Mixed micelles-mediated dephenolisation of table olive processing's wastewaters.
Olive processing wastewaters account for highly pollutant agro-industrial effluents. Their phenolic compounds are responsible for their toxicity. Those natural compounds have to be degraded or recovered before any discharge into the environment. This investigation deals with the extraction and concentration of the phenolic compounds into an aqueous phase using a mixture of nonionic/anionic surfactants. A synergistic effect for the extraction of the natural phenolic compounds was observed when Genapol X-80 was combined with sodium dodecyl sulphate (SDS). For the tested Genapol X-80 concentration (1-5%), a minimum concentration of 2.5 mM SDS was demonstrated to be necessary to reach maximum extraction rates. The extraction efficiencies were only slightly affected by temperatures between 20 and 50 °C. However, the recovery rate of the phenolic compounds increased with the augmentation of the contact time. The pH has also been found to greatly influence the extraction of the phenolic compounds and the coacervate volume fraction. At optimal conditions, the coacervate phase was enriched up to four times whereas the maximum reduction of the phenolic content in the diluted phase reached more than 40% in one step extraction.


Addressing barriers to optimal oral anticoagulation use and persistence among patients with atrial fibrillation: Proceedings, Washington, DC, December 3-4, 2012.
Approximately half of patients with atrial fibrillation and with risk factors for stroke are not treated with oral anticoagulation (OAC), whether it be with vitamin K antagonists (VKAs) or novel OACs (NOACs); and of those treated, many discontinue treatment. Leaders from academia, government, industry, and professional societies convened in Washington, DC, on December 3-4, 2012, to identify barriers to optimal OAC use and adherence and to generate potential solutions. Participants identified a broad range of barriers, including knowledge gaps about stroke risk and the relative risks and benefits of anticoagulant therapies; lack of awareness regarding the potential use of NOAC agents for VKA-unsuitable patients; lack of recognition of expanded eligibility for OAC; lack of availability of reversal agents and the difficulty of anticoagulant effect monitoring for the NOACs; concerns with the bleeding risk of anticoagulant therapy, especially with the NOACs and particularly in the setting of dual antiplatelet therapy; suboptimal time in therapeutic range for VKA; and costs and insurance coverage. Proposed solutions were to define reasons for oral anticoagulant underuse classified in ways that can guide intervention and improve use, to increase awareness of stroke risk as well as the benefits and risks of OAC use via educational initiatives and feedback mechanisms, to better define the role of VKA in the current therapeutic era including eligibility and ineligibility for different anticoagulant therapies, to identify NOAC reversal agents and monitoring strategies and make knowledge regarding their use publicly available, to minimize the duration of dual antiplatelet therapy and concomitant OAC where possible, to improve time in therapeutic range for VKA, to leverage observational data sets to refine understanding of OAC use and outcomes in general practice, and to better align health system incentives.


Measurement of compliance with New York City's regulations on beverages, physical activity, and screen time in early child care centers.
Policy interventions designed to change the nutrition environment and increase physical activity in child care centers are becoming more common, but an understanding of the implementation of these interventions is yet to be developed. The objective of this study was to explore the extent and consistency of compliance with a policy intervention designed to promote nutrition and physical activity among licensed child care centers in New York City. We used a multimethod cross-sectional approach and 2 independent components of data collection (Center Evaluation Component and Classroom Evaluation Component). The methods were designed to evaluate the impact of regulations on beverages served, physical activity, and screen time at child care centers. We calculated compliance scores for each evaluation component and each regulation and percentage agreement between compliance in the center and classroom components. Compliance with certain requirements of the beverage regulations was high and fairly consistent between components, whereas compliance with the physical activity regulation varied according to the data collection component. Compliance with the regulation on amount and content of screen time was high and consistent. Compliance with the physical activity regulation may be a more fluid, day-to-day issue, whereas compliance with the regulations on beverages and television viewing may be easier to control at the center level. Multiple indicators over multiple time points may provide a more complete picture of compliance - especially in the assessment of compliance with physical activity policies.


SuRankCo: supervised ranking of contigs in de novo assemblies.
Evaluating the quality and reliability of a de novo assembly and of single contigs in particular is challenging since commonly a ground truth is not readily available and numerous factors may influence results. Currently available procedures provide assembly scores but lack a comparative quality ranking of contigs within an assembly. We present SuRankCo, which relies on a machine learning approach to predict quality scores for contigs and to enable the ranking of contigs within an assembly. The result is a sorted contig set which allows selective contig usage in downstream analysis. Benchmarking on datasets with known ground truth shows promising sensitivity and specificity and favorable comparison to existing methodology. SuRankCo analyzes the reliability of de novo assemblies on the contig level and thereby allows quality control and ranking prior to further downstream and validation experiments.


Defined DNA-mediated assemblies of gene-expressing giant unilamellar vesicles.
The technological aspects of artificial vesicles as prominent cell mimics are evolving toward higher-order assemblies of functional vesicles with tissuelike architectures. Here, we demonstrate the spatially controlled DNA-directed bottom-up synthesis of complex microassemblies and macroassemblies of giant unilamellar vesicles functionalized with a basic cellular machinery to express green fluorescent protein and specified neighbor-to-neighbor interactions. We show both that the local and programmable DNA pairing rules on the nanoscale are able to direct the microscale vesicles into macroscale soft matter assemblies and that the highly sensitive gene-expression machinery remains intact and active during multiple experimental steps. An in silico model recapitulates the experiments performed in vitro and covers additional experimental setups highlighting the parameters that control the DNA-directed bottom-up synthesis of higher-order self-assembled structures. The controlled assembly of a functional vesicle matrix may be useful not only as simplified natural tissue mimics but also as artificial scaffolds that could interact and support living cells.


Genomics-driven discovery of a biosynthetic gene cluster required for the synthesis of BII-Rafflesfungin from the fungus Phoma sp. F3723.
Phomafungin is a recently reported broad spectrum antifungal compound but its biosynthetic pathway is unknown. We combed publicly available Phoma genomes but failed to find any putative biosynthetic gene cluster that could account for its biosynthesis. Therefore, we sequenced the genome of one of our Phoma strains (F3723) previously identified as having antifungal activity in a high-throughput screen. We found a biosynthetic gene cluster that was predicted to synthesize a cyclic lipodepsipeptide that differs in the amino acid composition compared to Phomafungin. Antifungal activity guided isolation yielded a new compound, BII-Rafflesfungin, the structure of which was determined. We describe the NRPS-t1PKS cluster 'BIIRfg' compatible with the synthesis of the cyclic lipodepsipeptide BII-Rafflesfungin [HMHDA-L-Ala-L-Glu-L-Asn-L-Ser-L-Ser-D-Ser-D-allo-Thr-Gly]. We report new Stachelhaus codes for Ala, Glu, Asn, Ser, Thr, and Gly. We propose a mechanism for BII-Rafflesfungin biosynthesis, which involves the formation of the lipid part by BIIRfg_PKS followed by activation and transfer of the lipid chain by a predicted AMP-ligase on to the first PCP domain of the BIIRfg_NRPS gene.


FK506--its influence on anti-class 1 MHC alloantibody responses to blood transfusions.
The influence of FK506 on in vivo alloantibody responses to major histocompatability class 1 antigens was investigated in inbred rat strains, and compared with the effect of cyclosporine. AO rats received transfusions of DA blood on days 0 and 7. From days 0 to 14 the rats also received, daily, either FK506 0.3 mg/kg suspended in saline or dissolved in olive oil, or CsA 10 mg/kg. The administration of FK506 suspended in saline at the time of blood transfusion completely abrogated the development of anti-MHC class 1 alloantibodies as detected by indirect hemagglutination (IHA)* and 51Cr release complement dependent cytotoxicity assays (CDC). Isotyping studies showed that FK506 suspended in saline suppressed IgM production and inhibited the switch to IgG production. Similar responses were seen in CsA-treated animals. In contrast, rats treated with FK506 dissolved in olive oil developed high titers of anti-class 1 alloantibodies. On days 49 and 56 the rats were challenged with further DA blood transfusions given without immunosuppression. In the groups given FK506 suspended in saline or CsA, cytotoxic antibodies did not develop; low titer antibodies were, however, detected by IHA in the animals that had previously received FK506 suspended in saline. The results indicate that FK506, in common with CsA, inhibits anti-class 1 MHC alloantibody production, and at the same time enables the development of tolerance. The vehicle in which FK506 is administered is, however, critical to its efficacy at the low doses used. These results may be of relevance to clinical transplantation as similar antibodies mediate hyperacute renal allograft rejection in man.


Dyskinesias induced by subthalamotomy in Parkinson's disease are unresponsive to amantadine.
Dyskinesias are a transient but severe complication of subthalamotomy in some patients. Three patients with Parkinson's disease undergoing bilateral micro-recording guided surgery of the subthalamic nucleus (STN) are described; deep brain stimulation (DBS) was used in one case, and subthalamotomy in the other two. Prior to surgery, levodopa induced dyskinesia had improved (< or = 50%) under treatment with amantadine (400 mg/day, po) in all three patients. The patient treated with DBS developed severe dyskinesia a few days after discharge and began self medication with amantadine but showed no improvement. This suggested a possible lack of response to amantadine for treatment of dyskinesias induced by surgery of the STN. Both patients treated with bilateral subthalamotomy developed unilateral choreoballistic movements immediately after surgery, despite not taking levodopa (L-dopa). Patients were scored using the dyskinesia scale and started treatment with 400 mg amantadine (po) for 4 days within the first postoperative week with no effect on dyskinesia score or its phenomenology. Amantadine was therefore discontinued. One month after surgery both patients were free of involuntary movements with an improvement of about 60% in the "off" state UPDRS motor score. Six month follow up showed maintained antiparkinsonian benefit, without need for levodopa treatment and complete absence of dyskinesia. The present findings suggest that: (i) amantadine probably exerts its anti-dyskinetic effect by acting on the "indirect" pathway; (ii) the pathophysiological mechanisms of subthalamotomy induced dyskinesias may differ from those involved in L-dopa induced dyskinesias; (iii) dyskinesias induced by STN surgery resolve spontaneously as compensatory mechanisms develop.


Use of spatial communication in aphasia.
Spatial communication consists of both verbal spatial language and gesture. There has been minimal research investigating the use of spatial communication, and even less focussing on people with aphasia. The aims of this exploratory study were to describe the frequency and variability of spatial language and gesture use by three participants with aphasia in comparison to nine control participants. This included: 1) frequency of gestures; 2) types of gesture; 3) number of spatial descriptions described by gestures but no language; and 4) frequency and variety of locative prepositional, verb, and noun phrases. Each participant was videoed undertaking 11 spatial communication tasks: four description tasks, and seven tasks involving directing the researcher in the placement of objects or pictures. Gestures and language produced were transcribed and analysed. Participants with aphasia used significantly more gesture. Participants with aphasia also used more gesture without spoken phrases when spatial vocabulary was unavailable. Finally, there were differences between the participants with regards to the types of gesture that they used when they were unable to access language. The results suggest that the analysis of gesture produced by people with aphasia may provide insight into their underlying language impairment. As this was an exploratory study, with just three participants with aphasia, further research is needed.


Cerebellopontine angle meningiomas: postoperative outcomes in a modern cohort.
Tumors of the cerebellopontine angle (CPA) have always proven difficult for neurosurgeons to optimally manage. Studies investigating the natural history and treatment of vestibular schwannomas have dominated the literature in this regard. Distinguishing meningiomas from schwannomas in this location carries particular importance as each tumor type has certain prognostic and surgical considerations. In this study, the authors have characterized the outcomes of 34 patients surgically treated for CPA meningiomas and have investigated various factors that may affect postoperative neurological function. The medical records of patients with CPA meningiomas who underwent surgery from 2005 to 2013 at the Duke University Health System were reviewed. Various patient, clinical, and tumor data were gathered from the medical records including patient demographics, pre- and postoperative neurological examinations, duration of symptoms, procedural details, tumor pathology and size, and treatment characteristics. Differences in continuous variables were then analyzed using the Student t-test while categorical variables were evaluated using the chi-square test. A total of 34 patients underwent surgical treatment for CPA meningiomas during the 8-year period. Jugular foramen invasion was seen in 17.6% of tumors, with nearly half (41.2%) extending into the internal acoustic canal. The most common presenting symptom was hearing loss (58.8%), followed by headache (52.9%) and facial numbness/pain (50.0%). The most common cranial nerve (CN) affected was CN X (11.8%), followed by CNs VI and VII (5.9%). Postoperatively, no patients experienced a decrease in hearing, with only 5.9% of patients experiencing facial nerve palsies. Patients with tumors larger than 3 cm had a significantly higher incidence of permanent CN deficits than those with smaller tumors (45.5% vs 5.9%, respectively; p = 0.011). Also, tumor extension into the jugular foramen was associated with the occurrence of lower CN deficits, none of which occurred in tumors without jugular foramen invasion. Internal acoustic canal tumor extension was not seen to be associated with postoperative complications or CN deficits. Meningiomas of the CPA are challenging lesions to treat surgically. However, the risk of facial palsy and hearing loss is significantly lower when compared with vestibular schwannomas. Novel methods for preoperative differentiation are needed to appropriately counsel patients on surgical risks. Also, due to the significant potential for neurological deficits, further studies are needed to investigate the utility of radiotherapy for these lesions.


Persons with chronic conditions. Their prevalence and costs.
To determine (1) the number and proportion of Americans living with chronic conditions, and (2) the magnitude of their costs, including direct costs (annual personal health expenditures) and indirect costs to society (lost productivity due to chronic conditions and premature death). Analysis of the 1987 National Medical Expenditure Survey for prevalence and direct health care costs; indirect costs based on the 1990 National Health Interview Survey and Vital Statistics of the United States. US population. For the estimate of prevalence and direct costs, the National Medical Expenditure Survey sample of persons who reported health conditions associated with (1) use of health services or supplies or (2) periods of disability. None. The number of persons with chronic conditions, their annual direct health care costs, and indirect costs from lost productivity and premature deaths. In 1987, 90 million Americans were living with chronic conditions, 39 million of whom were living with more than 1 chronic condition. Over 45% of noninstitutionalized Americans have 1 or more chronic conditions and their direct health care costs account for three fourths of US health care expenditures. Total costs projected to 1990 for people with chronic conditions amounted to $659 billion--$425 billion for direct health care costs and $234 billion in indirect costs. The prevalence and costs of chronic conditions as a whole have rarely been estimated. Because the number of persons with limitations due to chronic conditions is more regularly reported in the literature, the total prevalence of chronic conditions has perhaps been minimized. The majority of persons with chronic conditions are not disabled, nor are they elderly. Chronic conditions affect all ages. Because persons with chronic conditions have greater health needs at any age, their costs are disproportionately high.


Histone deacetylase 1 (HDAC1) participates in the down-regulation of corticotropin releasing hormone gene (crh) expression.
The paraventricular nucleus of the hypothalamus (PVH) plays a central role in regulating the hypothalamic-pituitary-adrenal (HPA) axis. Medial parvocellular neurons of the PVH (mpPVH) integrate sensory and humoral inputs to maintain homeostasis. Humoral inputs include glucocorticoids secreted by the adrenals, which down-regulate HPA activation. A primary glucocorticoid target is the population of mpPVH neurons that synthesize and secrete corticotropin-releasing factors, the most potent of which is corticotropin-releasing hormone (CRH). Although CRH gene (crh) expression is known to be down-regulated by glucocorticoids, the mechanisms by which this process occurs are still poorly understood. To begin this study we postulated that glucocorticoid repression of crh involves HDAC recruitment to the region of the crh proximal promoter. To evaluate this hypothesis, we treated hypothalamic cells that express CRH with the HDAC inhibitor trichostatin A (TSA). As predicted, treatment with TSA led to increased CRH mRNA levels and crh promoter activity. Although co-treatment with Dex (10(-7)M) reduced the TSA effect on mRNA levels, it failed to reduce promoter activity; however co-transfection of HDAC1 but not 3 restored Dex inhibition. A distinction between HDAC1 and 3 was also apparent with respect to crh promoter occupancy. Dex led to increased HDAC1 but not HDAC3 occupancy. In vivo studies revealed that CRH-immunoreactive (-ir) neurons contained HDAC1- and HDAC3-ir. Collectively, these data point to a role for HDAC1 in the physiologic regulation of crh.


Penetration of Ibrexafungerp (Formerly SCY-078) at the Site of Infection in an Intra-abdominal Candidiasis Mouse Model.
Ibrexafungerp (IBX), formerly SCY-078, is a novel, oral and intravenous, semisynthetic triterpenoid glucan synthase inhibitor in clinical development for treating multiple fungal infections, including invasive candidiasis. Intra-abdominal candidiasis (IAC) is one of the most common types of invasive candidiasis associated with high mortality largely due to poor drug exposure in infected lesions. To better understand the potential of IBX to treat such infections, we investigated its penetration at the site of infection. Using matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) and laser capture microdissection (LCM)-directed high-pressure liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), we investigated tissue distribution and lesion-specific drug exposure of IBX in a clinically relevant IAC mouse model. After a single-dose treatment, IBX quickly distributed into tissues and efficiently accumulated within lesions. Drug concentrations of IBX within the liver abscesses were almost 100-fold higher than the serum concentration. In addition, drug penetration after repeated treatment of IBX was compared with micafungin. IBX exhibited robust and long-lasting lesion penetration after repeated treatment. These data indicate that IBX penetrates into intra-abdominal abscesses highly efficiently and holds promise as a potential therapeutic option for IAC patients.


Opinions of women with high inherited breast cancer risk about prophylactic mastectomy: an initial evaluation from a screening trial including magnetic resonance imaging and ductal lavage.
Prophylactic mastectomy (PM) is often considered, but variably chosen by women at high inherited risk of breast cancer; few data exist on patient tolerance of intensive breast screening as an alternative to PM. We performed an evaluation of high-risk women's tolerance of a breast screening protocol using clinical breast examination, mammography, breast magnetic resonance imaging (MRI) and ductal lavage (DL), and of change in attitudes toward PM after screening. A questionnaire assessing tolerance of screening procedures and change in opinion towards PM was designed and administered to 43 study participants, after a median follow-up of 13 months. Responses were evaluated according to patient characteristics, including type of study-prompted interventions, BRCA mutation status, and prior history of cancer, via univariate analysis. Most patients [85.3% (68.9-95.1%)] were more opposed or unchanged in their attitudes towards PM after study participation, with only 14.7% (5.0-31.1%) less opposed (P = 0.017) despite a short-interval follow-up MRI rate of 71.7% and a biopsy rate of 37%. Lower rates of maximal discomfort were reported with mammogram [2.8% (0-14.5%)] and MRI [5.6% (0-18.7%)] than with DL [28.6% (14.6-46.3%)], with P = 0.035. Most high-risk women tolerated intensive breast screening well; they were not more inclined towards PM after participating. Future studies should prospectively evaluate larger numbers of high-risk women via multivariate analysis, to determine characteristics associated with preference for breast screening vs. PM.


Adaptive dynamic surface control of flexible-joint robots using self-recurrent wavelet neural networks.
A new method for the robust control of flexible-joint (FJ) robots with model uncertainties in both robot dynamics and actuator dynamics is proposed. The proposed control system is a combination of the adaptive dynamic surface control (DSC) technique and the self-recurrent wavelet neural network (SRWNN). The adaptive DSC technique provides the ability to overcome the "explosion of complexity" problem in backstepping controllers. The SRWNNs are used to observe the arbitrary model uncertainties of FJ robots, and all their weights are trained online. From the Lyapunov stability analysis, their adaptation laws are induced, and the uniformly ultimately boundedness of all signals in a closed-loop adaptive system is proved. Finally, simulation results for a three-link FJ robot are utilized to validate the good position tracking performance and robustness against payload uncertainties and external disturbances of the proposed control system.


Reduction of disulphide bonds unmasks potent antimicrobial activity of human β-defensin 1.
Human epithelia are permanently challenged by bacteria and fungi, including commensal and pathogenic microbiota. In the gut, the fraction of strict anaerobes increases from proximal to distal, reaching 99% of bacterial species in the colon. At colonic mucosa, oxygen partial pressure is below 25% of airborne oxygen content, moreover microbial metabolism causes reduction to a low redox potential of -200 mV to -300 mV in the colon. Defensins, characterized by three intramolecular disulphide-bridges, are key effector molecules of innate immunity that protect the host from infectious microbes and shape the composition of microbiota at mucosal surfaces. Human β-defensin 1 (hBD-1) is one of the most prominent peptides of its class but despite ubiquitous expression by all human epithelia, comparison with other defensins suggested only minor antibiotic killing activity. Whereas much is known about the activity of antimicrobial peptides in aerobic environments, data about reducing environments are limited. Herein we show that after reduction of disulphide-bridges hBD-1 becomes a potent antimicrobial peptide against the opportunistic pathogenic fungus Candida albicans and against anaerobic, Gram-positive commensals of Bifidobacterium and Lactobacillus species. Reduced hBD-1 differs structurally from oxidized hBD-1 and free cysteines in the carboxy terminus seem important for the bactericidal effect. In vitro, the thioredoxin (TRX) system is able to reduce hBD-1 and TRX co-localizes with reduced hBD-1 in human epithelia. Hence our study indicates that reduced hBD-1 shields the healthy epithelium against colonisation by commensal bacteria and opportunistic fungi. Accordingly, an intimate interplay between redox-regulation and innate immune defence seems crucial for an effective barrier protecting human epithelia.


Genetic and epigenetic events generate multiple pathways in colorectal cancer progression.
Colorectal cancer (CRC) is one of the most common causes of death, despite decades of research. Initially considered as a disease due to genetic mutations, it is now viewed as a complex malignancy because of the involvement of epigenetic abnormalities. A functional equivalence between genetic and epigenetic mechanisms has been suggested in CRC initiation and progression. A hallmark of CRC is its pathogenetic heterogeneity attained through at least three distinct pathways: a traditional (adenoma-carcinoma sequence), an alternative, and more recently the so-called serrated pathway. While the alternative pathway is more heterogeneous and less characterized, the traditional and serrated pathways appear to be more homogeneous and clearly distinct. One unsolved question in colon cancer biology concerns the cells of origin and from which crypt compartment the different pathways originate. Based on molecular and pathological evidences, we propose that the traditional and serrated pathways originate from different crypt compartments explaining their genetic/epigenetic and clinicopathological differences. In this paper, we will discuss the current knowledge of CRC pathogenesis and, specifically, summarize the role of genetic/epigenetic changes in the origin and progression of the multiple CRC pathways. Elucidation of the link between the molecular and clinico-pathological aspects of CRC would improve our understanding of its etiology and impact both prevention and treatment.


Supramolecular complexes of MHC class I, MHC class II, CD20, and tetraspan molecules (CD53, CD81, and CD82) at the surface of a B cell line JY.
The results of previous biochemical studies indicated that a fraction of MHC class II proteins is associated with four proteins of the tetraspan family, CD37, CD53, CD81, and CD82, and possibly with other membrane components, at the surface of JY B lymphoma cells. In the present communication we used a biophysical technique, namely the flow cytometric energy transfer method, to demonstrate the proximity of these molecules at the surface of the cells. Significant energy transfer (and, therefore, proximity within the 2-10 nm range) was observed between fluorescently labeled mAbs to DR, DQ, and the tetraspan molecules CD53, CD81, and CD82. Moreover, two other B cell surface molecules, CD20 and MHC class I, were found to be close to each other and to MHC class II and the tetraspan proteins, based on the observed high energy transfer efficiencies between the relevant fluorescently labeled mAbs. The character of simultaneous energy transfer from CD20, CD53, CD81, and CD82 to DR suggests that all these molecules are in a single complex with the DR molecules (or a complex of several DR molecules) rather than that each of them is separately associated with different DR molecules. Based on these data and previous biochemical results, a model is proposed predicting that the B cell membrane contains multicomponent supramolecular complexes consisting of at least two MHC class I and at least one DR, DQ, CD20, CD53, CD81, and CD82 molecules. Closer analysis of the energy transfer efficiencies makes it possible to suggest mutual orientations of the components within the complex. Participation of other molecules, not examined in this study (CD19 and CD37), in these supramolecular structures cannot be ruled out. These large assemblies of multiple B cell surface molecules may play a role in signaling through MHC molecules and in Ag presentation to T cells.


Survey of European clinical geneticists on awareness, experiences and attitudes towards direct-to-consumer genetic testing.
The advent of direct-to-consumer (DTC) genetic testing (GT) has sparked a number of debates regarding the scientific validity of tests, their broad health and ethical implications for society as well as their legal status. To date, relatively few empirical studies have been published regarding this phenomenon. We conducted a survey of European clinical geneticists to gauge their awareness of, experiences with, and attitudes towards DTC GT. We invited 300 clinical geneticists from 28 European countries to complete an online questionnaire. Statistical analyses of closed-ended questions were performed using the STATISTICA software package. Answers to open-ended questions were analysed for recurring themes. One hundred and thirty-one clinical geneticists answered our survey (response rate, 44%). Eighty-six percent (110/128) of respondents were aware of DTC GT, and over one-third had been contacted by at least one patient regarding these services. The majority (84%) of respondents did not agree with telephone medical supervision outside of an established doctor-patient relationship. The majority of clinical geneticists also found it unacceptable to provide non-face-to-face medical supervision for: (i) a presymptomatic test for a condition with very high penetrance; (ii) a predictive test for a condition that has a 'medium' penetrance of 50% to 60%; and (iii) carrier testing. For conditions that are neither treatable nor preventable and for disorders with serious health consequences, clinical geneticists were almost unanimous in expressing the unacceptability of offering such genetic tests outside of the traditional healthcare setting, without an established physician-patient relationship and without face-to-face medical supervision. A high percentage of European clinical geneticists are aware of DTC GT and the majority do not agree with the model of provision used by many commercial companies for certain severe or actionable health conditions. Despite this disagreement with the DTC model of provision, >85% of respondents said that they would offer genetic counselling to patients who asked for a consultation after having undergone DTC genetic testing. The understanding of the views and opinions of this expert stakeholder group should be considered in the attempts to shape responsible policy and guidelines for these services.


Dynamics of intramural and transmural reentry during ventricular fibrillation in isolated swine ventricles.
The intramural dynamics of ventricular fibrillation (VF) remain poorly understood. Recent investigations have suggested that stable intramural reentry may underlie the mechanisms of VF. We performed optical mapping studies of VF in isolated swine right ventricles (RVs) and left ventricles (LVs). Nine RV walls were cut obliquely in their distal edge exposing the transmural surface. Six LV wedge preparations were also studied. Results showed that intramural reentry was present. In RV, 28 of 44 VF episodes showed reentry; 15% of the activation pathways were reentrant. Except for 4 episodes, reentry was transmural, involving subendocardial structures as the papillary muscle (PM) or trabeculae. In LV, reentry was observed in 27 of 27 VF episodes; 23% of the activations were part of reentrant pathways (P<0.05 compared with RV). All LV reentrant pathways were truly intramural (confined to the wall) and were frequently located at the PM insertion. In both ventricles, reentry was spatially and temporally unstable. Histological studies showed abrupt changes in fiber orientation at sites of reentry and wave splitting. Connexin 40 immunostaining demonstrated intramyocardial Purkinje fibers at sites of reentry in the PM root and around endocardial trabeculae. Our results confirm that reentry is frequent-but unstable-in the myocardial wall during VF. In RV, reentry is mostly transmural and requires participation of subendocardial structures. The LV has a greater incidence of reentry and is intramural. Anisotropic anatomic structures played key roles in the generation of wave splitting and in the maintenance of reentry.


Discriminative Block-Diagonal Representation Learning for Image Recognition.
Existing block-diagonal representation studies mainly focuses on casting block-diagonal regularization on training data, while only little attention is dedicated to concurrently learning both block-diagonal representations of training and test data. In this paper, we propose a discriminative block-diagonal low-rank representation (BDLRR) method for recognition. In particular, the elaborate BDLRR is formulated as a joint optimization problem of shrinking the unfavorable representation from off-block-diagonal elements and strengthening the compact block-diagonal representation under the semisupervised framework of LRR. To this end, we first impose penalty constraints on the negative representation to eliminate the correlation between different classes such that the incoherence criterion of the extra-class representation is boosted. Moreover, a constructed subspace model is developed to enhance the self-expressive power of training samples and further build the representation bridge between the training and test samples, such that the coherence of the learned intraclass representation is consistently heightened. Finally, the resulting optimization problem is solved elegantly by employing an alternative optimization strategy, and a simple recognition algorithm on the learned representation is utilized for final prediction. Extensive experimental results demonstrate that the proposed method achieves superb recognition results on four face image data sets, three character data sets, and the 15 scene multicategories data set. It not only shows superior potential on image recognition but also outperforms the state-of-the-art methods.


PCRPi: Presaging Critical Residues in Protein interfaces, a new computational tool to chart hot spots in protein interfaces.
Protein-protein interactions (PPIs) are ubiquitous in Biology, and thus offer an enormous potential for the discovery of novel therapeutics. Although protein interfaces are large and lack defining physiochemical traits, is well established that only a small portion of interface residues, the so-called hot spot residues, contribute the most to the binding energy of the protein complex. Moreover, recent successes in development of novel drugs aimed at disrupting PPIs rely on targeting such residues. Experimental methods for describing critical residues are lengthy and costly; therefore, there is a need for computational tools that can complement experimental efforts. Here, we describe a new computational approach to predict hot spot residues in protein interfaces. The method, called Presaging Critical Residues in Protein interfaces (PCRPi), depends on the integration of diverse metrics into a unique probabilistic measure by using Bayesian Networks. We have benchmarked our method using a large set of experimentally verified hot spot residues and on a blind prediction on the protein complex formed by HRAS protein and a single domain antibody. Under both scenarios, PCRPi delivered consistent and accurate predictions. Finally, PCRPi is able to handle cases where some of the input data is either missing or not reliable (e.g. evolutionary information).


Nociceptive stimuli enhance anesthetic-induced neuroapoptosis in the rat developing brain.
Anesthetic-induced neurodegeneration in the developing brain has been well documented. However, the experiments carried out so far do not include surgical conditions. This proof of concept study was designed to investigate the impact of nociceptive stimuli on anesthetic induced neuroapoptosis in the rat developing brain. Separate cohorts of 7-day-old Sprague-Dawley rat pups were randomly assigned to six groups: Naïve (room air); Anesthesia alone (70% nitrous oxide and 0.75% isoflurane for 6 h); Formalin injection alone (subcutaneous injection with 10 μL 5% formalin into the left hind paw); Anesthesia+formalin injection; Surgical incision (to the left hind paw) alone; Anesthesia+surgical incision. Apoptosis (Caspase-3) and neuronal activation (c-Fos) in the brain and spinal cord section, and cortical TNF-α and IL-1β were measured with in situ immunostaining and western blot respectively. Cognition was tested using Trace Fear conditioning 40 days after the insult. Prolonged anesthesia caused widespread apoptosis in the central nervous system compared to naïve animals. Nociceptive stimulation with formalin (F) or surgical incision (S) increased the injury in the brain cortex (F: 60% or S: 40% increase) and spinal cord (F: 80% vs. S: 50% increase) respectively. Both nociceptive stimuli further augmented cognitive impairment induced by the anesthetics when assessed 40 days later. The activated pain pathway and the increased expression of the pro-inflammatory cytokine, IL-1β, in the cortex may be responsible for the enhanced neuroapoptosis. Nociceptive stimulation and prolonged anesthesia produced significantly more apoptosis than prolonged anesthesia alone when administered to neonates during the synaptogenic period.


Low-dose stimulation of growth of the harmful alga, Prymnesium parvum, by glyphosate and glyphosate-based herbicides.
Glyphosate-based herbicides (GBH) are widely used around the globe. While generally toxic to phototrophs, organic phosphorus in glyphosate can become available to glyphosate-resistant phytoplankton and contribute to algal bloom development. Few studies have examined the effects of GBH on growth of eukaryotic microalgae and information for the toxic bloom-forming haptophyte, Prymnesium parvum, is limited. Using a batch-culture system, this study examined the effects on P. parvum growth of a single application of Roundup Weed and Grass Killer Super Concentrate Plus® (Roundup SC), Roundup Weed and Grass Killer Ready-to-Use III® (Roundup RtU), and technical-grade glyphosate at low concentrations [0-1000 μg glyphosate acid equivalent (ae) l-1]. Roundup formulations differ in the percent of glyphosate as active ingredient (Roundup SC, ∼50%; Roundup RtU, 2%), allowing indirect evaluation of the influence of inactive ingredients. Roundup SC enhanced exponential growth rate at 10-1000 μg glyphosate ae l-1, and a positive monotonic association was noted between Roundup SC concentration and early (pre-exponential growth) but not maximum cell density. Glyphosate and both Roundup formulations enhanced growth rate at 100 μg glyphosate l-1, but only Roundup SC and glyphosate significantly stimulated early and maximum density. This observation suggests the higher concentration of inactive ingredients and other compounds in Roundup RtU partially counteracts glyphosate-dependent growth stimulation. When phosphate concentration was varied while maintaining other conditions constant, addition of Roundup SC and glyphosate at 100 μg l-1 influenced growth more strongly than equivalent changes in phosphate-associated phosphorus. It appears, therefore, that low doses of glyphosate stimulate growth by mechanisms unrelated to the associated small increases in total phosphorus. In conclusion, glyphosate and GBH stimulate P. parvum growth at low, environmentally relevant concentrations. This finding raises concerns about the potential contribution to P. parvum blooms by glyphosate-contaminated runoff or by direct application of GBH to aquatic environments.


Antagonistic effects of TGF-beta 1 and MSF on fibroblast migration and hyaluronic acid synthesis. Possible implications for dermal wound healing.
The migration of adult skin fibroblasts into three-dimensional collagen gel matrices is differentially affected by cell density, with subconfluent cells displaying a significantly elevated level of migration compared to confluent ones. Fetal fibroblasts differ from adult cells in that they display an elevated level of migration at both subconfluent and confluent cell densities. We have previously reported that this difference in behaviour results from the secretion by fetal fibroblasts of a 'migration stimulating factor' (MSF) which is not made by their normal adult counterparts, and that MSF appears to act by stimulating the synthesis of hyaluronic acid (HA). Data presented in this communication indicate that (a) MSF specifically stimulates the synthesis of high molecular weight species of HA, (b) TGF-beta 1 inhibits the elevated migration of adult fibroblasts plated at subconfluent cell density, (c) under these conditions, TGF-beta 1 induces a parallel decrease in the synthesis of high molecular weight HA and increase in the synthesis of low molecular weight HA, (d) TGF-beta 1 is a potent antagonist of MSF, effectively blocking its stimulation of cell migration and synthesis of high molecular weight HA, and (e) the inhibition of fibroblast migration by TGF-beta 1 does not appear to be a chemotactic response dependent upon the existence of a concentration gradient of the cytokine. Our observations regarding the inhibitory effects of TGF-beta 1 on fibroblast migration into 3D collagen gels stand in marked contrast to various published reports indicating that this cytokine stimulates the migration of human skin fibroblasts through the pores of polycarbonate filters as used in modified Boyden chamber assays; this discrepancy underscores the importance of the substratum in modulating cellular response to cytokines. Our results are discussed in terms of the possible combined contribution of MSF and TGF-beta 1 to wound healing.


Long-term clinical outcomes in a cohort of patients with solitary plasmacytoma treated in the modern era.
The risk of recurrence of solitary plasmacytoma (SP)/progression to MM is well established, but patient, imaging and treatment factors influencing risk of progression require further evaluation. This is a retrospective analysis of 66 SP patients (23 UK, 43 Brazil) diagnosed 1989-2016. Patient baseline characteristics were recorded. The incidence of progression to MM was calculated, including biochemical and imaging findings and the treatment modality received. Survival estimates were determined by Kaplan-Meier analyses. With a median follow-up of 53.6 months the 5 year overall survival (OS) was 90.7% (95%CI 79-96%). The median progression free survival (PFS) from diagnosis was 61 months. Cumulative incidence of progression to MM was 49.9% at 5 years (95% CI 35.6-62.6%) and was significantly higher with bone plasmacytoma (47.2%, 95%CI 31.9-61.1%), than an extramedullary location (8.3%, 95%CI 0.4-32.3%, Gray test p = 0.0095)). The majority of patients with solitary bony plasmacytoma (SBP) received radiotherapy (RT) (51/53, 96.2%) whereas most extramedullary cases were treated with surgical resection (7/13, 53.8%). A small proportion of SBP patients received additional upfront chemotherapy, with 5/6 in remission after a median follow-up (FU) of 10 years. The diagnostic yield of surveillance functional FU imaging without other indications of relapse/progression was low. The positive predictive value of functional FU imaging was high but with a low negative predictive value, especially in cases of suspected relapse/progression. Our data suggests functional imaging should be used if clinical suspicion of relapse/progression, rather than a routine surveillance tool, and upfront adjuvant chemotherapy is worthy of prospective evaluation.


Functional roles for the cytoplasmic domain of the type III transforming growth factor beta receptor in regulating transforming growth factor beta signaling.
Transforming growth factor beta (TGF-beta) signals through three high affinity cell surface receptors, TGF-beta type I, type II, and type III receptors. The type III receptor, also known as betaglycan, binds to the type II receptor and is thought to act solely by "presenting" the TGF-beta ligand to the type II receptor. The short cytoplasmic domain of the type III receptor is thought to have no role in TGF-beta signaling because deletion of this domain has no effect on association with the type II receptor, or with the presentation role of the type III receptor. Here we demonstrate that the cytoplasmic domains of the type III and type II receptors interact specifically in a manner dependent on the kinase activity of the type II receptor and the ability of the type II receptor to autophosphorylate. This interaction results in the phosphorylation of the cytoplasmic domain of the type III receptor by the type II receptor. The type III receptor with the cytoplasmic domain deleted is able to bind TGF-beta, to bind the type II receptor, and to enhance TGF-beta binding to the type II receptor but is unable to enhance TGF-beta2 signaling, determining that the cytoplasmic domain is essential for some functions of the type III receptor. The type III receptor functions by selectively binding the autophosphorylated type II receptor via its cytoplasmic domain, thus promoting the preferential formation of a complex between the autophosphorylated type II receptor and the type I receptor and then dissociating from this active signaling complex. These studies, for the first time, elucidate important functional roles of the cytoplasmic domain of the type III receptor and demonstrate that these roles are essential for regulating TGF-beta signaling.


Atrial natriuretic peptide transcription, storage, and release in rats with myocardial infarction.
To study the role of atrial natriuretic peptide (ANP) in chronic heart failure, ANP synthesis, storage, and release were examined by measuring atrial ANP messenger ribonucleic acid (mRNA) levels and atrial and plasma ANP concentrations in rats with myocardial infarction produced by coronary artery ligation. Three groups were defined as the following: 1) controls, sham-operated, or operated, but noninfarcted; 2) moderate infarcts, involving 5-30% of the left ventricular circumference; and 3) large infarcts (greater than or equal to 30%). In addition, to determine a possible modulation by dietary Na intake on ANP levels in heart failure, plasma immunoreactive ANP (iANP) levels were measured in rats with and without infarcts given low, regular, or high Na intake for 2 wk, by which time all groups were in neutral balance. Plasma iANP levels varied directly with increasing infarct and atrial sizes, irrespective of Na intake. In contrast, atrial ANP concentration varied inversely with increasing infarct size. The ANP mRNA content index, a measure of total atrial ANP mRNA, was significantly increased in rats with large infarcts compared with control rats. These results indicate that in rats with myocardial infarction, the severity of left ventricular dysfunction, as inferred from infarct size, but not chronic Na intake, is the primary determinant of the extent of activation of the ANP system. Elevated circulating ANP levels are maintained through enhanced atrial synthesis and release. ANP may thus play an important role in the hemodynamic and renal adaptations to chronic heart failure.


Carfilzomib and pomalidomide in patients with relapsed and/or refractory multiple myeloma with baseline risk factors.
While survival times have increased over the last decade, most patients with multiple myeloma (MM) eventually relapse and become refractory to therapy. The treatment of patients with relapsed and/or refractory MM is frequently further complicated by the presence of pre-existing comorbidities that arise from an advanced disease state and of toxicities stemming from prior antimyeloma treatment. Carfilzomib and pomalidomide have recently been approved for the treatment of patients with relapsed and refractory MM. While these agents represent important additions to the available treatment options, the identification of patients who may best benefit from the use of each of therapy is still being investigated. A number of patient-related and disease-related factors may impact treatment efficacy and/or tolerability, and the clinical presentation and medical history of each patient must be carefully considered to optimize treatment. Here, we review results from carfilzomib and pomalidomide clinical trials in patients with relapsed and/or refractory MM who also have baseline comorbidities or treatment-induced or disease-induced complications (including the presence of renal impairment, cardiac risk factors, peripheral neuropathy, or high-risk chromosomal abnormalities) to evaluate the safety and efficacy of the two agents in these difficult-to-treat patients and to provide treatment recommendations specific to each scenario.


Quality of outpatient clinical notes: a stakeholder definition derived through qualitative research.
There are no empirically-grounded criteria or tools to define or benchmark the quality of outpatient clinical documentation. Outpatient clinical notes document care, communicate treatment plans and support patient safety, medical education, medico-legal investigations and reimbursement. Accurately describing and assessing quality of clinical documentation is a necessary improvement in an increasingly team-based healthcare delivery system. In this paper we describe the quality of outpatient clinical notes from the perspective of multiple stakeholders. Using purposeful sampling for maximum diversity, we conducted focus groups and individual interviews with clinicians, nursing and ancillary staff, patients, and healthcare administrators at six federal health care facilities between 2009 and 2011. All sessions were audio-recorded, transcribed and qualitatively analyzed using open, axial and selective coding. The 163 participants included 61 clinicians, 52 nurse/ancillary staff, 31 patients and 19 administrative staff. Three organizing themes emerged: 1) characteristics of quality in clinical notes, 2) desired elements within the clinical notes and 3) system supports to improve the quality of clinical notes. We identified 11 codes to describe characteristics of clinical notes, 20 codes to describe desired elements in quality clinical notes and 11 codes to describe clinical system elements that support quality when writing clinical notes. While there was substantial overlap between the aspects of quality described by the four stakeholder groups, only clinicians and administrators identified ease of translation into billing codes as an important characteristic of a quality note. Only patients rated prioritization of their medical problems as an aspect of quality. Nurses included care and education delivered to the patient, information added by the patient, interdisciplinary information, and infection alerts as important content. Perspectives of these four stakeholder groups provide a comprehensive description of quality in outpatient clinical documentation. The resulting description of characteristics and content necessary for quality notes provides a research-based foundation for assessing the quality of clinical documentation in outpatient health care settings.


Ionic contrast across a lipid membrane for Debye length extension: towards an ultimate bioelectronic transducer.
Despite technological advances in biomolecule detections, evaluation of molecular interactions via potentiometric devices under ion-enriched solutions has remained a long-standing problem. To avoid severe performance degradation of bioelectronics by ionic screening effects, we cover probe surfaces of field effect transistors with a single film of the supported lipid bilayer, and realize respectable potentiometric signals from receptor-ligand bindings irrespective of ionic strength of bulky solutions by placing an ion-free water layer underneath the supported lipid bilayer. High-energy X-ray reflectometry together with the circuit analysis and molecular dynamics simulation discovered biochemical findings that effective electrical signals dominantly originated from the sub-nanoscale conformational change of lipids in the course of receptor-ligand bindings. Beyond thorough analysis on the underlying mechanism at the molecular level, the proposed supported lipid bilayer-field effect transistor platform ensures the world-record level of sensitivity in molecular detection with excellent reproducibility regardless of molecular charges and environmental ionic conditions.


High risk of human papillomavirus infection and cervical squamous intraepithelial lesions among women with symptomatic human immunodeficiency virus infection.
We investigated the relationship of human papillomavirus (by cervicovaginal lavage and Southern blot), human immunodeficiency virus, and squamous intraepithelial lesions in 96 high-risk women in the Bronx, New York. Antibodies for human immunodeficiency virus were detected in 51 (53%) women. Of the 33 women with symptomatic human immunodeficiency virus infection, 23 (70%) had human papillomavirus infection compared with 4 of 18 (22%) asymptomatic women who were human immunodeficiency virus seropositive and 10 of 45 (22%) uninfected women (p less than 0.0001). The rate of squamous intraepithelial lesions was 52% (14 of 27) for women with both viruses detected, 18% (6 of 34) for women with either virus detected, and 9% (3 of 35) for uninfected women. Among symptomatic human immunodeficiency virus-infected women, a strong association between human papillomavirus infection and squamous intraepithelial lesions was demonstrated (odds ratio, 12; 95% confidence interval, 1.3 to 108). Risk was highest for younger women from ethnic or racial minority groups. Advanced human immunodeficiency virus-related disease, with its associated immunosuppression, seems to exacerbate human papillomavirus-mediated cervical cytologic abnormalities. Public health measures are needed to provide Papanicolaou smear screening and appropriate clinical follow-up and treatment for women at high risk for human immunodeficiency virus infection.


Effect of Shenqin biochemical extract on hypoxia-inducible factor-1α expression in ultraviolet B-irradiated HaCaT cells.
Hypoxia-inducible factor-1α (HIF-1α) is considered the main transcriptional regulator of the hypoxia-specific cellular and developmental response. This study was performed to investigate the effect of Shenqin biochemical extract (SQBE) on HIF-1α expression in ultraviolet B (UVB)-irradiated HaCaT cells and the possible action mechanisms of SQBE against UVB-induced skin cancer. HaCaT cells in logarithmic growth phase were seeded in Dulbecco's modified Eagle's medium with 10% fetal bovine serum, and conventionally cultured at 37°C with 5% CO2. Cells were divided into control group (administered the same amounts of dimethyl sulfoxide), SQBE1 group (12.5 μg/mL SQBE), SQBE2 group (25.0 μg/mL SQBE), and SQBE3 group (50.0 μg/mL SQBE). Four hours post administration, the control and treatment groups were irradiated with UVB (0, 20, 40, and 60 mJ/cm2). After 24 h, cell survival rate was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Expression levels of HIF-1α mRNA and protein were detected by polymerase chain reaction and western blotting, respectively. SQBE-treated, UVB-irradiated cells had improved survival rates. This increase was most significant in SQBE3 group (P < 0.01), which also had effectively reduced expression of intracellular HIF-1α mRNA and protein. Hence, SQBE had a protective effect on UVB-irradiated HaCaT cells and inhibited the UVB irradiation-induced expression of HIF-1α. This indicates that SQBE could prevent the occurrence of UVB radiation-induced skin cancer.


Genetic modulation of oral anticoagulation with warfarin.
Cytochrome P450 CYP2C9 gene variants have been associated with hyperresponsiveness to small doses of warfarin and a higher bleeding complication rate. The aim of this study was to investigate whether CYP2C9 gene variants affect doses of drug prescribed to acquire the target anticoagulation intensity and the occurence of bleeding complications. In a cohort of 180 patients followed up at one specialized clinic from the start of the anticoagulation with warfarin, we have investigated whether CYP2C9 gene variants have affected doses of drug prescribed to acquire the target anticoagulation intensity and the incidence of bleeding complications. The adjusted dose required of warfarin was higher among patients with the CYP2C9*1 haplotype (5.6 mg) than those of patients carrying the CYP2C9*2 (4.7 mg; p = 0.007, Scheffé's test) or the CYP2C9*3 haplotype (4.0 mg; p <0.001, Scheffé's test). The occurrence of bleeding complications was more frequent among patients with the CYP2C9*2 and/or the CYP2C9*3 haplotype than in carriers of the CYP2C9*1 haplotype (OR: 2.57; 95% CI; 1.16-5.73). An interaction between the presence of local bleeding sources and the CYP2C9*2 and/or the CYP2C9*3 haplotype was observed (p <0.001). Patients with both local sites of potential bleeding and CYP2C9*2 and/or the CYP2C9*3 haplotype had the higher estimated risk of bleeding (OR: 12.81; 95% CI: 2.86-57.26). CYP2C9 gene variants modulate the anticoagulant effect of the dose of warfarin prescribed. The incidence of bleeding complications in CYP2C9*2 and CYP2C9*3 carriers was significantly higher than that in noncarriers and interacted with the presence of local bleeding sources.


Role of ubiquitin-like protein FAT10 in epithelial apoptosis in renal disease.
Dysregulated apoptosis of renal tubular epithelial cells (RTEC) is an important component of the pathogenesis of several renal diseases, including HIV-associated nephropathy (HIVAN), the most common cause of chronic kidney failure in HIV-infected patients. In HIVAN, RTEC become infected by HIV-1 in a focal distribution, and HIV-1 infection has been shown to induce apoptosis in vitro. In microarray studies that used a novel renal tubular epithelial cell line from a patient with HIVAN, it was found that the ubiquitin-like protein FAT10 is one of the most upregulated genes in HIV-infected cells. Previously, FAT10 was shown to induce apoptosis in murine fibroblasts. The expression of FAT10 in HIVAN and the ability of FAT10 to induce apoptosis in human RTEC therefore were studied. This study revealed that FAT10 expression is induced after infection of RTEC by HIV-1 and that expression of FAT10 induces apoptosis in RTEC in vitro. Moreover, it was found that inhibition of endogenous FAT10 expression abrogated HIV-induced apoptosis of RTEC. Immunohistochemical studies demonstrated increased FAT10 expression in a murine model of HIVAN, in HIVAN biopsy samples, and in autosomal dominant polycystic kidney disease, another renal disease that is characterized by cystic tubular enlargement and epithelial apoptosis. These results suggest a novel role for FAT10 in epithelial apoptosis, which is an important component of the pathogenesis of many renal diseases.


Association of Pulse Pressure With Clinical Outcomes in Patients Under Different Antiplatelet Strategies After Percutaneous Coronary Intervention: Analysis of GLOBAL LEADERS.
We evaluated the association of pulse pressure (PP) and different antiplatelet regimes with clinical and safety outcomes in an all-comers percutaneous coronary intervention (PCI) population. In this analysis of GLOBAL LEADERS (n = 15,936) we compared the experimental therapy of 23 months of ticagrelor after 1 month of dual-antiplatelet therapy (DAPT) vs standard DAPT for 12 months followed by aspirin monotherapy in subjects who underwent PCI and were divided into 2 groups according to the median PP (60 mm Hg). The primary end point (all-cause death or new Q-wave myocardial infarction) and the composite end points: patient-oriented composite end points (POCE), Bleeding Academic Research Consortium (BARC) 3 or 5, and net adverse clinical events (NACE) were evaluated. At 2 years, subjects in the high-PP group (n = 7971) had similar rates of the primary end point (4.3% vs 3.9%; P = 0.058), POCE (14.9% vs 12.7%; P = 0.051), and BARC 3 or 5 (2.5% vs 1.7%; P = 0.355) and higher rates of NACE (16.4% vs 13.7%; P = 0.037) compared with the low-PP group (n = 7965). Among patients with PP < 60 mm Hg, the primary end point (3.4% vs 4.4%, adjusted hazard ratio [aHR] 0.77, 95% confidence interval [CI] 0.61-0.96), POCE (11.8% vs 13.5%, aHR 0.86, 95% CI 0.76-0.98), NACE (12.8% vs 14.7%, aHR 0.85, 95% CI 0.76-0.96), and BARC 3 or 5 (1.4% vs 2.1%, aHR 0.69, 95% CI 0.49-0.97) were lower with ticagrelor monotherapy compared with DAPT. The only significant interaction was for BARC 3 or 5 (P = 0.008). After contemporary PCI, subjects with high PP levels experienced high rates of NACE at 2 years. In those with low PP, ticagrelor monotherapy led to a lower risk of bleeding events compared with standard DAPT.


Reduction of unnecessary transfusion and intravenous fluids in severely malnourished children is not enough to reduce mortality.
To test whether standardising the use of blood transfusions and intravenous (IV) infusions could reduce fatality in severely malnourished children admitted to Mulago Hospital, Kampala. Improved adherence to the WHO protocol for blood transfusion and IV fluids was effected in patients with severe malnutrition by continuous medical education. A 'before and after' design was used to study 450 severely malnourished children (weight-for-height < -3 Z-score or presence of oedema) under 60 months of age. A total of 220 pre- and 230 post-'improved practice' patients were enrolled consecutively during the periods September to November 2003 and September to December 2004, respectively. Patients were followed up until discharge or death. The Kaplan-Meier survival curve and the Cox regression hazard model were used for univariate and multivariate analyses, respectively. Overall case fatality was 23.6% (52/220) in the pre-period and 24.8% (57/230) in the post-period (p=0.78). Most of the deaths occurred in the 1st week of admission (73%, 38/52 in the pre-period and 61%, 35/57 in the post-period) and were of children who had received blood transfusion or IV infusion or both in the pre-period. Mortality in children transfused and/or infused was significantly reduced in the post-period (82%, 31/38 in the pre-period vs 23%, 8/35 in the post-period, p=0.008). In the post-period, there was a significant reduction in the number of inappropriate blood transfusions (18%, 34/194 vs 3.5%, 8/230, p=0.01) and IV fluid infusions (27%, 52/194 vs 9%, 20/230, p<0.001). Survival improved in children who received blood transfusions in the post-period [hazards ratio (HR) 0.22, 95% CI 0.30-1.67 vs HR 4.80, 95% CI 1.71-13.51], as did that of children who received IV infusions (HR 2.10, 95% CI 0.84-5.23 vs HR 3.91, 95% CI 1.10-14.04). Management according to the WHO protocol for severe malnutrition can reduce the need for blood and IV infusions. However, further studies are required to verify whether full implementation of the WHO protocol reduces the high case fatality in sub-Saharan hospitals.


Public-Medicine Dissonance: Why in a World of Evidence-based Medicine?
The evolution of medicine is quite remarkable and astounding. Modern medicine is successfully treating or providing long-term control of conditions which in the not-so-distant past were lethal or resulted in permanent disability. The strong emphasis on evidence-based medicine in today's medical profession has led to a more organized approach toward evaluating the safety and efficacy of new medical treatments. Despite attempts to meet the complex needs of an ever-aging population, an almost cynical or inherent distrust of physicians in general and their medical claims is being increasingly noted. For many physicians this has led to an uncomfortable sense of professional frustration as doubt is cast on themselves or the medical profession in general when the expectations and goals of patients or their families are not achieved. The causes of this apparent malady of contemporary medicine are myriad and may be explored from various perspectives, depending on the particular issue. To understand better the issues and challenges involved, today's medical practitioner needs to be aware of the complex mix of organizational, professional, ethical, and at times anthropological perspectives contributing to this dissonance between medical professionals and the public. Improving our insight into the forces at work in this dissonance will help medical professionals improve medical services to the public and contribute to the preservation of medicine's admirable historical legacy.


Forecasting the global shortage of physicians: an economic- and needs-based approach.
Global achievements in health may be limited by critical shortages of health-care workers. To help guide workforce policy, we estimate the future demand for, need for and supply of physicians, by WHO region, to determine where likely shortages will occur by 2015, the target date of the Millennium Development Goals. Using World Bank and WHO data on physicians per capita from 1980 to 2001 for 158 countries, we employ two modelling approaches for estimating the future global requirement for physicians. A needs-based model determines the number of physicians per capita required to achieve 80% coverage of live births by a skilled health-care attendant. In contrast, our economic model identifies the number of physicians per capita that are likely to be demanded, given each country's economic growth. These estimates are compared to the future supply of physicians projected by extrapolating the historical rate of increase in physicians per capita for each country. By 2015, the global supply of physicians appears to be in balance with projected economic demand. Because our measure of need reflects the minimum level of workforce density required to provide a basic health service that is met in all but the least developed countries, the needs-based estimates predict a global surplus of physicians. However, on a regional basis, both models predict shortages for many countries in the WHO African Region in 2015, with some countries experiencing a needs-based shortage, a demand-based shortage, or both. The type of policy intervention needed to alleviate projected shortages, such as increasing health-care training or adopting measures to discourage migration, depends on the type of shortage projected.


Programmed database system at the Chang Gung Craniofacial Center: part II--digitizing photographs.
The archival tools used for digital images in advertising are not to fulfill the clinic requisition and are just beginning to develop. The storage of a large amount of conventional photographic slides needs a lot of space and special conditions. In spite of special precautions, degradation of the slides still occurs. The most common degradation is the appearance of fungus flecks. With the recent advances in digital technology, it is now possible to store voluminous numbers of photographs on a computer hard drive and keep them for a long time. A self-programmed interface has been developed to integrate database and image browser system that can build and locate needed files archive in a matter of seconds with the click of a button. This system requires hardware and software were market provided. There are 25,200 patients recorded in the database that involve 24,331 procedures. In the image files, there are 6,384 patients with 88,366 digital pictures files. From 1999 through 2002, NT400,000 dollars have been saved using the new system. Photographs can be managed with the integrating Database and Browse software for database archiving. This allows labeling of the individual photographs with demographic information and browsing. Digitized images are not only more efficient and economical than the conventional slide images, but they also facilitate clinical studies.


Functional connectivity of dorsal and ventral frontoparietal seed regions during auditory orienting.
Our ability to refocus auditory attention is vital for even the most routine day-to-day activities. Shifts in auditory attention can be initiated "voluntarily," or triggered "involuntarily" by unexpected novel sound events. Here we employed psychophysiological interaction (PPI) analyses of auditory functional MRI data, to compare functional connectivity patterns of distinct frontoparietal cortex regions during cued voluntary vs. novelty-driven involuntary auditory attention shifting. Overall, our frontoparietal seed regions exhibited significant PPI increases with auditory cortex (AC) areas during both cued and novelty-driven orienting. However, significant positive PPI patterns associated with voluntary auditory attention (cue>novel task regressor), but mostly absent in analyses emphasizing involuntary orienting (novel>cue task regressor), were observed with seeds within the frontal eye fields (FEF), superior parietal lobule (SPL), and right supramarginal gyri (SMG). In contrast, significant positive PPIs associated selectively with involuntary orienting were observed between ACs and seeds within the bilateral anterior interior frontal gyri (IFG), left posterior IFG, SMG, and posterior cingulate cortices (PCC). We also found indices of lateralization of different attention networks: PPI increases selective to voluntary attention occurred primarily within right-hemispheric regions, whereas those related to involuntary orienting were more frequent with left-hemisphere seeds. In conclusion, despite certain similarities in PPI patterns across conditions, the more dorsal aspects of right frontoparietal cortex demonstrated wider connectivity during cued/voluntary attention shifting, whereas certain left ventral frontoparietal seeds were more widely connected during novelty-triggered/involuntary orienting. Our findings provide partial support for distinct attention networks for voluntary and involuntary auditory attention.


Assessing Suicidal Ideation and Behaviors Among Survivors of Childhood Brain Tumors and Their Mothers During Sociobehavioral Research.
To describe the development and feasibility of a protocol for nonpsychiatric subspecialty research staff members to screen research participants who endorse suicidal ideations or behaviors during data collection . Descriptive protocol development. . The Children's Hospital of Philadelphia and the University of Pennsylvania. . 186 mother caregivers and 134 adolescent or young adult survivors of childhood brain tumors, with the protocol implemented for 5 caregivers and 11 survivors. During telephone- and home-based interviews, the interviewer assessed the participant using the Columbia-Suicide Severity Rating Scale (C-SSRS). Expressed suicidal ideation or behavior . Implementation of the C-SSRS by nonpsychiatric subspecialty staff members was feasible and valid. Interviewers' conclusions based on this instrument matched those of the mental health professional who followed up with participants. Process notes contained themes about the participants, including anger and sadness in survivors and the physical and emotional demands of the survivor in caregivers. Progress notes for the interviewer included a reiteration of events, whether the assessment was successful, and whether the recommendation of the interviewer was in agreement with that of the mental health professional . The protocol based on the C-SSRS was useful and feasible for nonpsychiatric subspecialty staff members to use in the collection of data from survivors of childhood brain tumors and their caregivers. Survivors of childhood brain tumors and their caregivers may experience psychosocial distress. Nurses, as research assistants or in other roles, can use tools such as the C-SSRS to assist in front-line assessments. .


Understanding the decision to take the predictive test for Huntington disease.
The predictive test for Huntington disease (HD) has allowed those at risk to determine gene status prior to symptoms. The purpose of this research was to understand the motivation and the anticipated reactions of those requesting the test. Forty persons at 50% risk for HD and 31 companions participated in a structured personal interview as part of the predictive test protocol. Reasons for taking the test centered on the reduction of anxiety and uncertainty associated with being at risk and enhanced planning and decision making. Participants also believed that taking the test would produce more positive than negative outcomes. With a favorable result, most anticipated a reduction of anxiety, a more normal future, and relief knowing their children would be at a very low risk. Most also cited benefits as more likely than consequences with an unfavorable result. Making the most of life, easier planning, and reduced uncertainty were rated as more likely than any of the adverse impacts, including short-term depression and becoming frightened. Almost all participants (95%) said they would rather learn that they have the HD gene than remain at 50% risk. The uncertainty, anxiety, and chronic stress associated with being at risk appears to underlie the motivation of many seeking the predictive test for HD.


Review of the Safety and Efficacy of Moringa oleifera.
Moringa oleifera leaves, seeds, bark, roots, sap, and flowers are widely used in traditional medicine, and the leaves and immature seed pods are used as food products in human nutrition. Leaf extracts exhibit the greatest antioxidant activity, and various safety studies in animals involving aqueous leaf extracts indicate a high degree of safety. No adverse effects were reported in association with human studies. Five human studies using powdered whole leaf preparations of M. oleifera have been published, which have demonstrated anti-hyperglycemic (antidiabetic) and anti-dyslipidemic activities. These activities have been confirmed using extracts as well as leaf powders in animal studies. A rapidly growing number of published studies have shown that aqueous, hydroalcohol, or alcohol extracts of M. oleifera leaves possess a wide range of additional biological activities including antioxidant, tissue protective (liver, kidneys, heart, testes, and lungs), analgesic, antiulcer, antihypertensive, radioprotective, and immunomodulatory actions. A wide variety of polyphenols and phenolic acids as well as flavonoids, glucosinolates, and possibly alkaloids is believed to be responsible for the observed effects. Standardization of products is an issue. However, the results of published studies to date involving M. oleifera are very promising. Additional human studies using standardized extracts are highly desirable.


Optic-guided vaginal repair of vesicovaginal fistula.
The transvaginal approach for the repair of vesicovaginal fistula (VVF) can sometimes be challenging, especially in fistulas located near the vaginal cuff. We describe a simple technique for the vaginal repair of VVF with the use of endoscopic optics. Three women were admitted to our department with urinary incontinence after total hysterectomy. Assessment with a clinical examination, imaging, and cystoscopy confirmed the diagnosis of VVF. All patients were operated on between December 2012 and January 2013. The operations were conducted under spinal anesthesia with the patients in the lithotomy position. Cystoscopy was performed and retrograde pyelography ruled out any ureteral damage or fistula. A 10F to 12F Foley catheter was inserted into the fistula. From this point, the operation proceeded with optic vision, mimicking laparoscopic dissection and suturing techniques using a standard 5 mm, 30-degree optic lens, a surgical monitor, and open surgical instruments. The fistula was circumferentially incised and widely mobilized from the surrounding tissues and closed without tension in two layers. A urethral Foley catheter was inserted and maintained for 14 days. The mean operative time was 70 (range 60-80) minutes. Estimated blood loss was minimal. All patients were discharged at postoperative day 1. No complications were observed. At the postoperative first and third month follow-up visits, all patients were voiding without any urinary leakage or complaints. The use of optics in the vaginal repair of VVF is a useful technique. Optic guidance facilitates surgical vision, dissection, and hemostasis. It is also excellent for surgeon comfort, ergonomics, and resident training.


Contributions of isolated Pacific populations to understanding neurodegenerative diseases.
Isolated human populations have provided a natural experimental laboratory for the ongoing study of human disease. In the mid-20th century a number of high-incidence foci of neurodegenerative diseases were brought to medical attention including kuru, amyotrophic lateral sclerosis, and parkinsonism-dementia. These foci were discovered in Papua New Guinea, West New Guinea, the Kii Peninsula of Japan, and in the Mariana Islands. The study of these diseases in isolated human groups has significantly contributed to our understanding of the cause and mechanisms of pathogenesis of these and related neurodegenerative disorders globally. This paper is dedicated to D. Carleton Gajdusek, a pioneer in the study of neurodegenerative diseases, whose decades of fieldwork and laboratory studies have led to numerous scientific discoveries that have reshaped our thinking and understanding about neurodegeneration.


Global threats from invasive alien species in the twenty-first century and national response capacities.
Invasive alien species (IAS) threaten human livelihoods and biodiversity globally. Increasing globalization facilitates IAS arrival, and environmental changes, including climate change, facilitate IAS establishment. Here we provide the first global, spatial analysis of the terrestrial threat from IAS in light of twenty-first century globalization and environmental change, and evaluate national capacities to prevent and manage species invasions. We find that one-sixth of the global land surface is highly vulnerable to invasion, including substantial areas in developing economies and biodiversity hotspots. The dominant invasion vectors differ between high-income countries (imports, particularly of plants and pets) and low-income countries (air travel). Uniting data on the causes of introduction and establishment can improve early-warning and eradication schemes. Most countries have limited capacity to act against invasions. In particular, we reveal a clear need for proactive invasion strategies in areas with high poverty levels, high biodiversity and low historical levels of invasion.


Whole-exome sequencing reveals a rapid change in the frequency of rare functional variants in a founding population of humans.
Whole-exome or gene targeted resequencing in hundreds to thousands of individuals has shown that the majority of genetic variants are at low frequency in human populations. Rare variants are enriched for functional mutations and are expected to explain an important fraction of the genetic etiology of human disease, therefore having a potential medical interest. In this work, we analyze the whole-exome sequences of French-Canadian individuals, a founder population with a unique demographic history that includes an original population bottleneck less than 20 generations ago, followed by a demographic explosion, and the whole exomes of French individuals sampled from France. We show that in less than 20 generations of genetic isolation from the French population, the genetic pool of French-Canadians shows reduced levels of diversity, higher homozygosity, and an excess of rare variants with low variant sharing with Europeans. Furthermore, the French-Canadian population contains a larger proportion of putatively damaging functional variants, which could partially explain the increased incidence of genetic disease in the province. Our results highlight the impact of population demography on genetic fitness and the contribution of rare variants to the human genetic variation landscape, emphasizing the need for deep cataloguing of genetic variants by resequencing worldwide human populations in order to truly assess disease risk.


Efficacy of a povidone-iodine foam dressing (Betafoam) on diabetic foot ulcer.
This study aimed to assess the efficacy of a new povidone-iodine (PVP-I) foam dressing (Betafoam) vs foam dressing (Medifoam) for the management of diabetic foot ulcers. This study was conducted between March 2016 and September 2017 at 10 sites in Korea. A total of 71 patients (aged ≥19 years) with type 1/2 diabetes and early-phase diabetic foot ulcers (Wagener classification grade 1/2) were randomised to treatment with PVP-I foam dressing or foam dressing for 8 weeks. Wound healing, wound infection, patient satisfaction, and adverse events (AEs) were assessed. The PVP-I foam and foam dressing groups were comparable in the proportion of patients with complete wound healing within 8 weeks (44.4% vs 42.3%, P = .9191), mean (±SD) number of days to complete healing (31.00 ± 15.07 vs 33.27 ± 12.60 days; P = .6541), and infection rates (11.1% vs 11.4%; P = 1.0000). Median satisfaction score (scored from 0 to 10) at the final visit was also comparable between groups (10 vs 9, P = .2889). There was no significant difference in AE incidence (27.8% vs 17.1%, P = .2836), and none of the reported AEs had a causal relationship with the dressings. The results of this study suggest that PVP-I foam dressing has wound-healing efficacy comparable with foam dressing, with no notable safety concerns. This study was funded by Mundipharma Korea Ltd and registered at ClinicalTrials.gov (identifier NCT02732886).


Mapping the knowledge of the main diseases affecting sea bass and sea bream in Mediterranean.
Good knowledge on the disease situation and its impact on production is a base mechanism for designing health surveillance, risk analysis and biosecurity systems. Mediterranean marine fish farming, as any aquaculture production, is affected by various infectious diseases. However, seabass and seabream, the main produced species, are not listed as susceptible host species for the notifiable pathogens listed in the current EU legislation, which generates a lack of systematic reporting. The results presented in this study come from a survey directly to fish farms (50 hatchery and on-growing units from 10 Mediterranean countries), with data from 2015 to 2017, conducted by the H2020 project MedAID. Seabass showed a higher survival rate (85%) through a production cycle than seabream (80%) in spite of equal mortality due to pathogen infections (10%). The differences in survival may be explained by mortality 'of other causes'. Seabream and seabass have different disease profiles, and the profile is slightly different between geographical regions. Among the most important diseases, tenacibaculosis and vibriosis were identified in seabass and Sparicotyle chrysophrii (a gill fluke) and nodavirus in seabream. Correlating mortality data to management variables showed that increasing density, buying fingerlings from external sources and treatments due to disease are factors that negatively influence mortality rate. Most of the surveyed farms did not keep sufficient quality data to implement good health status reports and perform detailed impact studies, which shows the necessity of updating the current legislative framework to provide the basis for better reporting of relevant pathogens in the Mediterranean basin.


Macrophage-mediated degradation of crosslinked collagen scaffolds.
Biological scaffolds used in tissue engineering are incorporated in vivo by a process of cellular in-growth, followed by host-mediated degradation and replacement of these scaffolds, in which phagocytic cells from the monocyte/macrophage cell lineage play a key role. The chemical degradation of scaffolds with collagenases is well established, but to date this has not been correlated with an in vitro model of cell mediated scaffold degradation. RAW264.7, a murine monocyte/macrophage cell line, was cultured on collagen scaffolds crosslinked either by dehydrothermal treatment (DHT) or by carbodiimide (EDC). These cells attached to collagen scaffolds, proliferated and exhibited macrophage aggregation to form giant cells. Crosslinking the scaffolds by either DHT or EDC increased the resistance of the scaffold to degradation by macrophages. Increasing the amount of crosslinking in the scaffold made them more resistant to degradation by collagenase. However, while EDC increased the scaffolds' thermal and mechanical properties and decreased the swelling ratio, DHT increased the mechanical properties, but decreased the denaturation temperature and swelling ratio. Altering the scaffold properties by crosslinking affects the rate of degradation by macrophages, and this is correlated with chemical degradation (r=0.658, p<0.01). This will help in the design of scaffolds with task-specific profiles for use in tissue engineering.


LabTrove: a lightweight, web based, laboratory "blog" as a route towards a marked up record of work in a bioscience research laboratory.
The electronic laboratory notebook (ELN) has the potential to replace the paper notebook with a marked-up digital record that can be searched and shared. However, it is a challenge to achieve these benefits without losing the usability and flexibility of traditional paper notebooks. We investigate a blog-based platform that addresses the issues associated with the development of a flexible system for recording scientific research. We chose a blog-based approach with the journal characteristics of traditional notebooks in mind, recognizing the potential for linking together procedures, materials, samples, observations, data, and analysis reports. We implemented the LabTrove blog system as a server process written in PHP, using a MySQL database to persist posts and other research objects. We incorporated a metadata framework that is both extensible and flexible while promoting consistency and structure where appropriate. Our experience thus far is that LabTrove is capable of providing a successful electronic laboratory recording system. LabTrove implements a one-item one-post system, which enables us to uniquely identify each element of the research record, such as data, samples, and protocols. This unique association between a post and a research element affords advantages for monitoring the use of materials and samples and for inspecting research processes. The combination of the one-item one-post system, consistent metadata, and full-text search provides us with a much more effective record than a paper notebook. The LabTrove approach provides a route towards reconciling the tensions and challenges that lie ahead in working towards the long-term goals for ELNs. LabTrove, an electronic laboratory notebook (ELN) system from the Smart Research Framework, based on a blog-type framework with full access control, facilitates the scientific experimental recording requirements for reproducibility, reuse, repurposing, and redeployment.


Perceptions of the Implementation of Pediatric Behavioral Health Integration in 3 Community Health Centers.
Pediatric behavioral health integration (BHI) represents a promising approach to address unmet child mental health need but little research exists to guide BHI implementation. Through in-depth interviews with 38 professionals involved in a comprehensive pediatric BHI initiative at 3 community health centers, we explored perceptions of the impact of BHI on clinical practice, and facilitators and barriers to BHI implementation. Professionals identified 2 overarching themes about the impact of BHI on clinical practice (greater interdisciplinary collaboration/communication and enhanced provider wellness); 5 themes about facilitators of BHI (staff buy-in for BHI, leadership support, staff belonging to the same team culturally and/or structurally, co-location with close physical proximity, and data-driven quality improvement); and 5 themes about barriers to BHI (inadequate clinician staffing, insufficient space, limited provider time, billing/reimbursement issues, and care coordination challenges). Future pediatric BHI efforts may consider these findings to develop strategies to promote facilitators and reduce barriers during implementation.


Dispersion Engineering by Hybridizing the Back-Folded Soft Mode of Monomode Elastic Metamaterials with Stiff Acoustic Modes.
In many cases, the hybridization of two or more excitation modes in solids has led to new and useful dispersion relations of waves. Well-studied examples are phonon polaritons, plasmon polaritons, particle-plasmon polaritons, cavity polaritons, and magnetic resonances at optical frequencies. In all of these cases, the lowest propagating mode couples to a finite-frequency localized resonance. Herein, the unusual metamaterial phonon dispersion relations arising from the hybridization of an ordinary acoustical phonon mode with a back-folded soft or easy phonon mode of a monomode elastic metamaterial are discussed. Conceptually, the single easy mode can have strictly zero wave velocity. In reality, its wave velocity is very much smaller than that of all other modes. Considering polymeric three-dimensional printed elastic monomode metamaterials at ultrasound frequencies, it is shown theoretically and experimentally that the resulting pronounced avoided crossing, with a frequency splitting comparable to the mid-frequency, leads to backward-wave behavior for the lowest band over a broad frequency range, conceptually at zero loss.


Deregulation of epidermal stem cell niche contributes to pathogenesis of nonhealing venous ulcers.
The epidermis is maintained by epidermal stem cells (ESCs) that reside in distinct niches and contribute to homeostasis and wound closure. Keratinocytes at the nonhealing edges of venous ulcers (VUs) are healing-incompetent, hyperproliferative, and nonmigratory, suggesting deregulation of ESCs. To date, genes which regulate ESC niches have been studied in mice only. Utilizing microarray analysis of VU nonhealing edges, we identified changes in expression of genes harboring regulation of ESCs and their fate. In a prospective clinical study of 10 VUs, we confirmed suppression of the bone morphogenetic protein receptor (BMPR) and GATA binding protein 3 (GATA3) as well as inhibitors of DNA-binding proteins 2 and 4 (ID2 and ID4). We also found decreased levels of phosphorylated glycogen synthase kinase 3 (GSK3), nuclear presence of β-catenin, and overexpression of its transcriptional target, c-myc, indicating activation of the Wnt pathway. Additionally, we found down-regulation of leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1), a gene important for maintaining ESCs in a quiescent state, and absence of keratin 15 (K15), a marker of the basal stem cell compartment suggesting local depletion of ESCs. Our study shows that loss of genes important for regulation of ESCs and their fate along with activation of β-catenin and c-myc in the VU may contribute to ESC deprivation and a hyperproliferative, nonmigratory healing incapable wound edge.


Two-dimensional dielectrophoretic particle trapping in a hybrid crystal/PDMS-system.
Dielectrophoretic forces originating from highly modulated electric fields can be used to trap particles on surfaces. An all-optical way to induce such fields is the use of a photorefractive material, where the fields that modulate the refractive index are present at the surface. We present a method for two-dimensional particle alignment on an optically structured photorefractive lithium niobate crystal. The structuring is done using an amplitude-modulating spatial light modulator and laser illumination. We demonstrate trapping of uncharged graphite particles in periodic and arbitrary patterns and provide a discussion of the limitations and the necessary boundary conditions for maximum trapping efficiency. The photorefractive crystal is utilized as bottom part of a PDMS channel in order to demonstrate two-dimensional dielectrophoretic trapping in a microfluidic system.


Insulin use in NIDDM. Rationale based on pathophysiology of disease.
Because basal hyperglycemia is a major feature in non-insulin-dependent diabetes mellitus, diabetes control can be monitored by the fasting blood glucose concentration. A hierarchical sequence of therapies is proposed in which the major aim is to maintain near-normal fasting blood glucose concentrations, in the expectation that this will help prevent development of long-term complications. When diet and tablet therapy are no longer effective in keeping the fasting blood glucose level less than 6 mM, a basal insulin supplement from a long-acting insulin such as ultralente can be added. When monitored by fasting blood glucose concentration, there is little risk of hypoglycemia, and the patient can continue a normal life-style without restrictions concerning exercise or the size of individual meals. A basal insulin supplement does not induce marked weight gain. The dose of insulin required can be predicted from the level of the fasting blood glucose and the degree of obesity, which provides an index of the accompanying insulin resistance. Based on current evidence, insulin therapy is equally appropriate in patients with insulin deficiency and insulin resistance, because the benefit from maintaining near-normal glucose concentrations probably outweighs a putative risk of hyperinsulinemia. In more severely affected patients, additional regular insulin to cover meals is needed. Lowering fasting blood glucose to normal with a basal insulin supplement reduces endogenous insulin production, and this may be advantageous if accompanying production of islet amyloid polypeptide and islet amyloid formation are also reduced.


Normative Data for the NeuroCom Sensory Organization Test in US Military Special Operations Forces.
Postural stability is the ability to control the center of mass in relation to a person's base of support and can be affected by both musculoskeletal injury and traumatic brain injury. The NeuroCom Sensory Organization Test (SOT) can be used to objectively quantify impairments to postural stability. The ability of postural stability to predict injury and be used as an acute injury-evaluation tool makes it essential to the screening and rehabilitation process. To our knowledge, no published normative data for the SOT from a healthy, highly active population are available for use as a reference for clinical decision making. To present a normative database of SOT scores from a US Military Special Operations population that can be used for future comparison. Cross-sectional study. Human performance research laboratory. A total of 542 active military operators from Naval Special Warfare Combatant-Craft Crewmen (n = 149), Naval Special Warfare Command, Sea, Air, and Land (n = 101), US Army Special Operations Command (n = 171), and Air Force Special Operations Command (n = 121). Participants performed each of the 6 SOT conditions 3 times. Scores for each condition, total equilibrium composite score, and ratio scores for the somatosensory, visual, and vestibular systems were recorded. Differences were present across all groups for SOT conditions 1 (P < .001), 2 (P = .001), 4 (P > .001), 5 (P > .001), and 6 (P = .001) and total equilibrium composite (P = .000), visual (P > .001), vestibular (P = .002), and preference (P > .001) NeuroCom scores. Statistical differences were evident in the distribution of postural stability across US Special Operations Forces personnel. This normative database for postural stability, as assessed by the NeuroCom SOT, can provide context when clinicians assess a Special Operations Forces population or any other groups that maintain a high level of conditioning and training.


A single nucleotide polymorphism of TRAF1 predicts the clinical response to anti-TNF treatment in Japanese patients with rheumatoid arthritis.
Recent genome-wide association studies disclosed that several single nucleotide polymorphisms (SNPs), including tumour necrosis factor (TNF) receptor-associated factor 1 (TRAF1) (+16860A/G), are associated with the pathophysiology of rheumatoid arthritis (RA). We assessed the usefulness of TRAF1 genotyping as a genetic predictor of the response to anti-TNF treatment in Japanese RA patients. TRAF1 (+16860A/G) was genotyped using the TaqMan SNP genotyping assay in 101 Japanese RA patients treated with anti-TNF drugs for >24 weeks. We retrospectively analysed the association between SNP and the clinical response to treatment. TRAF1 mRNA and protein expression was also evaluated in CD4+, CD8+, CD14+, or CD19+ cells from 25 healthy subjects using quantitative polymerase chain reaction and intracellular staining flow cytometry, respectively. No statistical difference in DAS28-ESR at baseline was observed between the patient groups with the AA, AG, or GG genotype. The GG genotype was more frequent in non-responders than in good or moderate responders [odds ratio (OR) 7.4, 95% confidence interval (CI) 1.5-37.5]. The non-responders possessed the G allele more frequently than the good or moderate responders (OR 3.5, 95% CI 1.4-9.0). TRAF1 protein expression increased significantly in CD14+ monocytes from healthy subjects with the GG genotype compared with that in subjects with the AA or AG genotype. TRAF1 (+16860A/G) may be useful for predicting the clinical response to anti-TNF treatment and may contribute to resistance to treatment in RA patients with the GG genotype by increasing the TRAF1 expression in circulating inflammatory cells.