasis patients rely on treatment with a single drug, praziquantel. Therapeutic limitations and the threat of praziquantel resistance underline the need to discover and develop next generation drugs. We studied the antischistosomal properties of the Medicines for Malaria Venture (MMV) malaria box containing 200 diverse drug-like and 200 probe-like compounds with confirmed in vitro activity against Plasmodium falciparum. Compounds were tested against schistosomula and adult Schistosoma mansoni in vitro. Based on in vitro performance, available pharmacokinetic profiles and toxicity data, selected compounds were investigated in vivo. Promising antischistosomal activity (IC50: 1.4-9.5 µM) was observed for 34 compounds against schistosomula. Three compounds presented IC50 values between 0.8 and 1.3 µM against adult S. mansoni. Two promising early leads were identified, namely a N,N'-diarylurea and a 2,3-dianilinoquinoxaline. Treatment of S. mansoni infected mice with a single oral 400 mg/kg dose of these drugs resulted in significant worm burden reductions of 52.5% and 40.8%, respectively. The two candidates identified by investigating the MMV malaria box are characterized by good pharmacokinetic profiles, low cytotoxic potential and easy chemistry and therefore offer an excellent starting point for antischistosomal drug discovery and development.


Methane indicator values for peatlands: a comparison of species and functional groups.
Previous studies have shown a correspondence between the abundance of particular plant species and methane flux. Here, we apply multivariate analyses, and weighted averaging, to assess the suitability of vegetation composition as a predictor of methane flux. We developed a functional classification of the vegetation, in terms of a number of plant traits expected to influence methane production and transport, and compared this with a purely taxonomic classification at species level and higher. We applied weighted averaging and indirect and direct ordination approaches to six sites in the United Kingdom, and found good relationships between methane flux and vegetation composition (classified both taxonomically and functionally). Plant species and functional groups also showed meaningful responses to management and experimental treatments. In addition to the United Kingdom, we applied the functional group classification across different geographical regions (Canada and the Netherlands) to assess the generality of the method. Again, the relationship appeared good at the site level, suggesting some general applicability of the functional classification. The method seems to have the potential for incorporation into large-scale (national) greenhouse gas accounting programmes (in relation to peatland condition/management) using vegetation mapping schemes. The results presented here strongly suggest that robust predictive models can be derived using plant species data (for use in national-scale studies). For trans-national-scale studies, where the taxonomic assemblage of vegetation differs widely between study sites, a functional classification of plant species data provides an appropriate basis for predictive models of methane flux.


Relative and absolute reliability of measures of linoleic acid-derived oxylipins in human plasma.
Modern analytical techniques allow for the measurement of oxylipins derived from linoleic acid in biological samples. Most validatory work has concerned extraction techniques, repeated analysis of aliquots from the same biological sample, and the influence of external factors such as diet and heparin treatment upon their levels, whereas less is known about the relative and absolute reliability of measurements undertaken on different days. A cohort of nineteen healthy males were used, where samples were taken at the same time of day on two occasions, at least 7 days apart. Relative reliability was assessed using Lin's concordance correlation coefficients (CCC) and intraclass correlation coefficients (ICC). Absolute reliability was assessed by Bland-Altman analyses. Nine linoleic acid oxylipins were investigated. ICC and CCC values ranged from acceptable (0.56 [13-HODE]) to poor (near zero [9(10)- and 12(13)-EpOME]). Bland-Altman limits of agreement were in general quite wide, ranging from ±0.5 (12,13-DiHOME) to ±2 (9(10)-EpOME; log10 scale). It is concluded that relative reliability of linoleic acid-derived oxylipins varies between lipids with compounds such as the HODEs showing better relative reliability than compounds such as the EpOMEs. These differences should be kept in mind when designing and interpreting experiments correlating plasma levels of these lipids with factors such as age, body mass index, rating scales etc.


Optimal noise reduction in 3D reconstructions of single particles using a volume-normalized filter.
The high noise level found in single-particle electron cryo-microscopy (cryo-EM) image data presents a special challenge for three-dimensional (3D) reconstruction of the imaged molecules. The spectral signal-to-noise ratio (SSNR) and related Fourier shell correlation (FSC) functions are commonly used to assess and mitigate the noise-generated error in the reconstruction. Calculation of the SSNR and FSC usually includes the noise in the solvent region surrounding the particle and therefore does not accurately reflect the signal in the particle density itself. Here we show that the SSNR in a reconstructed 3D particle map is linearly proportional to the fractional volume occupied by the particle. Using this relationship, we devise a novel filter (the "single-particle Wiener filter") to minimize the error in a reconstructed particle map, if the particle volume is known. Moreover, we show how to approximate this filter even when the volume of the particle is not known, by optimizing the signal within a representative interior region of the particle. We show that the new filter improves on previously proposed error-reduction schemes, including the conventional Wiener filter as well as figure-of-merit weighting, and quantify the relationship between all of these methods by theoretical analysis as well as numeric evaluation of both simulated and experimentally collected data. The single-particle Wiener filter is applicable across a broad range of existing 3D reconstruction techniques, but is particularly well suited to the Fourier inversion method, leading to an efficient and accurate implementation.


The clinical spectrum of microcystic macular edema.
Microcystic macular edema (MME), originally described in British literature as microcystic macular oedema (MMO), defines microcysts in the inner nuclear layer (INL) of the retina. Microcystic macular edema was described in multiple sclerosis (MS), but can be found in numerous disorders. The presence of MME has important prognostic and therapeutic implications; however, the differential diagnosis is unknown. This study aimed to describe the clinical spectrum of MME. A single-center, retrospective cohort study. A bootstrap analysis was performed to reduce the 5865 patients (22,376 scans), who had undergone OCT imaging between January 2010 and February 2013, to a representative dataset. The presence of MME was rated by independent observers. The dataset consisted of 1368 patients (mean age 62, range, 4-101 years), 2589 eyes and 6449 scans. Microcystic macular edema was present in 133/1303 (10%) of patients and 0/65 (0%) of healthy controls. The interrater agreement for detecting MME was substantial (kappa 0.6) and could be further improved after refining the criteria (kappa 0.8). The clinical spectrum included age-related macular degeneration, epiretinal membranes, postoperative lesions, diabetic retinopathy, vascular occlusion, MS (with/without optic neuritis), optic neuropathy, central serous chorioretinopathy, medication, and miscellaneous causes. The longitudinal pattern of MME was transient (84%) or static. Microcystic macular edema could be associated with an increase or decrease in INL thickness and was predominantly located nasally (48%) and/or temporally (50%). This study substantially widened the clinical spectrum of MME. Diagnostic criteria were refined and validated. The associated phenotype may imply Müller cell dysfunction within the watershed zone. The longitudinal data and evidence from previous studies suggest follow-up of these patients and their visual function.


Utility of dermoscopy in alopecia areata.
Alopecia areata (AA) shows several well-defined dermoscopic features which may help in confirming diagnosis in AA. We carried out a study to examine the dermoscopic features of AA and develop a protocol for diagnosis of AA by dermoscopy. Dermoscopy was performed in 66 patients with AA. Hanse HVS-500NP dermoscope (magnification of ×32 and ×140) was used. The mean age of the patients (46 males and 20 females) was 26.85 years. The mean age of onset was 25.15 years. The mean duration of alopecia was 10.3 months. Most common AA in our study was patchy type (57/66, 87.7%). Single patch was seen in 24 patients and multiple patches in 33 patients. Diffuse AA was seen in five patients. Ophiasis and alopecia universalis were seen in two patients each. Nail changes were fine pitting (4), ridging (2), thinning of nail plate (2). Twenty nail dystrophy, distal onycholysis, striate leukonychia and coarse pitting were seen in one patient each. Intralesional triamcinolone acetonide was the most common therapy offered. Others were oral betamethasone minipulse therapy, dexamethasone pulse, minoxidil, anthralin and corticosteroids. The most common dermoscopic finding was yellow dots seen in 54 patients (81.8%), followed by black dots (44 patients, 66.6%), broken hairs (36 patients, 55.4%), short vellus hair (27 patients, 40.9%) and tapering hairs (8 patients, 12.1%). The most common dermoscopic finding of AA in our study was yellow dots, followed by black dots, broken hairs, short vellus hair and tapering hairs. Dermoscopic findings were not affected by the type of AA or the severity of the disease.


Application of indium tin oxide (ITO)-based microheater chip with uniform thermal distribution for perfusion cell culture outside a cell incubator.
This study reports a transparent indium tin oxide (ITO)-based microheater chip and its applicability for perfusion cell culture outside a cell incubator. The attempt of the proposed ITO microheater is to take the role of conventional bulky incubator for cell culture in order to improve integratability with the experimental setup for continuous/perfusion cell culture, to facilitate microscopic observation or other online monitoring activities during cell culture, or even to provide portability of cell culture operation. In this work, numerical simulation and experimental evaluation have been conducted to justify that the presented device is capable of providing a spatially uniform thermal environment and precise temperature control with a mild deviation of +/-0.2 degrees C, which is suitable for a general cell culture practice. Besides, to testify that the thermal environment generated by the presented device is well compatible with conventional cell incubator, chondrocyte perfusion culture was carried out. Results demonstrated that the physiology of the cultured chondrocytes on the developed ITO microheater chip was consistent with that of an incubator. All these not only demonstrate the feasibility of using the presented ITO microheater as a thermal control system for cell culture outside a cell incubator but also reveal its potential for other applications in which excellent thermal control is required.


Cytosolic accumulation of HSP60 during apoptosis with or without apparent mitochondrial release: evidence that its pro-apoptotic or pro-survival functions involve differential interactions with caspase-3.
Most heat shock proteins (HSPs) have pro-survival functions. However, the role of HSP60, a mitochondrial matrix protein, is somewhat controversial with both pro-survival and pro-apoptotic functions reported. Here we show that in numerous apoptotic systems HSP60 protein accumulates in the cytosol. In BMD188-induced cell death, HSP60 accumulates in the cytosol with significant mitochondrial release. In contrast, in apoptosis induced by multiple other inducers, the cytosolic HSP60 accumulates without an apparent mitochondrial release. The short interfering RNA-mediated knockdown experiments revealed that in BMD188-induced apoptosis, HSP60 has a pro-death function and that the pro-death role of HSP60 seems to involve caspase-3 maturation and activation in the cytosol. In contrast, HSP60 appears to play a pro-survival role in other apoptotic systems where there is no apparent mitochondrial release as its knockdown promotes cell death. In these latter apoptotic systems HSP60 does not associate with active caspase-3. In both cases, HSP60 does not appreciably interact with Bax. Taken together, our results suggest the following: 1) cytosolic accumulation of HSP60 represents a common phenomenon during apoptosis induction; 2) cytosolic HSP60 accumulation during apoptosis occurs either with or without apparent mitochondrial release; and 3) the cytosolically accumulated HSP60 possesses either pro-survival or pro-death functions, which involves differential interactions with caspase-3.


Artificial Saliva Formulations versus Human Saliva Pretreatment in Dental Erosion Experiments.
The aim of this study was to evaluate the erosion-preventive effect of different artificial saliva formulations and human saliva in vitro compared to human saliva in situ. In the in vitro experiment, bovine enamel and dentin specimens were stored in artificial saliva (4 different formulations, each n = 20), deionized water (n = 20) or human saliva (n = 6 enamel and dentin specimens/volunteer) for 120 min. In the in situ experiment, each of the 6 enamel and dentin specimens was worn intraorally by 10 volunteers for 120 min. The specimens were then eroded (HCl, pH 2.6, 60 s). Half of the specimens were subjected to microhardness analysis (enamel) and the determination of calcium release into the acid (enamel and dentin), while the other half were again placed in the respective medium or worn intraorally, respectively, for 120 min before a second erosion was performed. Knoop microhardness of enamel and the calcium release of enamel and dentin into the acid were again determined. Statistical analysis was conducted by two-way repeated-measures ANOVA or two-way ANOVA (α = 0.05). Enamel microhardness was not significantly different between all test groups after the first and the second erosive challenge, respectively. Enamel calcium loss was significantly lower in situ compared to the in vitro experiment, where there was no significant difference between all test groups. Dentin calcium loss was significantly lower than deionized water only after the first and than all except one artificial saliva after the second erosion. Under the conditions of this experiment, the use of artificial saliva formulations and human saliva in vitro does not reflect the intraoral situation in dental erosion experiments adequately.


Depth perception from image defocus in a jumping spider.
The principal eyes of jumping spiders have a unique retina with four tiered photoreceptor layers, on each of which light of different wavelengths is focused by a lens with appreciable chromatic aberration. We found that all photoreceptors in both the deepest and second-deepest layers contain a green-sensitive visual pigment, although green light is only focused on the deepest layer. This mismatch indicates that the second-deepest layer always receives defocused images, which contain depth information of the scene in optical theory. Behavioral experiments revealed that depth perception in the spider was affected by the wavelength of the illuminating light, which affects the amount of defocus in the images resulting from chromatic aberration. Therefore, we propose a depth perception mechanism based on how much the retinal image is defocused.


Honokiol Inhibits DNA Polymerases β and λ and Increases Bleomycin Sensitivity of Human Cancer Cells.
A major concept to sensitize cancer cells to DNA damaging agents is by inhibiting proteins in the DNA repair pathways. X-family DNA polymerases play critical roles in both base excision repair (BER) and nonhomologous end joining (NHEJ). In this study, we examined the effectiveness of honokiol to inhibit human DNA polymerase β (pol β), which is involved in BER, and DNA polymerase λ (pol λ), which is involved in NHEJ. Kinetic analysis with purified polymerases showed that honokiol inhibited DNA polymerase activity. The inhibition mode for the polymerases was a mixed-function noncompetitive inhibition with respect to the substrate, dCTP. The X-family polymerases, pol β and pol λ, were slightly more sensitive to inhibition by honokiol based on the Ki value of 4.0 μM for pol β, and 8.3 μM for pol λ, while the Ki values for pol η and Kf were 20 and 26 μM, respectively. Next we extended our studies to determine the effect of honokiol on the cytotoxicity of bleomycin and temozolomide in human cancer cell lines A549, MCF7, PANC-1, UACC903, and normal blood lymphocytes (GM12878). Bleomycin causes both single strand DNA damage that is repaired by BER and double strand breaks that are repaired by NHEJ, while temozolomide causes methylation damage repaired by BER and O6-alkylguanine-DNA alkyltransferase. The greatest effects were found with the honokiol and bleomycin combination in MCF7, PANC-1, and UACC903 cells, in which the EC50 values were decreased 10-fold. The temozolomide and honokiol combination was less effective; the EC50 values decreased three-fold due to the combination. It is hypothesized that the greater effect of honokiol on bleomycin is due to inhibition of the repair of the single strand and double strand damage. The synergistic activity shown by the combination of bleomycin and honokiol suggests that they can be used as combination therapy for treatment of cancer, which will decrease the therapeutic dosage and side effects of bleomycin.


Informal education of medical doctors on the Internet.
Physicians achieve parts of their knowledge informally on the Internet. In a first study we analyzed the quality of online content of prenatal screening and diagnosis on elements like Wikipedia, Twitter or YouTube. Furthermore, own content was published on blogs, forums and static pages, and visitor's data was measured. The second study consists of three surveys among physicians: Doctors use public pages like blogs or Wikipedia rather than professional or scientific communities and talk about patients via mailing lists or direct messages.


Asymmetry, connectivity, and segmentation of the arcuate fascicle in the human brain.
The structure and function of the arcuate fascicle is still controversial. The goal of this study was to investigate the asymmetry, connectivity, and segmentation patterns of the arcuate fascicle. We employed diffusion spectrum imaging reconstructed by generalized q-sampling and we applied both a subject-specific approach (10 subjects) and a template approach (q-space diffeomorphic reconstruction of 30 subjects). We complemented our imaging investigation with fiber microdissection of five post-mortem human brains. Our results confirmed the highly leftward asymmetry of the arcuate fascicle. In the template, the left arcuate had a volume twice as large as the right one, and the left superior temporal gyrus provided five times more volume of fibers than its counterpart. We identified four cortical frontal areas of termination: pars opercularis, pars triangularis, ventral precentral gyrus, and caudal middle frontal gyrus. We found clear asymmetry of the frontal terminations at pars opercularis and ventral precentral gyrus. The analysis of patterns of connectivity revealed the existence of a strong structural segmentation in the left arcuate, but not in the right one. The left arcuate fascicle is formed by an inner or ventral pathway, which interconnects pars opercularis with superior and rostral middle temporal gyri; and an outer or dorsal pathway, which interconnects ventral precentral and caudal middle frontal gyri with caudal middle and inferior temporal gyri. The fiber microdissection results provided further support to our tractography studies. We propose the existence of primary and supplementary language pathways within the dominant arcuate fascicle with potentially distinct functional and lesional features.


Detection of Circulating Tumor DNA in Patients With Leiomyosarcoma With Progressive Disease.
Leiomyosarcoma (LMS) is a soft tissue sarcoma characterized by multiple copy number alterations (CNAs) and without common recurrent single nucleotide variants. We evaluated the feasibility of detecting circulating tumor DNA (ctDNA) with next-generation sequencing in a cohort of patients with LMS whose tumor burden ranged from no evidence of disease to metastatic progressive disease. Cell-free DNA in plasma samples and paired genomic DNA from resected tumors were evaluated from patients with LMS by ultra-low passage whole genome sequencing (ULP-WGS). Sequencing reads were aligned to the human genome and CNAs identified in cell-free DNA and tumor DNA by ichorCNA software to determine the presence of ctDNA. Clinical data were reviewed to assess disease burden and clinicopathologic features. We identified LMS ctDNA in eleven of sixteen patients (69%) with disease progression and total tumor burden over 5 cm. Sixteen patients with stable disease or low disease burden at the time of blood draw were found to have no detectable ctDNA. Higher ctDNA fraction of total cell-free DNA was associated with increasing tumor size and disease progression. Conserved CNAs were found between primary tumors and ctDNA in each case, and recurrent CNAs were found across LMS samples. ctDNA levels declined following resection of progressive disease in one case and became detectable upon disease relapse in another individual patient. These results suggest that ctDNA, assayed by a widely available sequencing approach, may be useful as a biomarker for a subset of uterine and extrauterine LMS. Higher levels of ctDNA correlate with tumor size and disease progression. Liquid biopsies may assist in guiding treatment decisions, monitoring response to systemic therapy, surveying for disease recurrence and differentiating benign and malignant smooth muscle tumors.


Oral health behaviours according to demographic characteristics in Korean adolescents: a national representative sample.
To provide information on how to teach correct oral health behaviour to youths and to develop programmes to that end, this study examined the oral health behaviour and demographic characteristics of adolescents. The raw data of 'The Third 2007 Youth Health Behavior Online Survey' carried out by the Korea Center for Disease Control and Prevention were analysed. Independent t-test, one-way ANOVA, and chi-squared analyses were used to assess the relationships between oral health behaviours and demographic characteristics. The oral health behaviour of the adolescents who were investigated differed significantly depending on their demographic characteristics (P<0.001). Tooth brushing frequency differed significantly depending on gender and student grade (P<0.001) and the frequency of visits to a dental clinic differed depending on the gender, student grade, type of residential area (urban/rural), and type of school (middle or high) (P<0.001). School grade, type of residential area, and type of school also affected the likelihood of receiving preventive dental treatment (P<0.001). Adolescents who were in lower grades, female, and lived in large urban communities visited dental clinics more frequently and received more preventive dental treatment than adolescents who were in higher grades, male and resided in small urban and rural areas. These results highlight the need for the further development and dissemination of oral health programmes.


Neuronal clearance of amyloid-β by endocytic receptor LRP1.
Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly population. Accumulation, aggregation, and deposition of amyloid-β (Aβ) peptides generated through proteolytic cleavage of amyloid precursor protein (APP) are likely initiating events in the pathogenesis of AD. While Aβ production is accelerated in familial AD, increasing evidence indicates that impaired clearance of Aβ is responsible for late-onset AD. Because Aβ is mainly generated in neurons, these cells are predicted to have the highest risk of encountering Aβ among all cell types in the brain. However, it is still unclear whether they are also involved in Aβ clearance. Here we show that receptor-mediated endocytosis in neurons by the low-density lipoprotein receptor-related protein 1 (LRP1) plays a critical role in brain Aβ clearance. LRP1 is known to be an endocytic receptor for multiple ligands including Aβ. Conditional knock-out of Lrp1 in mouse forebrain neurons leads to increased brain Aβ levels and exacerbated amyloid plaque deposition selectively in the cortex of amyloid model APP/PS1 mice without affecting Aβ production. In vivo microdialysis studies demonstrated that Aβ clearance in brain interstitial fluid is impaired in neuronal Lrp1 knock-out mice. Because the neuronal LRP1-deletion did not affect the mRNA levels of major Aβ degrading enzymes, neprilysin and insulin-degrading enzyme, the disturbed Aβ clearance is likely due to the suppression of LRP1-mediated neuronal Aβ uptake and degradation. Together, our results demonstrate that LRP1 plays an important role in receptor-mediated clearance of Aβ and indicate that neurons not only produce but also clear Aβ.


Studying large-scale programmes to improve patient safety in whole care systems: challenges for research.
Large-scale national and multi-institutional patient safety improvement programmes are being developed in the health care systems of several countries to address problems in the reliability of care delivered to patients. Drawing upon popular collaborative improvement models, these campaigns are ambitious in their aims to improve patient safety in macro-level systems such as whole health care organisations. This article considers the methodological issues involved in conducting research and evaluation of these programmes. Several specific research challenges are outlined, which result from the complexity of longitudinal, multi-level intervention programmes and the variable, highly sociotechnical care systems, with which they interact. Organisational-level improvement programmes are often underspecified due to local variations in context and organisational readiness for improvement work. The result is variable implementation patterns and local adaptations. Programme effects span levels and other boundaries within a system, vary dynamically or are cumulative over time and are problematic to understand in terms of cause and effect, where concurrent external influences exist and the impact upon study endpoints may be mediated by a range of organisational and social factors. We outline the methodological approach to research in the United Kingdom Safer Patients Initiative, to exemplify how some of the challenges for research in this area can be met through a multi-method, longitudinal research design. Specifically, effective research designs must be sensitive to complex variation, through employing multiple qualitative and quantitative measures, collect data over time to understand change and utilise descriptive techniques to capture specific interactions between programme and context for implementation. When considering the long-term, sustained impact of an improvement programme, researchers must consider how to define and measure the capability for continuous safe and reliable care as a property of the whole care system. This requires a sociotechnical approach, rather than focusing upon one microsystem, disciplinary perspective or single level of the system.


Effects of pentoxifylline on the adherence of polymorphonuclear neutrophils to oxidant-stimulated human endothelial cells: involvement of cyclic AMP.
Cultured human umbilical vein endothelial cells (HUVECs) treated with reactive oxygen species (ROS) show increased adherence of polymorphonuclear leukocytes (PMNs). Because pentoxifylline (PTX) is known to inhibit cell interactions, we studied PMN adherence to ROS-stimulated HUVECs pretreated with PTX. ROS were generated by the oxidation of hypoxanthine by xanthine oxidase, giving rise to superoxide anion and hydrogen peroxide. Human PMNs were then added to HUVEC monolayers. After various times, the cultures were washed and the number of adherent PMNs was estimated by measuring myeloperoxidase in the total cell homogenate. PTX inhibited adherence in a concentration-dependent manner. Moreover, the increase in intracellular cAMP content varied with the PTX concentration. Isobutylmethylxanthine (IBMX) and isoproterenol (ISO) which increase intracellular cAMP content, also inhibited the adherence of PMNs to ROS-stimulated HUVECs. We conclude that cAMP is probably involved in the intracellular regulation of ROS-mediated PMN adherence to endothelial cells.


Polycystin-2 expression is regulated by a PC2-binding domain in the intracellular portion of fibrocystin.
Autosomal dominant (ADPKD) and autosomal recessive (ARPKD) polycystic kidney disease are caused by mutations in Pkd1/Pkd2 and Pkhd1, which encode polycystins (PCs) and fibrocystin/polyductin (FPC). Our recent study reported that a deficiency in FPC increases the severity of cystic disease in Pkd2 mutants and down-regulates PC2 in vivo, but the precise molecular mechanism of these effects is unknown (Kim, I., Fu, Y., Hui, K., Moeckel, G., Mai, W., Li, C., Liang, D., Zhao, P., Ma, J., Chen, X.-Z., George, A. L., Jr., Coffey, R. J., Feng, Z. P., and Wu, G. (2008) J. Am. Soc. Nephrol. 19, 455-468). In this study, through the use of deletion and mutagenesis strategies, we identified a PC2-binding domain in the intracellular C terminus of FPC and an FPC-binding domain in the intracellular N terminus of PC2. These binding domains provide a molecular basis for the physical interaction between PC2 and FPC. In addition, we also found that physical interaction between the binding domains of PC2 and FPC is able to prevent down-regulation of PC2 induced by loss of FPC. In vivo, we generated a mouse model of ADPKD with hypomorphic Pkd2 alleles (Pkd2nf3/nf3) and show that PC2 down-regulation is accompanied by a phenotype similar to that of Pkhd1(-/-) mice. These findings demonstrate a common mechanism underlying cystogenesis in ADPKD and ARPKD and provide insight into the molecular relationship between PC2 and FPC.


Growing well-beings: The positive experience of care farms.
Care farms enable people who are in some way vulnerable to engage with agricultural places and farming activities. This study investigates how this impacts on the health and well-being of service users and explores associated processes and outcomes. A mixed methods design was adopted that allowed for the integration of quantitative measurements of change with qualitative descriptions of this change. A pragmatic approach provided sufficient flexibility to support the investigation of complex contexts. A total of 216 service users completed an initial questionnaire, and 137 (63%) of this number provided comparative data in a follow-up questionnaire. Questionnaires contained multiple choice and open-ended questions alongside standardized health and well-being measures requiring Likert-format responses. Semi-structured interviews with 33 service users allowed personal experiences to be detailed. Statistical analysis of well-being measure scores identified significant positive relationships with the length of time people had been attending the care farm. Questionnaire and interview data presented health benefits as being enabled by the farm environment, the positive experience as supporting personal development, and associated social interactions as becoming increasingly influential as time progressed. The health and well-being outcomes that result from participating at a care farm influence multiple elements of the human condition and apply amongst vulnerable people with a wide range of personal needs. Care farms have access to a potentially unique range of resources that can support many service users in becoming happier and healthier individuals. Statement of contribution What is already known on this subject? Care farming is increasingly practised and is suggested to support the health and well-being of people who are in some way vulnerable. Care farms utilize agricultural spaces and activities to provide benefits that are presented as having relevance to public health and social inclusion agendas. What does this study add? This is the first longitudinal study to include participants with such differing personal needs. Associated outcomes are explored to provide an understanding of how they impact on health. People and place are found to be mutually supportive in facilitating positive change.


Convergent acoustic field of view in echolocating bats.
Most echolocating bats exhibit a strong correlation between body size and the frequency of maximum energy in their echolocation calls (peak frequency), with smaller species using signals of higher frequency than larger ones. Size-signal allometry or acoustic detection constraints imposed on wavelength by preferred prey size have been used to explain this relationship. Here we propose the hypothesis that smaller bats emit higher frequencies to achieve directional sonar beams, and that variable beam width is critical for bats. Shorter wavelengths relative to the size of the emitter translate into more directional sound beams. Therefore, bats that emit their calls through their mouths should show a relationship between mouth size and wavelength, driving smaller bats to signals of higher frequency. We found that in a flight room mimicking a closed habitat, six aerial hawking vespertilionid species (ranging in size from 4 to 21 g, ref. 5) produced sonar beams of extraordinarily similar shape and volume. Each species had a directivity index of 11 ± 1 dB (a half-amplitude angle of approximately 37°) and an on-axis sound level of 108 ± 4 dB sound pressure level referenced to 20 μPa root mean square at 10 cm. Thus all bats adapted their calls to achieve similar acoustic fields of view. We propose that the necessity for high directionality has been a key constraint on the evolution of echolocation, which explains the relationship between bat size and echolocation call frequency. Our results suggest that echolocation is a dynamic system that allows different species, regardless of their body size, to converge on optimal fields of view in response to habitat and task.


A novel therapeutic approach with Caviunin-based isoflavonoid that en routes bone marrow cells to bone formation via BMP2/Wnt-β-catenin signaling.
Recently, we reported that extract of Dalbergia sissoo made from leaves and pods have antiresorptive and bone-forming effects. The positive skeletal effect attributed because of active molecules present in the extract of Dalbergia sissoo. Caviunin 7-O-[β-D-apiofuranosyl-(1-6)-β-D-glucopyranoside] (CAFG), a novel isoflavonoid show higher percentage present in the extract. Here, we show the osteogenic potential of CAFG as an alternative for anabolic therapy for the treatment of osteoporosis by stimulating bone morphogenetic protein 2 (BMP2) and Wnt/β-catenin mechanism. CAFG supplementation improved trabecular micro-architecture of the long bones, increased biomechanical strength parameters of the vertebra and femur and decreased bone turnover markers better than genistein. Oral administration of CAFG to osteopenic ovariectomized mice increased osteoprogenitor cells in the bone marrow and increased the expression of osteogenic genes in femur and show new bone formation without uterine hyperplasia. CAFG increased mRNA expression of osteoprotegerin in bone and inhibited osteoclast activation by inhibiting the expression of skeletal osteoclastogenic genes. CAFG is also an effective accelerant for chondrogenesis and has stimulatory effect on the repair of cortical bone after drill-hole injury at the tissue, cell and gene level in mouse femur. At cellular levels, CAFG stimulated osteoblast proliferation, survival and differentiation. Signal transduction inhibitors in osteoblast demonstrated involvement of p-38 mitogen-activated protein kinase pathway stimulated by BMP2 to initiate Wnt/β-catenin signaling to reduce phosphorylation of GSK3-β and subsequent nuclear accumulation of β-catenin. Osteogenic effects were abrogated by Dkk1, Wnt-receptor blocker and FH535, inhibitor of TCF-complex by reduction in β-catenin levels. CAFG modulated MSC responsiveness to BMP2, which promoted osteoblast differentiation via Wnt/β-catenin mechanism. CAFG at 1 mg/kg(/)day dose in ovariectomy mice (human dose ∼0.081 mg/kg) led to enhanced bone formation, reduced bone resorption and bone turnover better than well-known phytoestrogen genistein. Owing to CAFG's inherent properties for bone, it could be positioned as a potential drug, food supplement, for postmenopausal osteoporosis and fracture repair.


Chemotherapy rescues tumor-driven aberrant CD4+ T-cell differentiation and restores an activated polyfunctional helper phenotype.
The functional development of tumor-specific CD4(+) T cells has a critical impact on the outcome of antitumor immune responses. Adoptive immunotherapy involving tumor-specific CD4(+) T cells has shown encouraging clinical benefits in some cancer patients. To mount an effective antitumor immunity, it is desirable to elicit activated type 1 T helper cells. Here, we report that type 1 T helper cell-like effector cells that arose in tumor-bearing hosts progressively expressed programmed death 1 during tumor growth. The programmed death 1(hi) effector cells displayed a dysfunctional phenotype, characterized by selective down-regulation of interleukin-7 receptor, heightened apoptosis, and poor antitumor efficacy. This tumor-driven aberrant T-cell response could be prevented by a single dose of the widely used chemotherapy agent cyclophosphamide. We show that chemotherapy conditioned the host environment, creating a transient window for optimal effector differentiation for adoptively transferred CD4(+) T cells. This robust effector differentiation, which was antigen-driven and mechanistically dependent on an intact host response to type I interferon, gave rise to activated polyfunctional T helper cells with high interleukin-7 receptor, rapid clonal expansion, and potent antitumor activity against established B-cell lymphomas. We hypothesize that prevention of tumor-induced effector cell dysfunction is a major mechanism contributing to the efficacy of combined chemoimmunotherapy.


Theoretical models for electrochemical impedance spectroscopy and local ζ-potential of unfolded proteins in nanopores.
Single solid-state nanopores find increasing use for electrical detection and/or manipulation of macromolecules. These applications exploit the changes in signals due to the geometry and electrical properties of the molecular species found within the nanopore. The sensitivity and resolution of such measurements are also influenced by the geometric and electrical properties of the nanopore. This paper continues the development of an analytical theory to predict the electrochemical impedance spectra of nanopores by including the influence of the presence of an unfolded protein using the variable topology finite Warburg impedance model previously published by the authors. The local excluded volume of, and charges present on, the segment of protein sampled by the nanopore are shown to influence the shape and peak frequency of the electrochemical impedance spectrum. An analytical theory is used to relate the capacitive response of the electrical double layer at the surface of the protein to both the charge density at the protein surface and the more commonly measured zeta potential. Illustrative examples show how the theory predicts that the varying sequential regions of surface charge density and excluded volume dictated by the protein primary structure may allow for an impedance-based approach to identifying unfolded proteins.


Homocysteine and blood pressure.
Several studies, some population-based, have linked plasma homocysteine levels to blood pressure, especially systolic pressure. The strength of this association is weak, but may be underestimated due to inaccurate blood pressure measurements. In addition, the association may be confounded by renal function. Observations that homocysteine-lowering therapies with folic acid-based treatments have been followed by decreases in blood pressure, however, raise the possibility that the link between homocysteine and blood pressure is real, which is important as homocysteine levels can easily be lowered by folic acid-based regimens. Mechanisms that could explain the relationship between homocysteine and blood pressure include increased arterial stiffness, endothelial dysfunction with decreased availability of nitric oxide, low folate status, and insulin resistance. So far, however, no evidence has been provided that these mechanisms are operative in humans. Ongoing large intervention studies with homocysteine-lowering vitamins may indicate whether blood pressure is indeed lowered by these vitamins, whether the blood pressure decrease, if any, is explained by the decrease in homocysteine levels, and whether a vitamin treatment-associated decrease in cardiovascular morbidity (if any) is explained by the decrease in blood pressure.


Prediction of injury by limited and asymmetrical fundamental movement patterns in american football players.
Previous injury is the strongest risk factor for future injury in sports. It has been proposed that motor-control changes such as movement limitation and asymmetry associated with injury and pain may be perpetuated as part of an individual's movement strategy. Motor control of fundamental 1-×-body-weight tasks can reliably and efficiently be measured in the field. To determine whether the motor control of fundamental movement patterns and pattern asymmetry have a relationship with time-loss injury over the course of the preseason in professional football. Injury-risk study. American professional football facilities. 238 American professional football players. To measure the motor control of 1-×-body-weight fundamental movement patterns, Functional Movement Screen scores were obtained before the start of training camp. The previously established cutoff score of ≤14 and the presence of any asymmetries on the FMS were examined using relative risk to determine if a relationship exists with time-loss injury. Time-loss musculoskeletal injury defined as any time loss from practice or competition due to musculoskeletal injury. Players who scored ≤14 exhibited a relative risk of 1.87 (CI95 1.202.96). Similarly, players with at least 1 asymmetry displayed a relative risk of 1.80 (CI95 1.112.74). The combination of scoring below the threshold and exhibiting a movement asymmetry was highly specific for injury, with a specificity of .87 (CI95 .84.90). The results of this study suggest that fundamental movement patterns and pattern asymmetry are identifiable risk factors for time-loss injury during the preseason in professional football players.


Molecular biology of bladder cancer: prognostic and clinical implications.
The role of various molecular determinants involved in the genesis, progression, and outcome of bladder cancer has been the focus of investigations for the past 2 decades. Increasingly, the analysis of the interplay between these molecular factors is taking center stage. We review herein the studies examining the effects of deregulation of the various molecules implicated in the cell cycle, apoptosis, and angiogenesis pathways and analyze the central role of p53 in regulating these pathways. Technological advancements enable detection and quantification of gene transcripts and protein products, helping us move toward achieving the goal of establishing diagnostic, prognostic, and therapeutic marker panels. Recent studies have therefore focused on multiple-marker analyses to generate informative panels that can have greater clinical value for bladder cancer management. The use of molecular marker panels can provide a more objective alternative to clinical parameters for diagnosis and treatment decisions. Clinical trials aimed at treating urothelial carcinoma based on a patient's molecular profile can be predicted to empower clinicians to personalize patient management through increased therapeutic efficacy.


Implantation Metastasis of Synovial Cell Sarcoma: Lessons Learned from a Mistake.
Implantation metastasis occurs when tumor seeds into a wound or tissue by a significant amount of viable tumor cells. Here we describe the case of a 30-year-old man suffering from pain and swelling of the foot, which was misdiagnosed as a bone cyst. Surgery was performed involving curettage followed by bone grafting. After surgical pathology, the exact diagnosis was revealed as the synovial sarcoma (SS) of the foot. Implantation metastasis of SS in the iliac region, the grafting site, occurred 9 months post-surgery. Although there are a few reports on implantation metastasis of other types of tumoral lesions, to the best of our knowledge, we describe seeding of this type of tumor for the first time. Similar to other studies, we recommend that tumor surgeries should be carried out in a special setting to prevent any spread to or contamination of other sites by the tumor.


Endoscopic submucosal dissection of esophageal cancer using the Mucosectom2 device: a feasibility study.
Endoscopic submucosal dissection (ESD) is being increasingly used for superficial esophageal cancers. However, esophageal ESD is technically difficult, time consuming, and less safe compared with endoscopic mucosal resection (EMR). To perform ESD safely and more efficiently, various types of knives have been developed. This study compared the efficacy of our newly developed device, Mucosectom2, with that of conventional devices for esophageal ESD. Between May 2007 and February 2011, ESD was performed for 172 esophageal lesions. Of these, 120 lesions were treated by conventional devices only, whereas 52 lesions were treated by conventional devices and the Mucosectom2. Procedure time, en bloc and R0 resection rates, and adverse events were retrospectively compared between the conventional and Mucosectom2 groups. The median procedure time was 48.0 minutes in the conventional group and 21.5 minutes in the Mucosectom2 group; the procedure time was significantly shorter in the Mucosectom2 group than in the conventional group (P < 0.0001). The en bloc and R0 resection rates were lower in the conventional group than those in the Mucosectom2 group, although these differences were not significant. The rate of exposure of the muscle layer in the Mucosectom2 group was significantly lower than in the conventional group (P = 0.04). The rates of perforation and postoperative bleeding were not significantly different between the two groups. This feasibility study suggests that, compared with conventional ESD devices, the Mucosectom2 may decrease the time required for esophageal ESD. Although our groups appeared comparable, they were studied at different times. Endoscopic expertise and endoscope quality may have differed during these periods, thereby affecting the results of our study. A prospective trial is therefore required to confirm our results.


Large-Scale HLA Tetramer Tracking of T Cells during Dengue Infection Reveals Broad Acute Activation and Differentiation into Two Memory Cell Fates.
T cells play important multifaceted roles during dengue infection, and understanding their responses is important for defining correlates of protective immunity and identifying effective vaccine antigens. Using mass cytometry and a highly multiplexed peptide-HLA (human leukocyte antigen) tetramer staining strategy, we probed T cells from dengue patients-a total of 430 dengue and control candidate epitopes-together with key markers of activation, trafficking, and differentiation. During acute disease, dengue-specific CD8+ T cells expressed a distinct profile of activation and trafficking receptors that distinguished them from non-dengue-specific T cells. During convalescence, dengue-specific T cells differentiated into two major cell fates, CD57+ CD127--resembling terminally differentiated senescent memory cells and CD127+ CD57--resembling proliferation-capable memory cells. Validation in an independent cohort showed that these subsets remained at elevated frequencies up to one year after infection. These analyses aid our understanding of the generation of T cell memory in dengue infection or vaccination.


Redox status and expression of chemokines in the rat lungs on exposure to asbestos and asbestos substituents.
Activity of cytoplasmatic superoxide dismutase, glutathione peroxidase,- and reductase, gamma-glutamyl transpeptidase and expression of macrophage chemoattractant protein-1 and macrophage inhibitory protein-1alpha was determined in primary culture of rat alveolar macrophages and type II pneumocytes after exposure to stone-wool, wollastonite and crocidolite (blue asbestos). The activity of redox enzymes was examined by RANDOX kits, chemokines were studied by ELISA. The UICC crocidolite (positive control) decreased the activity of all redox enzymes and increased the expression of chemokines, whereas the two asbestos substituents did not alter the activity of redox enzymes either in the alveolar macrophages or pneumocytes. Stone-wool and wollastonite moderately increased the expression of chemokines in both cells. The redox status and production of chemokines changed in the opposite direction, presumably owing to stronger toxic effect of asbestos. These data suggest that stone-wool and wollastonite, as potential substituents for asbestos, are less toxic than the human carcinogenic and fibrogenic crocidolite.


Electrocorticographic activity over sensorimotor cortex and motor function in awake behaving rats.
Sensorimotor cortex exerts both short-term and long-term control over the spinal reflex pathways that serve motor behaviors. Better understanding of this control could offer new possibilities for restoring function after central nervous system trauma or disease. We examined the impact of ongoing sensorimotor cortex (SMC) activity on the largely monosynaptic pathway of the H-reflex, the electrical analog of the spinal stretch reflex. In 41 awake adult rats, we measured soleus electromyographic (EMG) activity, the soleus H-reflex, and electrocorticographic activity over the contralateral SMC while rats were producing steady-state soleus EMG activity. Principal component analysis of electrocorticographic frequency spectra before H-reflex elicitation consistently revealed three frequency bands: μβ (5-30 Hz), low γ (γ1; 40-85 Hz), and high γ (γ2; 100-200 Hz). Ongoing (i.e., background) soleus EMG amplitude correlated negatively with μβ power and positively with γ1 power. In contrast, H-reflex size correlated positively with μβ power and negatively with γ1 power, but only when background soleus EMG amplitude was included in the linear model. These results support the hypothesis that increased SMC activation (indicated by decrease in μβ power and/or increase in γ1 power) simultaneously potentiates the H-reflex by exciting spinal motoneurons and suppresses it by decreasing the efficacy of the afferent input. They may help guide the development of new rehabilitation methods and of brain-computer interfaces that use SMC activity as a substitute for lost or impaired motor outputs.


Communication with breast cancer survivors.
Breast cancer survivors must manage chronic side effects of original treatment. To manage these symptoms, communication must include both biomedical and contextual lifestyle factors. Sixty breast cancer survivors and 6 providers were recruited to test a conceptual model developed from uncertainty in illness theory and the dimensions of a patient-centered relationship. Visits were audio-taped, then coded using the Measure of Patient-Centered Communication (Brown, Stewart, & Ryan, 2001). Consultations were found to be 52% patient-centered. Chi-square Automatic Interaction Detection (CHAID) analysis showed that survivor self-reported fatigue level and conversation about symptoms were associated with survivor uncertainty, mood state, and survivor perception of patient-centered communication. Survivors may want to discuss persistent symptom concerns with providers, due to concerns about recurrence, and discuss lifestyle contextual concerns with others.


Identifying candidate genes for 2p15p16.1 microdeletion syndrome using clinical, genomic, and functional analysis.
The 2p15p16.1 microdeletion syndrome has a core phenotype consisting of intellectual disability, microcephaly, hypotonia, delayed growth, common craniofacial features, and digital anomalies. So far, more than 20 cases of 2p15p16.1 microdeletion syndrome have been reported in the literature; however, the size of the deletions and their breakpoints vary, making it difficult to identify the candidate genes. Recent reports pointed to 4 genes (XPO1, USP34, BCL11A, and REL) that were included, alone or in combination, in the smallest deletions causing the syndrome. Here, we describe 8 new patients with the 2p15p16.1 deletion and review all published cases to date. We demonstrate functional deficits for the above 4 candidate genes using patients' lymphoblast cell lines (LCLs) and knockdown of their orthologs in zebrafish. All genes were dosage sensitive on the basis of reduced protein expression in LCLs. In addition, deletion of XPO1, a nuclear exporter, cosegregated with nuclear accumulation of one of its cargo molecules (rpS5) in patients' LCLs. Other pathways associated with these genes (e.g., NF-κB and Wnt signaling as well as the DNA damage response) were not impaired in patients' LCLs. Knockdown of xpo1a, rel, bcl11aa, and bcl11ab resulted in abnormal zebrafish embryonic development including microcephaly, dysmorphic body, hindered growth, and small fins as well as structural brain abnormalities. Our multifaceted analysis strongly implicates XPO1, REL, and BCL11A as candidate genes for 2p15p16.1 microdeletion syndrome.


Income inequality and firearm homicide in the US: a county-level cohort study.
Income inequality has been rising in the US and thought to be associated with violence especially homicide. About 75% of homicides involve firearms. We quantified the association between county-level income inequality and all-race/ethnicity and race/ethnicity-specific firearm homicide rates among individuals aged 14-39 years. We conducted a cohort study of US counties to examine the association of Gini Index (ranging from 0 [perfect income equality] to 1.0 [perfect income inequality]) separately measured in 1990 and 2000 with all-race/ethnicity and race/ethnicity-specific firearm homicide rates in 2005-2015. Generalised linear mixed models with Poisson distribution including a random intercept for state provided IRRs and 95% CIs. Bayesian Poisson-lognormal hierarchical modelling with integrated nested Laplace approximations was used in exploratory spatial analyses. Models accounted for county-level age, sex and race/ethnicity composition, crime rate, deprivation, social capital, urbanicity, and firearm ownership. The Gini Index was associated with firearm homicide rates among all races/ethnicities. After accounting for contextual determinants of firearm homicide, the association persisted among African-Americans. In this group, a 1 SD greater Gini Index in 1990 (IRR=1.09; 95% CI 1.02 to 1.16) and 2000 (IRR=1.09; 95% CI 1.01 to 1.17) was associated with greater firearm homicide rates in 2005-2015. Exploratory spatial analyses did not materially change the results. Policies addressing the gap between the rich and the poor deserve further considerations for reducing firearm homicide rates. Incorporating income inequality to refine measures of socioeconomic position may advance public health and clinical research and practice for firearm violence prevention.


The role of Parafibromin/Hyrax as a nuclear Gli/Ci-interacting protein in Hedgehog target gene control.
The Hedgehog (Hh) pathway, an evolutionarily conserved key regulator of embryonic patterning and tissue homeostasis, controls its target genes by managing the processing and activities of the Gli/Ci transcription factors. Little is known about the nuclear co-factors the Gli/Ci proteins recruit, and how they mechanistically control Hh target genes. Here, we provide evidence for the involvement of Parafibromin/Hyx as a positive component in Hh signaling. We found that hyx RNAi impaired Hh pathway activity in Drosophila cell culture. Consistent with an evolutionarily conserved function in Hh signaling, RNAi-mediated knockdown of Parafibromin in mammalian cell culture experiments diminished the transcriptional activity of Gli1 and Gli2. In vivo, in Drosophila, genetic impairment of hyx decreased the expression of the high-threshold Hh target gene knot/collier. Conversely, hyx overexpression ameliorated the inhibitory activity of Ptc and Ci(75) misexpression during Drosophila wing development. We subsequently found that Parafibromin can form a complex with all three Glis, and provide evidence that Parafibromin/Hyx directly binds Region 1, the Su(fu) interaction domain, in the N-terminus of all Glis and Ci. Taken together, our results suggest a target gene-selective involvement of the PAF1 complex in Hh signaling via the Parafibromin/Hyx-mediated recruitment to Gli/Ci.


[The effects of pharmacological and psychotherapeutic treatment of comorbid anxiety disorders in patients with bipolar disorder].
The co-occurrence of bipolar disorder and anxiety disorder is associated with a worse prognosis. Clinical guidelines do not give clear therapeutic recommendations on this subject.
 AIM: To review the evidence on the effectiveness of both psychotherapy and pharmacotherapy for anxiety disorders in patients with a bipolar disorder.
 METHOD: A systematic search in PubMed, Embase, Cochrane en Psycinfo and subsequent screening of potential studies resulted in 11 included studies.
 RESULTS: Five studies examined the effect of pharmacotherapy on treatment of comorbid anxiety disorders. One of these studies showed that both olanzapine and lamotrigine provided positive results in treating the anxiety disorders, with olanzapine being the more effective of the two. Conflicting results were found for quetiapine and valproic acid. The conclusion of one study was that risperidone was not effective. No studies were found researching the effect of psychotherapy on treatment of comorbid anxiety disorders. However, two case studies and four studies that included patients with mixed diagnoses, including bipolar disorder, proposed evidence that behavioral and cognitive behavioral therapy (cbt) had a positive effect on treatment of the comorbid anxiety disorder.
 CONCLUSION: There is little evidence on the treatment of comorbid anxiety disorders in people with bipolar disorder. Psychotherapy is preferred due to the uncertainty of the effects of pharmacotherapy and the associated risk of causing side effects. Pharmacotherapy can be considered in cases where this is insufficiently effective.


Integrating remote sensing methods during controlled exposure experiments to quantify group responses of dolphins to navy sonar.
Human noise can be harmful to sound-centric marine mammals. Significant research has focused on characterizing behavioral responses of protected cetacean species to navy mid-frequency active sonar (MFAS). Controlled exposure experiments (CEE) using animal-borne tags have proved valuable, but smaller dolphins are not amenable to tagging and groups of interacting individuals are more relevant behavioral units for these social species. To fill key data gaps on group responses of social delphinids that are exposed to navy MFAS in large numbers, we describe novel approaches for the coordinated collection and integrated analysis of multiple remotely-sensed datasets during CEEs. This involves real-time coordination of a sonar source, shore-based group tracking, aerial photogrammetry to measure fine-scale movements and passive acoustics to quantify vocal activity. Using an example CEE involving long-beaked common dolphins (Delphinus delphis bairdii), we demonstrate how resultant quantitative metrics can be used to estimate behavioral changes and noise exposure-response relationships.


Influence of nursing staff characteristics on seclusion in acute mental health care-A prospective two-year follow-up study.
Seclusion still occurs on mental health wards, despite absence of therapeutic efficacy and high risks of adverse patient effects. Literature on the effect of nursing teams, and the role of psychological characteristics in particular, on frequency of seclusion is scarce. To explore the influence of demographic, professional or psychological, nursing team-level, and shift characteristics on the frequency of use of seclusion. Prospective two-year follow-up study. We found that the probability of seclusion was lower when nursing teams with at least 75% males were on duty, compared to female only teams, odds ratio (OR = 0.283; 95% CrI 0.046-0.811). We observed a trend indicating that teams scoring higher on the openness personality dimension secluded less, (OR = 0.636; 95% CrI 0.292-1.156). Higher proportions of male nurses in teams on duty were associated with lower likelihood of seclusion. We found an indication that teams with a higher mean openness personality trait tended to seclude less. These findings, if causal, could serve as an incentive to reflect on staff mix if circumstances demand better prevention of seclusion.


Chiropractic treatment for gastrointestinal problems: a systematic review of clinical trials.
Many chiropractors believe that chiropractic treatments are effective for gastrointestinal disorders. The aim of the present systematic review was to critically evaluate the evidence from controlled clinical trials supporting or not supporting this notion. Six electronic databases were searched for relevant studies. No limits were applied to language or publication date. Prospective, controlled, clinical trials of any type of chiropractic treatment for any type of gastrointestinal problem, except infant colic, were included. Only two trials were found--one was a pilot study, and the other had reached a positive conclusion; however, both had serious methodological flaws. There is no supportive evidence that chiropractic is an effective treatment for gastrointestinal disorders.


Mitigation of ROS insults by Streptomyces secondary metabolites in primary cortical neurons.
Oxidative stress is a common point in neurodegenerative diseases, widely connected with mitochondrial dysfunction. In this study, we screened seven natural products from Streptomyces sources against hydrogen peroxide insult in primary cortical neurons, an oxidative stress in vitro model. We showed the ability of these compounds to inhibit neuronal cytotoxicity and to reduce ROS release after 12 h treatment. Among the tested compounds, the quinone anhydroexfoliamycin and the red pyrrole-type pigment undecylprodigiosin stand out. These two compounds displayed the most complete protection against oxidative stress with mitochondrial function improvement, ROS production inhibition, and increase of antioxidant enzyme levels, glutathione and catalase. Further investigations confirmed that anhydroexfoliamycin acts over the Nrf2-ARE pathway, as a Nrf2 nuclear translocation inductor, and is able to strongly inhibit the effect of the mitochondrial uncoupler FCCP over cytosolic Ca(2+), pointing to mitochondria as a cellular target for this molecule. In addition, both compounds were able to reduce caspase-3 activity induced by the apoptotic enhancer staurosporine, but undecylprodigiosin failed to inhibit FCCP effects and it did not act over the Nrf2 pathway as was the case for anhydroexfoliamycin. These results show that Streptomyces metabolites could be useful for the development of new drugs for prevention of neurodegenerative disorders such as Parkinson's and Alzheimer's diseases and cerebral ischemia.


Structural, Electronic and Vibrational Properties of YAl3(BO3)4.
The crystal structure of YAl3(BO3)4 is obtained by Rietveld refinement analysis in the present study. The dynamical properties are studied both theoretically and experimentally. The experimental Raman and Infrared spectra are interpreted using the results of ab initio calculations within density functional theory. The phonon band gap in the Infrared spectrum is observed in both trigonal and hypothetical monoclinic structures of YAl3(BO3)4. The electronic band structure is studied theoretically, and the value of the band gap is obtained. It was found that the YAl3(BO3)4 is an indirect band gap dielectric material.


Modulation of human immune responses by bovine interleukin-10.
Cytokines can be functionally active across species barriers. Bovine IL-10 has an amino acid sequence identity with human IL-10 of 76.8%. Therefore, the aim of this study was to evaluate whether bovine IL-10 has immunomodulatory activities on human monocytes and dendritic cells. Peripheral blood monocytes were isolated from healthy donors, and used directly or allowed to differentiate to dendritic cells under the influence of IL-4 and GM-CSF. Recombinant bovine IL-10 inhibited TLR induced activation of monocytes, and dose-dependently inhibited LPS-induced activation of monocyte-derived DCs comparable to human IL-10. By using blocking antibodies to either bovine IL-10 or the human IL-10 receptor it was demonstrated that inhibition of monocyte activation by bovine IL-10 was dependent on binding of bovine IL-10 to the human IL-10R. These data demonstrate that bovine IL-10 potently inhibits the activation of human myeloid cells in response to TLR activation. Bovine IL-10 present in dairy products may thus potentially contribute to the prevention of necrotizing enterocolitis and allergy, enhance mucosal tolerance induction and decrease intestinal inflammation and may therefore be applicable in infant foods and in immunomodulatory diets.


Watch your step! A frustrated total internal reflection approach to forensic footwear imaging.
Forensic image retrieval and processing are vital tools in the fight against crime e.g. during fingerprint capture. However, despite recent advances in machine vision technology and image processing techniques (and contrary to the claims of popular fiction) forensic image retrieval is still widely being performed using outdated practices involving inkpads and paper. Ongoing changes in government policy, increasing crime rates and the reduction of forensic service budgets increasingly require that evidence be gathered and processed more rapidly and efficiently. A consequence of this is that new, low-cost imaging technologies are required to simultaneously increase the quality and throughput of the processing of evidence. This is particularly true in the burgeoning field of forensic footwear analysis, where images of shoe prints are being used to link individuals to crime scenes. Here we describe one such approach based upon frustrated total internal reflection imaging that can be used to acquire images of regions where shoes contact rigid surfaces.


The expanded scope of emergency medical practice necessary for initial disaster response: lessons from Haiti.
A team of emergency physicians and nurses from Stanford University responded to the devastating January 2010 earthquake in Haiti. Because of the extreme nature of the situation, combined with limited resources, the team provided not only acute medical and surgical care to critically injured and ill victims, but was required to uniquely expand its scope of practice. Using a narrative format and discussion, it is the purpose of this paper to highlight our experience in Haiti and use these to estimate some of the skills and capabilities that will be useful for physicians who respond to similar future disasters.


A facile signal-on electrochemical DNA sensing platform for ultrasensitive detection of pathogenic bacteria based on Exo III-assisted autonomous multiple-cycle amplification.
A facile signal-on electrochemical DNA biosensor has been developed for ultrasensitive detection of pathogenic bacteria using an Exo III-assisted autonomous multiple-cycle amplification strategy. The strategy relies on pathogens and aptamer binding-initiated release of a trigger, which combines with the 3'-protruding terminus of the hairpin probe 1, leading to the formation of double-stranded DNA with a blunt 3' terminus which starts the Exo III-assisted multiple signal amplification reaction. In addition, hairpin probe 2 labeled with an electroactive reporter at the middle of the loop region is ingeniously designed to contain a short hairpin-embedded segment, which can fold into a hairpin structure via an Exo III-assisted cleavage reaction, thus bringing the redox molecule in proximity to the electrode surface for "signal-on" sensing. Under optimal conditions, this biosensor exhibits a very low detection limit as low as 8 cfu mL-1 and a wide linear range from 1.0 × 101 to 1.0 × 107 cfu mL-1 of target pathogenic bacteria. As far as we know, this is the first time that the Exo III-assisted autonomous multiple-cycle amplification strategy has been used for signal-on electrochemical sensing of pathogenic bacteria. In addition, the proposed sensor can also be used for highly sensitive detection of other targets by changing the aptamer sequence, such as nucleic acids, proteins and small molecules. Therefore, the proposed signal-on electrochemical sensing strategy might provide a simple and practical new platform for detection of pathogenic bacteria and related biological analysis, food safety inspection and environmental monitoring.


A user profile ontology based approach for assisting people with dementia in mobile environments.
Personalization and context-aware applications have attracted increasing amounts of attention over recent years due to the emergence of pervasive computing applications. Nevertheless, it still remains a challenge to meet the needs of users while they are on the move. This paper introduces a novel approach for providing personalized, context-aware assistance services for users in mobile environments. Central to the approach is the use of ontological user profile modeling which captures various characteristics of a user in order to create a unique set of profile information. In addition, user profiles can adapt to changing user behavior, thus enabling services to respond to evolving user needs and preferences. We describe the overall system architecture of the proposed approach with special emphasis being placed on the user profile modelling and its expected utility based on a typical use case scenario, i.e., using a smart-phone to address the problem of the outdoor mobility of a person with Dementia. A prototype based on the Android OS is used to illustrate the application. The use of everyday technology for a real world problem highlights the potential and utility of our approach.


Profit, payment and pharmaceutical practices: perspectives from hospitals in Bangkok.
Means by which to improve the quality of care offered in the private sector have received increasing interest. This paper considers the influences upon hospital physician prescribing practices. It presents data on drug management practices and prescribing patterns in a sample of private for-profit, private non-profit and public hospitals in Bangkok. Clear differences emerge in prescription patterns between the different groups of hospitals: public hospitals exhibit greater use of essential drugs and generic prescribing than either group of private hospital, and prescriptions at private for-profit hospitals tended to have more essential drugs and drugs prescribed by generic name than non-profit hospitals. Prescribing patterns in public hospitals are probably largely explained by national government policy on pharmaceutical procurement. In contrast, prescribing patterns in private for-profit hospitals appear heavily influenced by pressure upon management to contain costs, in circumstances where high drug costs cannot be passed on to purchasers. Hence hospital management have developed policies encouraging the use of generic drugs and essential drugs. These same financial pressures also explain some less desirable forms of behaviour in private for-profit hospitals such as prescribing courses of antibiotic treatment of extremely short duration. Possible measures which government may take to encourage appropriate prescribing within private hospitals are discussed.


[Radiotherapy for outpatients].
Radiotherapy can be done on an outpatient basis depending on the patient's cancer stage, radiation method, concurrent therapy, treatment purpose and general condition. Daily treatment time takes only about 1 minute, but the patient has to come 5 times a week for about 6 weeks for radical treatment and about 3 weeks for palliative treatment. If treated with radiotherapy alone, most patients suffer no severe adverse effects in their daily life. Therefore, radiotherapy can be done on an outpatient basis only if the patient is able to come frequently to the clinic for several weeks. Breast cancer patients commonly undergo radiotherapy in the outpatient clinic, such as breast conserving therapy, postoperative therapy and radiotherapy for local recurrence after mastectomy. Prostate cancer is also commonly treated with radical radiotherapy, postoperative therapy and radiotherapy for local recurrence after prostatectomy. Usually, postoperative irradiation for other cancers and radiotherapy for bone metastases are also undergone on an outpatient basis. During outpatient treatment, it is important to predict and avoid severe normal tissue reactions to radiotherapy, such as myelosuppression and/or pneumonitis, before they are apparent by watching the patient carefully.


Unraveling the Complexity in the Design and Implementation of Bundled Payments: A Scoping Review of Key Elements From a Payer's Perspective.
Policy Points Because bundled payments are relatively new and require a different type of collaboration among payers, providers, and other actors, their design and implementation process is complex. By sorting the 53 key elements that contribute to this complexity into specific pre- and postcontractual phases as well as the actors involved in the health system, this framework provides a comprehensive overview of this complexity from a payer's perspective. Strategically, the design and implementation of bundled payments should not be approached by payers as merely the introduction of a new contracting model, but as part of a broader transformation into a more sustainable, value-based health care system. Traditional fee-for-service (FFS) payment models in health care stimulate volume-driven care rather than value-driven care. To address this issue, increasing numbers of payers are adopting contracts based on bundled payments. Because their design and implementation are complex, understanding the elements that contribute to this complexity from a payer's perspective might facilitate their adoption. Consequently, the objective of our study was to identify and structure the key elements in the design and implementation of bundled payment contracts. Two of us independently and systematically examined the literature to identify all the elements considered relevant to our objective. We then developed a framework in which these elements were arranged according to the specific phases of a care procurement process and actors' interactions at various levels of the health system. The final study sample consisted of 147 articles in which we identified the 53 elements included in the framework. These elements were found in all phases of the pre- and postcontractual procurement process and involved actors at different levels of the health care system. Examples of elements that were cited frequently and are typical of bundled payment procurement, as opposed to FFS procurement, are (1) specification of care services, patients' characteristics, and corresponding costs, (2) small and heterogeneous patient populations, (3) allocation of payment and savings/losses among providers, (4) identification of patients in the bundle, (5) alignment of the existing care delivery model with the new payment model, and (6) limited effects on quality and costs in the first pilots and demonstrations. Compared with traditional FFS payment models, bundled payment contracts tend to introduce an alternative set of (financial) incentives, touch on almost all aspects of governance within organizations, and demand a different type of collaboration among organizations. Accordingly, payers should not strategically approach their design and implementation as merely the adoption of a new contracting model, but rather as part of a broader transformation toward a more sustainable value-based health care system, based less on short-term transactional negotiations and more on long-term collaborative relationships between payers and providers.


Expansion and Contraction of the Indo-Pacific Tropical Rain Belt over the Last Three Millennia.
The seasonal north-south migration of the intertropical convergence zone (ITCZ) defines the tropical rain belt (TRB), a region of enormous terrestrial and marine biodiversity and home to 40% of people on Earth. The TRB is dynamic and has been shown to shift south as a coherent system during periods of Northern Hemisphere cooling. However, recent studies of Indo-Pacific hydroclimate suggest that during the Little Ice Age (LIA; AD 1400-1850), the TRB in this region contracted rather than being displaced uniformly southward. This behaviour is not well understood, particularly during climatic fluctuations less pronounced than those of the LIA, the largest centennial-scale cool period of the last millennium. Here we show that the Indo-Pacific TRB expanded and contracted numerous times over multi-decadal to centennial scales during the last 3,000 yr. By integrating precisely-dated stalagmite records of tropical hydroclimate from southern China with a newly enhanced stalagmite time series from northern Australia, our study reveals a previously unidentified coherence between the austral and boreal summer monsoon. State-of-the-art climate model simulations of the last millennium suggest these are linked to changes in the structure of the regional manifestation of the atmosphere's meridional circulation.


Parallel helix bundles and ion channels: molecular modeling via simulated annealing and restrained molecular dynamics.
A parallel bundle of transmembrane (TM) alpha-helices surrounding a central pore is present in several classes of ion channel, including the nicotinic acetylcholine receptor (nAChR). We have modeled bundles of hydrophobic and of amphipathic helices using simulated annealing via restrained molecular dynamics. Bundles of Ala20 helices, with N = 4, 5, or 6 helices/bundle were generated. For all three N values the helices formed left-handed coiled coils, with pitches ranging from 160 A (N = 4) to 240 A (N = 6). Pore radius profiles revealed constrictions at residues 3, 6, 10, 13, and 17. A left-handed coiled coil and a similar pattern of pore constrictions were observed for N = 5 bundles of Leu20. In contrast, N = 5 bundles of Ile20 formed right-handed coiled coils, reflecting loosened packing of helices containing beta-branched side chains. Bundles formed by each of two classes of amphipathic helices were examined: (a) M2a, M2b, and M2c derived from sequences of M2 helices of nAChR; and (b) (LSSLLSL)3, a synthetic channel-forming peptide. Both classes of amphipathic helix formed left-handed coiled coils. For (LSSLLSL)3 the pitch of the coil increased as N increased from 4 to 6. The M2c N = 5 helix bundle is discussed in the context of possible models of the pore domain of nAChR.


Improving IMRT dose accuracy via deliverable Monte Carlo optimization for the treatment of head and neck cancer patients.
The purpose of this work is to investigate the effect of dose-calculation accuracy on head and neck (H&N) intensity modulated radiation therapy (IMRT) plans by determining the systematic dose-prediction and optimization-convergence errors (DPEs and OCEs), using a superposition/convolution (SC) algorithm. Ten patients with locally advanced H&N squamous cell carcinoma who were treated with simultaneous integrated boost IMRT were selected for this study. The targets consisted of gross target volume (GTV), clinical target volume (CTV), and nodal target volumes (CTV nodes). The critical structures included spinal cord, parotid glands, and brainstem. For all patients, three IMRT plans were created: A: an SC optimized plan (SCopt), B: an SCopt plan recalculated with Monte Carlo [MC(SCopt)], and C: an MC optimized plan (MCopt). For each structure, DPEs and OCEs were estimated as DPE(SC)=D(B)-D(A) and OCE(SC)=D(C)-D(B) where A, B, and C stand for the three different optimized plans as defined above. Deliverable optimization was used for all plans, that is, a leaf-sequencing step was incorporated into the optimization loop at each iteration. The range of DPE(SC) in the GTV D98 varied from -1.9% to -4.9%, while the OCE(SC) ranged from 0.9% to 7.0%. The DPE(SC) in the contralateral parotid D50 reached 8.2%, while the OCE(SC) in the contralateral parotid D50 varied from 0.91% to 6.99%. The DPE(SC) in cord D2 reached -3.0%, while the OCE(SC) reached to -7.0%. The magnitude of the DPE(SC) and OCE(SC) differences demonstrate the importance of using the most accurate available algorithm in the deliverable IMRT optimization process, especially for the estimation of normal structure doses.


Astrocyte Transforming Growth Factor Beta 1 Protects Synapses against Aβ Oligomers in Alzheimer's Disease Model.
Alzheimer's disease (AD) is characterized by progressive cognitive decline, increasingly attributed to neuronal dysfunction induced by amyloid-β oligomers (AβOs). Although the impact of AβOs on neurons has been extensively studied, only recently have the possible effects of AβOs on astrocytes begun to be investigated. Given the key roles of astrocytes in synapse formation, plasticity, and function, we sought to investigate the impact of AβOs on astrocytes, and to determine whether this impact is related to the deleterious actions of AβOs on synapses. We found that AβOs interact with astrocytes, cause astrocyte activation and trigger abnormal generation of reactive oxygen species, which is accompanied by impairment of astrocyte neuroprotective potential in vitro We further show that both murine and human astrocyte conditioned media (CM) increase synapse density, reduce AβOs binding, and prevent AβO-induced synapse loss in cultured hippocampal neurons. Both a neutralizing anti-transforming growth factor-β1 (TGF-β1) antibody and siRNA-mediated knockdown of TGF-β1, previously identified as an important synaptogenic factor secreted by astrocytes, abrogated the protective action of astrocyte CM against AβO-induced synapse loss. Notably, TGF-β1 prevented hippocampal dendritic spine loss and memory impairment in mice that received an intracerebroventricular infusion of AβOs. Results suggest that astrocyte-derived TGF-β1 is part of an endogenous mechanism that protects synapses against AβOs. By demonstrating that AβOs decrease astrocyte ability to protect synapses, our results unravel a new mechanism underlying the synaptotoxic action of AβOs in AD.SIGNIFICANCE STATEMENT Alzheimer's disease is characterized by progressive cognitive decline, mainly attributed to synaptotoxicity of the amyloid-β oligomers (AβOs). Here, we investigated the impact of AβOs in astrocytes, a less known subject. We show that astrocytes prevent synapse loss induced by AβOs, via production of transforming growth factor-β1 (TGF-β1). We found that AβOs trigger morphological and functional alterations in astrocytes, and impair their neuroprotective potential. Notably, TGF-β1 reduced hippocampal dendritic spine loss and memory impairment in mice that received intracerebroventricular infusions of AβOs. Our results describe a new mechanism underlying the toxicity of AβOs and indicate novel therapeutic targets for Alzheimer's disease, mainly focused on TGF-β1 and astrocytes.


Green fluorescent protein-expressing Escherichia coli as a model system for investigating the antimicrobial activities of silver nanoparticles.
Recombinant Escherichia coli (E. coli) bacteria expressing green fluorescent protein (GFP) was used as a model system to investigate the antimicrobial activities of Ag nanoparticles (NPs). A convenient in situ method of Ag NP synthesis using sodium borohydride, in the bacterial growth medium, was developed to produce preformed NPs for the study. Fluorescence spectroscopic and microscopic techniques allowed rapid detection of time-dependent changes in bacterial growth as well as fluorescence characteristics in the presence of Ag NPs. In addition, X-ray diffraction, UV-vis spectroscopic, and transmission electron microscopic measurements were carried out to understand the effect of Ag NPs on the bacteria. Our observations indicated that Ag NPs, above a certain concentration, not only were bactericidal but also were found to reduce the sizes of treated bacteria in comparison to untreated ones. Cell lysis of Ag NP-treated bacteria was suggested by the increased GFP fluorescence obtained in the medium. In vitro DNA-Ag NP interaction was detected by spectrophotometric analysis. However, electrophoresis studies indicated no direct effect of Ag NPs on DNA or protein profiles.


Determination of the Electrostatic Potential of Oil-in-Water Emulsion Droplets by Combined Use of Two Membrane Potential-Sensitive Dyes.
The fluorescence behaviors of potential-sensitive dyes including anionic DiBAC4(3) (denoted by dye A), DiSBAC2(3) (dye B), and zwitterionic di-4-ANEPPS (dye C) were studied in oil-in-water (O/W) emulsions. In this study, the equilibrium Galvani potential difference (ΔOWφeq) of the O/W-emulsion droplets was controlled by changing the ratio of the concentrations of electrolytes added to the O (=1,2-dichloroethane) and W phases. When using an adequate combination of the dyes, i.e., B and C, we could observe that the ratio of their fluorescence peak intensities was changed from 1.08 to 1.38, depending on the change of (ΔOWφeq from 26 to 73 mV. It is desirable to apply this method to study the potential-dependent ion or electron-transfer reactions occurring at vesicles or liposomes, and also to biomembranes.


Climate variance influence on the non-stationary plankton dynamics.
We examined plankton responses to climate variance by using high temporal resolution data from 1988 to 2007 in the Western English Channel. Climate variability modified both the magnitude and length of the seasonal signal of sea surface temperature, as well as the timing and depth of the thermocline. These changes permeated the pelagic system yielding conspicuous modifications in the phenology of autotroph communities and zooplankton. The climate variance envelope, thus far little considered in climate-plankton studies, is closely coupled with the non-stationary dynamics of plankton, and sheds light on impending ecological shifts and plankton structural changes. Our study calls for the integration of the non-stationary relationship between climate and plankton in prognostic models on the productivity of marine ecosystems.


The roles of HIV-1 proteins and antiretroviral drug therapy in HIV-1-associated endothelial dysfunction.
Since the emergence of highly active antiretroviral therapy (HAART), human immunodeficiency virus-1 (HIV-1)-infected patients have demonstrated dramatic decreases in viral burden and opportunistic infections, and an overall increase in life expectancy. Despite these positive HAART-associated outcomes, it has become increasingly clear that HIV-1 patients have an enhanced risk of developing cardiovascular disease over time. Clinical studies are instrumental in our understanding of vascular dysfunction in the context of HIV-1 infection. However, most clinical studies often do not distinguish whether HIV-1 proteins, HAART, or a combination of these 2 factors cause cardiovascular complications. This review seeks to address the roles of both HIV-1 proteins and antiretroviral drugs in the development of endothelial dysfunction because endothelial dysfunction is the hallmark initial step of many cardiovascular diseases. We analyze recent in vitro and in vivo studies examining endothelial toxicity in response to HIV-1 proteins or in response to the various classes of antiretroviral drugs. Furthermore, we discuss the multiple mechanisms by which HIV-1 proteins and HAART injure the vascular endothelium in HIV-1 patients. By understanding the molecular mechanisms of HIV-1 protein- and antiretroviral-induced cardiovascular disease, we may ultimately improve the quality of life of HIV-1 patients through better drug design and the discovery of new pharmacological targets.


Differential water mite parasitism, phenoloxidase activity, and resistance to mites are unrelated across pairs of related damselfly species.
Related host species often demonstrate differences in prevalence and/or intensity of infection by particular parasite species, as well as different levels of resistance to those parasites. The mechanisms underlying this interspecific variation in parasitism and resistance expression are not well understood. Surprisingly, few researchers have assessed relations between actual levels of parasitism and resistance to parasites seen in nature across multiple host species. The main goal of this study was to determine whether interspecific variation in resistance against ectoparasitic larval water mites either was predictive of interspecific variation in parasitism for ten closely related species of damselflies (grouped into five "species pairs"), or was predicted by interspecific variation in a commonly used measure of innate immunity (total Phenoloxidase or potential PO activity). Two of five species pairs had interspecific differences in proportions of individuals resisting larval Arrenurus water mites, only one of five species pairs had species differences in prevalence of larval Arrenurus water mites, and another two of five species pairs showed species differences in mean PO activity. Within the two species pairs where species differed in proportion of individuals resisting mites the species with the higher proportion did not have correspondingly higher PO activity levels. Furthermore, the proportion of individuals resisting mites mirrored prevalence of parasitism in only one species pair. There was no interspecific variation in median intensity of mite infestation within any species pair. We conclude that a species' relative ability to resist particular parasites does not explain interspecific variation in parasitism within species pairs and that neither resistance nor parasitism is reflected by interspecific variation in total PO or potential PO activity.


Relationship between handwriting and keyboarding performance among fast and slow adult keyboarders.
We examined the relationship between handwriting and keyboarding performance and between these writing modes and underlying performance skills. Sixty-three young, healthy adults who used the computer daily were recruited for this study by means of a convenience sample (mean = 25.3, standard deviation = 3.0); 15 were slow keyboarders and 17 were fast keyboarders. Participants were administered handwriting and keyboarding assessments, as well as measures of finger function, kinesthetic processing, and eye movement. Although handwriting and keyboarding speed were moderately correlated, these activities did not share underlying performance skills. In addition, different correlation patterns between written communication modes and performance skills were found among slow and fast keyboarders. Results suggest that occupational therapists and educators should consider a variety of factors before recommending keyboarding as an alternative written communication method for people with handwriting difficulties. Moreover, different recommendations appear to be warranted for slow and fast keyboarders.