Identification of Cardiac Glycosides as Novel Inhibitors of eIF4A1-Mediated Translation in Triple-Negative Breast Cancer Cells.
The eukaryotic translation initiation factor 4F complex (eIF4F) is a potential chemotherapeutic target in triple-negative breast cancer (TNBC). This complex regulates cap-dependent translational initiation and consists of three core proteins: eIF4E, eIF4G, and eIF4A1. In this study, we focus on repositioning compounds as novel inhibitors of eIF4A1-mediated translation. In order to accomplish this goal, a modified synthetic reporter assay was established. More specifically, a (CGG)4 motif, which confers eIF4A dependency, was incorporated into the 5'-leader region of a luciferase-tdTomato lentiviral reporter construct. The Prestwick Chemical Library was then screened in multiple TNBC cell lines by measuring the tdTomato fluorescent intensity. We identified several cardiac glycosides as potential inhibitors of eIF4A1-mediated translation. Based on our studies, we find that cardiac glycosides inhibit the expression of eIF4A1. To identify a potential mechanism by which this was occurring, we utilized the Integrative Library of Integrated Network-Based Cellular Signatures (iLINCS). Our pursuits led us to the discovery that cardiac glycosides also decrease levels of c-MYC. Quantitative PCR confirmed that decreases in c-MYC and eIF4A were occurring at the transcriptional level. As such, disruption of the eIF4A1-c-MYC axis may be a viable approach in the treatment of TNBC. The novel combination of rocaglamide A and digoxin exhibited synergistic anti-cancer activity against TNBC cells in vitro. The findings in this study and others are important for formulating potential combination chemotherapies against eIF4A1 in vivo. Thus, drug repositioning may be one classical approach to successfully target eIF4A1 in TNBC patients.


Vitamin D enhances corneal epithelial barrier function.
The purpose of this study was to determine whether 25-hydroxyvitamin D(3) (25(OH)D(3)) and/or its active metabolite, 1α,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), can enhance corneal epithelial barrier function. The authors also determined if corneas contain mRNA for the vitamin D receptor (VDR) and 1α-hydroxylase, the enzyme required to convert 25(OH)D(3) to 1,25(OH)(2)D(3), and measured vitamin D metabolite concentrations in aqueous and vitreous humor. RT-PCR was used to examine mouse, rabbit, and human corneal epithelial VDR and 1α-hydroxylase mRNA. Vitamin D metabolites were measured using a selective vitamin D derivatizing agent and mass spectroscopy. Barrier function experiments were performed by measuring inulin permeability (IP) and/or transepithelial resistance (TER) in control, 25(OH)D(3)-, and 1,25(OH)(2)D(3)-treated human and rabbit corneal epithelial monolayers cultured on permeable inserts. Ca(2+) was removed, then reintroduced to the culture medium while IP and TER readings were taken. Occludin levels were examined using Western blotting. All corneal samples were positive for both VDR and 1α-hydroxylase mRNA. All vitamin D metabolites except for unhydroxylated vitamin D(3) were detected in aqueous and vitreous humor. Epithelial cells showed increased TER, decreased IP, and increased occludin levels when cultured with 25(OH)D(3) and 1,25(OH)(2)D(3). We conclude that corneas contain mRNA for VDR and 1α-hydroxylase as well as significant vitamin D concentrations. 25(OH)D(3) and its active metabolite 1,25(OH)(2)D(3), both enhance corneal epithelial barrier function.


Systematic review of school tobacco prevention programs in African countries from 2000 to 2016.
The World Bank has reported that global smoking rates declined from 2000 to 2012, with the only exception found in males in Sub-Saharan Africa. Sub-Saharan Africa is considered to be in stage one of the tobacco epidemic continuum. To address this problem, school-based programs for smoking prevention are considered cost-effective and promising. Since tobacco prevention programs are influenced by social competence or customs of each country, tobacco prevention programs that have success in Western countries are not always effective in African countries. Therefore, the current study systematically reviewed relevant literature to examine the effects of these types of programs in African countries. Online bibliographic databases and a hand search were used. We included the studies that examined the impact of school-based programs on preventing tobacco use in Africa from 2000 to 2016. Six articles were selected. Four were conducted in South Africa and two were performed in Nigeria. Four programs were systematically incorporated into annual curriculums, targeting 8th to 9th graders, while the other two were temporary programs. All programs were based on the hypothesis that providing knowledge and/or social skills against smoking would be helpful. All studies utilized smoking or polydrug use rates to compare outcomes before/after intervention. There were no significant differences between intervention and control groups in three studies, with the other three demonstrating only partial effectiveness. Additionally, three studies also examined change of knowledge/attitudes towards smoking as an outcome. Two of these showed significant differences between groups. All RCTs studies showed no significant change of smoking-rate by the intervention. The effectiveness of intervention was observed only in some sub-group. The cohort studies showed school-based interventions may be effective in improving knowledge and attitudes about smoking. However, they reported no significant change of smoking-rate by the intervention.


Quantitative genetic modeling of variation in human brain morphology.
The degree to which individual variation in brain structure in humans is genetically or environmentally determined is as yet not well understood. We studied the brains of 54 monozygotic (33 male, 21 female) and 58 dizygotic (17 male, 20 female, 21 opposite sex) pairs of twins and 34 of their full siblings (19 male, 15 female) by means of high resolution magnetic resonance imaging scans. Structural equation modeling was used to quantify the genetic and environmental contributions to phenotypic (co)variance in whole brain, gray and white matter volume of the cerebrum, lateral ventricle volume and associated variables such as intracranial volume and height. Because the cerebral cortex makes up more that two-thirds of the brain mass and almost three-quarters of its synapses, our data predominantly concerns the telencephalon. Genetic factors accounted for most of the individual differences in whole brain (90%), gray (82%) and white (88%) matter volume. Individual differences in lateral ventricle volume were best explained by a model containing common (58%) and unique (42%) environmental factors, indicating genes to be of no or minor influence. In our sample, genetic or environmental influences were not different for males and females. The same genes influenced brain volumes and intracranial volume and almost completely explained their high phenotypic correlation. Genes influencing gray and white matter overlapped to a large extent and completely determined their phenotypic correlation. The high heritability estimates that were found indicate that brain volumes may be useful as intermediate phenotypes in behavioral genetic research.


Trace determination of arsenic species by capillary electrophoresis with direct UV detection using sensitivity enhancement by counter- or co-electroosmotic flow stacking and a high-sensitivity cell.
Stacking techniques used independently and also with a high-sensitivity cell (HSC) were employed to optimise sensitivity and detection limits in the direct photometric detection of the following eight arsenic species by capillary zone electrophoresis (CZE): arsenite, arsenate, monomethylarsonic acid (MMA), dimethylarsinic acid (DMA), 4-hydroxy-3-nitrophenylarsonic acid (Roxarsone), p-aminophenylarsonic acid (p-ASA), 4-nitrophenylarsonic acid (4-NPAA), and phenylarsonic acid (PAA) (target analytes). The stacking mechanisms, optimised stacking and separation conditions, and concentration sensitivity enhancement factors were discussed and compared for (i) normal stacking mode (NSM, sometimes also referred to as field-amplified stacking) in an uncoated fused-silica capillary in the counter-electroosmotic flow (EOF) mode, (ii) large-volume sample stacking (LVSS) with polarity switching, and (iii) the less often applied stacking method of co-EOF NSM stacking with EOF reversal using a poly(diallydimethylammonium chloride) (PDDAC)-coated capillary. The optimal injection volumes were 7.4, 60 and 17.2% of the total capillary volume, for the above three methods, respectively. LVSS with polarity switching gave the lowest limit of detection (LOD). The use of the HSC further reduced the LOD of each target analytes by a factor of 5-8 times. By combining LVSS and HSC, LODs of the target analytes could be reduced by a factor of 218-311, to 5.61, 9.15, 11.1, and 17.1 microg/L for As(III), DMA, MMA, and As(V), respectively. The method was demonstrated to be applicable to the determination of the target analytes in tap water and lake water, with recoveries in the range of 89.4-103.3%.


Cementless total hip arthroplasty and limb-length equalization in patients with unilateral Crowe type-IV hip dislocation.
Total hip arthroplasty in patients with unilateral congenital high dislocation of the hip (Crowe type IV) presents many challenges, including the problem of a marked limb-length discrepancy. The purpose of this retrospective study was to analyze the results of total hip replacement with limb-length equalization in these patients. From 1988 to 1996, fifty-six patients (forty-seven women and nine men) with unilateral Crowe type-IV dislocation of the hip were treated with a cementless total hip arthroplasty at a mean age of 35.4 years. The preoperative limb-length discrepancy averaged 4.9 cm. Prior to the total hip arthroplasty, forty-eight patients with a limb-length discrepancy of >4.0 cm underwent iliofemoral distraction with use of an external fixator for eight to seventeen days. The acetabular cup was placed in the anatomical position in every patient. Shortening femoral osteotomies were not required. The iliac fixator pins loosened in six patients. No patient had a pin-site infection, hip joint infection, or nerve palsy. At the time of follow-up, at an average of 147.2 months, the Harris hip score averaged 90.2 points. Overall, the mean lengthening after the total hip arthroplasty was 4.6 cm. There were no revisions of the femoral stem. Nine cups were revised, four because of polyethylene wear and five because of loosening. We were able to safely place the acetabular cup at the anatomical position without femoral shortening by bringing the femoral head to the normal level preoperatively; thus, we could restore nearly normal limb length. We believe that our twelve-year results are similar to those of total hip arthroplasty in patients without dysplasia.


Catabolite repression of the lac operon. Separt epressionof two enzymes.
1. Catabolite repression of beta-galactosidase and of thiogalactoside transacetylase was studied in several strains of Escherichia coli K 12, in an attempt to show whether a single site within the structural genes of the lac operon co-ordinately controls translational repression for the two enzymes. In all experiments the rate of synthesis of the enzymes was compared in glycerol-minimal medium and in glucose-minimal medium. 2. In a wild-type strain, glucose repressed the synthesis of the two enzymes equally. 3. The possibility that repression was co-ordinate was investigated by studies of mutant strains that carry deletions in the genes for beta-galactosidase or galactoside permease or both. In all of the strains with deletions, the repression of thiogalactoside transacetylase persisted, and it is concluded that there is no part of the structural gene for beta-galactosidase that is essential for catabolite repression of thiogalactoside transacetylase. 4. Subculture of one strain through several transfers in rich medium greatly increased its susceptibility to catabolite repression by glucose. It is concluded that unknown features of the genotype can markedly affect sensitivity to catabolite repression. 5. These results make it clear that one cannot draw valid conclusions about the effect of known genotypic differences on catabolite repression from a comparison of two separate strains; to study the effect of a particular genetic change in a lac operon it is necessary to construct a partially diploid strain so that catabolite repression suffered by one lac operon can be compared with that suffered by another. 6. Four such partial diploids were constructed. In all of them catabolite repression of beta-galactosidase synthesized by one operon was equal in extent to catabolite repression of thiogalactoside transacetylase synthesized by the other. 7. Taken together, these results suggest that catabolite repression of beta-galactosidase and thiogalactoside transacetylase is separate but equal.


Potential role of ferritin heavy chain in oxidative stress and apoptosis in human mesothelial and mesothelioma cells: implications for asbestos-induced oncogenesis.
Exposure to asbestos is a known etiological factor in malignant mesothelioma (MM). However, in vitro cell culture studies have provided paradoxical evidence that asbestos exposure to mesothelial cells causes cytotoxicity or apoptosis rather than malignant transformation. Although it has been shown that the iron associated with asbestos participates in the cell toxicity and probably MM pathogenesis via generation of reactive oxygen species (ROS), the molecular mechanisms largely remain unknown. Here, we demonstrate that ferritin heavy chain (FHC), a core subunit of iron-binding protein ferritin, works as an anti-apoptotic protein against toxic asbestos and oxidative stress in human mesothelial cells and MM cells. We found that FHC was induced in asbestos-exposed MeT-5A human mesothelial cells. The mesothelial cell line stably expressing FHC generated less amount of hydrogen peroxide (H2O2), one of the main ROS, after asbestos exposure and was more resistant to apoptosis induced by H2O2 compared with the cells transfected with the empty vector. Next, we investigated biological roles of FHC in human MM cell. We found that NCI-H2052, a human MM cell line, had a higher expression of endogenous FHC than MeT-5A and used the cell to address FHC function in MM. NCI-H2052 showed reduced H2O2 production and an apoptosis-resistant phenotype compared with MeT-5A. Suppression of the over-expressed FHC by using FHC small interfering RNA rendered the MM cells sensitive to apoptosis, suggesting the contribution of FHC to apoptosis resistance of the MM cells. Our findings highlight the potential role of FHC in the pathogenesis of asbestos-induced mesothelioma.


Effect of olfactory bulb ablation on spread of a neurotropic coronavirus into the mouse brain.
Previous results suggested that, after intranasal inoculation, mouse hepatitis virus (MHV), a neurotropic coronavirus, entered the central nervous system (CNS) via the olfactory and trigeminal nerves. To prove this hypothesis, the effect of interruption of the olfactory pathway on spread of the virus was studied using in situ hybridization. Unilateral surgical ablation of this pathway prevented spread of the virus via the olfactory tract on the side of the lesion. MHV RNA could be detected, however, at distal sites on the operated side, indicating that the virus spread via well-described circuits involving the anterior commissure from the control (intact) side of the brain. Viral transport via the trigeminal nerve was not affected by removal of the olfactory bulb, showing that the surgical procedure was specific for the olfactory pathway. These results prove conclusively that MHV gains entry to the CNS via a transneuronal route, and spreads to additional sites in the brain via known neuroanatomic pathways.


Evaluating common outcomes for measuring treatment success for chronic low back pain.
Systematic review. To identify, describe, and evaluate common outcome measures in patients with chronic low back pain (CLBP). The treatment of CLBP has been associated with multiple clinical challenges. Further complicating this is the myriad of outcome scores used to assess treatment of CLBP. These scores have been used to examine different domains of patient satisfaction and quality of life in the literature. Critical assessment of the frequency, parity, and the quality of these outcomes are essential to improve our understanding of CLBP. A systematic review of the English-language literature was undertaken for articles published from January 2001 through December 31, 2010. Electronic databases and reference lists of key articles were searched to identify measures used to evaluate outcomes in six different domains in patients with CLBP. The titles and abstracts of the peer-reviewed literature of LBP were searched to determine which of these measures were most commonly reported in the literature and which have been validated in populations with CLBP. We identified 75 outcome measures cited to evaluate CLBP. Twenty-nine of these outcome measures were excluded because of only a single citation leaving 46 measures for the evaluation. The most commonly used functional outcomes were the Oswestry Disability Index, Roland Morris Disability Index, and range of motion. For pain, the Numeric Pain Rating Scale, Brief Pain Inventory, Pain Disability Index, McGill Pain Questionnaire, and visual analog scale were most commonly cited. For psychosocial function, the Fear Avoidance Beliefs Questionnaire, Tampa Scale for Kinesiophobia, and Beck Depression Inventory were most commonly used. For generic quality of life, short form 36, Nottingham Health Profile, short form 12, and Sickness Impact Profile were the most common measures. For objective measures, the work status/return to work, complications or adverse events, and medications used were the most commonly cited. For preference-based measures, the Euro-Quol 5 dimensions and short form 6 dimensions were most commonly cited. The validity, reliability, responsiveness, universality, and potential proprietary requirements are summarized for each. Outcome measures should be routinely assessed in patients with CLBP. The choice of appropriate outcome measure should be influenced by the study objectives and design, as well as properties of the particular measure within the context of CLBP. Recommendation 1: When selecting the appropriate outcome measures for clinical or research purposes, consider domains that best measure what are most important to patients. Measures that are valid, reliable, and responsive to change should be considered first. Other considerations include the number of items required (especially in the context of multiple measures), whether the measure is validated in the relevant language, and the associated costs or fees. Strength: Strong Recommendation 2: Domains of greatest importance include pain, function, and quality of life. If cost utilization is a priority, then preference-based measures should be considered. For pain, we recommend the VAS and NRPS because of their ease of administration and responsiveness. For function, we recommend the ODI and RMDQ. The SF-36 and its shorter versions are most commonly used and should be considered if quality of life is important. If cost utility is important, consider the EQ-5D or SF-6D. Psychosocial tests are best used as screening tools prior to surgery because of their lack of responsiveness. Complications should always be assessed as a standard of clinical practice. Return to work and medication use are complicated outcome measures and not recommended unless the specific study question is focused on these domains. Consider staff and patient burden when prioritizing one's battery of measures.


Article processing charges, funding, and open access publishing at Journal of Experimental & Clinical Assisted Reproduction.
Journal of Experimental & Clinical Assisted Reproduction is an Open Access, online, electronic journal published by BioMed Central with full contents available to the scientific and medical community free of charge to all readers. Authors maintain the copyright to their own work, a policy facilitating dissemination of data to the widest possible audience without requiring permission from the publisher. This Open Access publishing model is subsidized by authors (or their institutions/funding agencies) in the form of a single pound330 article processing charge (APC), due at the time of manuscript acceptance for publication. Payment of the APC is not a condition for formal peer review and does not apply to articles rejected after review. Additionally, this fee is waived for authors whose institutions are BioMed Central members or where genuine financial hardship exists. Considering ordinary publication fees related to page charges and reprints, the APC at Journal of Experimental & Clinical Assisted Reproduction is comparable to costs associated with publishing in some traditional print journals, and is less expensive than many. Implementation of the APC within this Open Access framework is envisioned as a modern research-friendly policy that supports networking among investigators, brings new research into reach rapidly, and empowers authors with greater control over their own scholarly publications.


Efficiency in stroke management from acute care to rehabilitation: bedside versus telemedicine consultation.
Telemedicine has changed over the last years, becoming an integrated service used in various clinical settings such as stroke units or radiological departments, but also as an important tool for home rehabilitation. Assessment of usefulness and efficiency of performing teleconsultations to manage stroke from acute care hospital to tertiary care rehabilitation hospital has not been referred by scientific literature. This article analyzes the process of discharging stroke patients from acute care to intensive rehabilitation, based on the comparison between conventional bedside patient evaluations and teleconsultation patient evaluations, to assess efficiency and efficacy of two different discharging workflows. Retrospective study. Consultations were carried out between the Acute Care Stroke Unit and the Stroke Rehabilitation Unit of Valduce Hospital System. The study included 257 stroke patients who underwent physiatric consultation during 2 years considered in this study and 101 patients were considered eligible for intensive rehabilitation treatment after a physiatric consultation. We compared the efficiency and efficacy of the dismission workflow of bedside medical consultation and teleconsultation over a 12 months period. We considered the following outcome measures: time elapsed between consultation and Rehabilitation Unit admission, number of re-admissions to acute care hospital, complications occurred during rehabilitation, length of stay in the rehabilitation hospital and clinical outcomes of rehabilitation process. We observed a significant reduction in waiting time from the acute event to the admission in rehabilitation department, an improvement in efficiency of the admission process itself in the Rehabilitation Unit and a reduction of clinical complications occurred during rehabilitation period, without changes in rehabilitative outcomes. It has been highlighted that the use of telemedicine to perform medical consultation as a tool to evaluate patients eligible for tertiary care rehabilitation hospital admission from Stroke Care Unit is feasible and more efficient when compared with conventional bedside consultations. This study reveals teleconsultations as a useful tool to improve efficiency of the stroke management workflow.


Prevalence of juvenile chronic arthritis in a population of 12-year-old children in urban Australia.
To conduct a cross-sectional, community-based, point prevalence study of inflammatory joint disease and other rheumatic disorders in 12-year-old children in a metropolitan community. After completion of a pilot study of 816 10-year-old children, a cross-sectional prevalence study was performed 2 years later on a randomized sample of 2241 12-year-old children (including the cohort from the pilot study) from a community of approximately 221 700 children aged 12 years or younger, with 17 300 children aged approximately 12 years. A rheumatologic examination was performed on each child by a single observer after perusal of completed questionnaires from parents and children. Three of 816 children in the pilot study were shown to have juvenile chronic arthritis (JCA), fulfilling the criteria of the European League Against Rheumatism for the diagnosis of JCA. Only 1 of 3 had a previous diagnosis of JCA. The prevalence was 3.7 per 1000. Of 2241 children examined 2 years later, 89% returned two questionnaires (one completed by the parent and one by the child). At examination, 38 swollen joints were identified in 32 children. Nine children were identified with JCA, of whom 7 had not had previous diagnoses. No questions from the questionnaires identified the 7 children with previously undiagnosed JCA. The point prevalence of JCA in this community was 4.0 per 1000. Although the children with newly diagnosed cases tended to have mild disease, it was associated with significant morbidity and the potential for serious morbidity. This is the first reported prevalence study of JCA in which case ascertainment was based on clinical examination by a rheumatologist of children within a community. The prevalence of 4.0 per 1000 was significantly higher than the accepted prevalence of 0.6 to 1.1 per 1000. A study based on known cases would have significantly underestimated the true prevalence of JCA in this community, with 7 of 9 cases being previously undiagnosed. Questionnaires were not effective in identifying children with undiagnosed JCA, clinical examination supported by a history from the parent and child providing the only reliable means of diagnosis. It is possible throughout the world that the numbers of undiagnosed cases of JCA significantly exceed the numbers of known cases with the true prevalence being significantly higher than the levels currently accepted.


Glutamine amidotransferase activity of NAD+ synthetase from Mycobacterium tuberculosis depends on an amino-terminal nitrilase domain.
NAD(+) synthetase (NadE; E.C. 188.8.131.52) from Mycobacterium tuberculosis utilizes both glutamine and ammonia to catalyze NAD(+) production, in contrast to the corresponding NH(3)-dependent enzymes from other prokaryotes. Here we report the site-directed mutagenesis of amino acids located in the N-terminal domain and predicted to be essential for glutamine hydrolysis. The residues forming the putative catalytic triad (Cys176, Glu52 and Lys121) were replaced by alanine; the mutated enzymes were expressed in the Escherichia coli Origami (DE3) strain and purified. The three mutants completely lost their glutamine-dependent activity, clearly indicating that Cys176, Glu52 and Lys121 are crucial for this activity. In contrast, the C176A and E52A variants, respectively, retained 90 and 30% of the original NH(3)-dependent specific activity, while the K121A mutant lost this activity. The results show that glutamine-amidotransferase activity is mediated by an N-terminal domain belonging to the superfamily of nitrilases. This domain, a new type of glutamine amide transfer (GAT) domain, is the first to be characterized in bacterial NAD(+) synthetases.


Ecological Factors Generally Not Altitude Related Played Main Roles in Driving Potential Adaptive Evolution at Elevational Range Margin Populations of Taiwan Incense Cedar (Calocedrus formosana).
Population diversification can be shaped by a combination of environmental factors as well as geographic isolation interacting with gene flow. We surveyed genetic variation of 243 samples from 12 populations of Calocedrus formosana using amplified fragment length polymorphism (AFLP) and scored a total of 437 AFLP fragments using 11 selective amplification primer pairs. The AFLP variation was used to assess the role of gene flow on the pattern of genetic diversity and to test environments in driving population adaptive evolution. This study found the relatively lower level of genetic diversity and the higher level of population differentiation in C. formosana compared with those estimated in previous studies of conifers including Cunninghamia konishii, Keteleeria davidiana var. formosana, and Taiwania cryptomerioides occurring in Taiwan. BAYESCAN detected 26 F ST outlier loci that were found to be associated strongly with various environmental variables using multiple univariate logistic regression, latent factor mixed model, and Bayesian logistic regression. We found several environmentally dependent adaptive loci with high frequencies in low- or high-elevation populations, suggesting their involvement in local adaptation. Ecological factors, including relative humidity and sunshine hours, that are generally not altitude related could have been the most important selective drivers for population divergent evolution in C. formosana. The present study provides fundamental information in relation to adaptive evolution and can be useful for assisted migration program of C. formosana in the future conservation of this species.


Revised criteria of International Workshop on Ocular Sarcoidosis (IWOS) for the diagnosis of ocular sarcoidosis.
International criteria for the diagnosis of ocular sarcoidosis (OS) was established by the first International Workshop on Ocular Sarcoidosis (IWOS) and validations studies revealed certain limitations of the criteria. To overcome the limitations, revised IWOS criteria was established in an international meeting. This manuscript was aimed at reporting the revised IWOS criteria. A consensus workshop was carried out to discuss and revise the IWOS criteria. The workshop was held on 27 April 2017, in Nusa Dua, Bali, Indonesia. Prior to the workshop, a questionnaire proposing revised criteria and consisting of one item for differential diagnosis, seven items for ocular clinical signs, 10 items for systemic investigations and three categories of diagnostic criteria was circulated to 30 uveitis specialists. Questionnaire items with over 75% support were taken as consensus agreement; items with below 50% support were taken as consensus disagreement and items with 50%-75% support were discussed at the workshop. Of the latter items, those supported by two-thirds majority in the workshop were taken as consensus agreement. The survey and subsequent workshop reached consensus agreements of the revised criteria for the diagnosis of OS as follows: (1) other causes of granulomatous uveitis must be ruled out; (2) seven intraocular clinical signs suggestive of OS; (3) eight results of systemic investigations in suspected OS and (4) three categories of diagnostic criteria depending on biopsy results and combination of intraocular signs and results of systemic investigations. Revised IWOS criteria were proposed by a consensus workshop.


Prenatal stress enhances severity of atherosclerosis in the adult apolipoprotein E-deficient mouse offspring via inflammatory pathways.
Atherosclerosis is the underlying cause of cardiovascular disease and stroke. Endothelial cell dysfunctions are early events in atherosclerosis, resulting in the recruitment of circulating monocytes. The immune system can elicit an inflammatory response toward the atherosclerotic lesion, thereby accelerating lesion growth. Risk factors for atherosclerosis include hypertension, smoking, stress perception or low birth weight. As prenatal stress challenge decreases the birth weight and affects the offspring's postnatal immune response, we aimed to investigate whether prenatal stress contributes to the development of atherosclerosis in mice. Syngenic pregnant apolipoprotein E-deficient (apoE-/-) dams were exposed to sound stress on gestation days 12.5 and 14.5. The presence and size of atherosclerotic plaques in the offspring at the age of 15 weeks was evaluated by histomorphology, accompanied by flow cytometric analysis of the frequency and phenotype of monocytes/macrophages and regulatory T (Treg) cells in the blood. Further, cytokine secretion of peripheral blood lymphocytes was analyzed. In response to prenatal stress challenge, an increased frequency of large atherosclerotic plaques was detectable in apoE-/- offspring, which was particularly profound in females. Prenatal stress also resulted in alterations of the offspring's immune response, such as a decreased frequency of Treg cells in blood, alterations of macrophage populations in blood and an increased secretion of inflammatory cytokines. We provide novel evidence that prenatally stressed adult offspring show an increased severity of atherosclerosis. As Treg cells are key players in dampening inflammation, the observed increase in atherosclerosis may be due to the lack of Treg cell frequency. Future interdisciplinary research is urgently required to understand the developmental origin of prenatal stress-induced atherosclerosis. The availability of our model may facilitate and foster such research endeavors.


Experimental determination of residence time distribution in continuous dry granulation.
With increasing importance of continuous manufacturing, the interest in integrating dry granulation into a continuous manufacturing line is growing. Residence time distribution measurements are of importance as they provide information about duration of materials within the process. These data enable traceability and are highly beneficial for developing control strategies. A digital image analysis system was used to determine the residence time distribution of two materials with different deformation behavior (brittle, plastic) in the milling unit of dry granulation systems. A colorant was added to the material (20%w/w iron oxide), which did not affect the material properties excessively, so the milling process could be mimicked well. Experimental designs were conducted to figure out which parameters effect the mean residence time strongly. Moreover, two types of dry granulation systems were contrasted. Longer mean residence times were obtained for the oscillating mill (OM) compared to the conical mill (CM). For co-processed microcrystalline cellulose residence times of 19.8-44.4s (OM) and 11.6-29.1s (CM) were measured, mainly influenced by the specific compaction force, the mill speed and roll speed. For dibasic calcium phosphate anhydrate residence times from 17.7-46.4 (OM) and 5.4-10.2s (CM) were measured, while here the specific compaction force, the mill speed and their interactions with the roll speed had an influence on the mean residence time.


Prevalence of peripheral neuropathy in type 2 diabetic patients attending a diabetes center in Turkey.
The aim of this study was to determine the prevalence and risk factors for neuropathy in type 2 diabetic patients attending a major Turkish diabetes center. Eight hundred and sixty-six consecutive type 2 diabetic patients were included in the study. A single observer performed biothesiometry studies on these patients. The presence of diabetic neuropathy was investigated using neurological symptom scale (NSS) and neurological disability score (NDS) performed. Neuropathy was determined with standardized neurological examinations and defined as the presence of abnormal NSS and NDS together with abnormal sensory or motor signs and symptoms as well as decreased great toe vibration perception. Overall, 60% (n = 520) of the patients were diagnosed as having neuropathy. The prevalence of neuropathy increased with age (p < 0.001) and duration of diabetes (p < 0.001). Multiple logistic regression analysis revealed the duration of diabetes (p < 0.001) and HbA1c levels (p < 0.001) as the risk factors for neuropathy. The overall prevalence of neuropathy in Turkish type 2 diabetic population was 60%. Age, duration of diabetes, and poor glycemic control were considered to be the risk factors for neuropathy.


Safety of Tioguanine During Pregnancy in Inflammatory Bowel Disease.
Conventional thiopurine [azathioprine and mercaptopurine] treatment during pregnancy in patients with inflammatory bowel disease [IBD] is considered to be safe; however data on the safety and teratogenicity of the non-conventional thiopurine tioguanine [TG] in pregnant IBD patients are lacking. We aim to describe the safety and teratogenicity of TG treatment during pregnancy in IBD patients. This was a retrospective, multicentre descriptive case series of female IBD patients using TG during pregnancy. Data on disease and medication history, pregnancy complications, pregnancy outcome, mode of delivery, preterm birth, birthweight, congenital abnormalities, laboratory signs of myelosuppression or hepatotoxicity, and 6-thioguaninenucleotide [6-TGN] concentrations in mother and neonate were collected. In all, 13 patients [77% Crohn's disease, 23% ulcerative colitis] used TG [median dose 18 g/day] during pregnancy; 19 pregnancies, including 1 twin pregnancy, were included. Spontaneous abortion occurred in three pregnancies. In 7 of the 16 ongoing pregnancies a caesarean section was performed. One neonate had a mild congenital abnormality [distal shaft hypospadias]. In the singleton pregnancies, the median birthweight was 3410 g at a median of gestational age of 39 weeks. No preterm birth [< 37 weeks] or low birthweight [< 2500 g] was observed in the singleton newborns. In the twin pregnancy an induction of labour was performed at 35 + 1 weeks of gestation because of pre-eclampsia. Both neonates had a low birthweight. This relatively small case series supports safe use of TG in pregnant IBD patients. Still, consideration should be given to the indication and continuation of TG during pregnancy.


Effect of a stannous fluoride dentifrice on the sulcular microbiota: a prospective cohort study in subjects with various levels of periodontal inflammation.
To assess the effects of an experimental 0.454% stannous fluoride (SnF2) dentifrice on the oral sulcular microbiota in patients with various stages of oral diseases using checkerboard DNA-DNA hybridization. In the present one-month, single center, single product, prospective cohort trial, 37 adults (mean age 37.6) were assigned to one of four oral health condition cohorts with seven to 10 subjects each: 1. mild gingivitis, 2. marked generalized gingivitis to moderate periodontitis, 3. caries-prone and 4. treated moderate to advanced chronic periodontitis in supportive periodontal care. All four groups were asked to use the test dentifrice and a power toothbrush twice a day for one minute during a four-week test period. Before and after the trial period, Plaque Indices (PII, Silness and Löe, 1964) and Gingival Indices (GI, Löe and Silness, 1963) were recorded. Subgingival plaque samples were collected from all patients at Baseline, as well as after two and four weeks. These samples were analyzed for content of 40 bacterial species using checkerboard DNA-DNA hybridization. As a result of the only one minute brushing with the stannous fluoride dentifrice, the mean PII at Baseline was significantly lower (p < 0.05) from the mean PII at four weeks. No statistically significant differences were found between premolar and molar mean values. Moreover, no statistically significant differences were found between the mean GI at Baseline and at four weeks. The microbiological analysis showed that at baseline subjects in groups 2 and 4 had significantly higher bacterial loads of bacteria than groups 1, and 3 (i.e. A. actinomyctemcomitans P. gingivalis, T. forsythia, and T. denticola. Over the study period, the total bacterial load did not change in groups 2, 3 and 4. In groups 1 and 3, however, an increase in the loads of Streptococci spp. were noticed (p < 0.05) including S. mitis, S. intermedius, and S. sanguis (p < 0.01) suggesting an increase in the presence of early colonizing and health associated bacteria. One minute brushing with a 0.454% stannous fluoride dentifrice did--after four weeks--not affect the subgingival microbial profiles in patients with moderate periodontitis and treated moderate to advanced periodontitis. However, the sulcular microbial profiles of mild gingivitis and caries-prone patients were affected, indicating a shift towards a gingival health associated microbiota in the sulcular region of patients not affected by attachment loss. RUNNING HEAD: Effect of stannous fluoride on sulcular microbiota.


The Effect of Pulmonary Rehabilitation in Mountain Environment on Exercise Capacity and Quality of Life in Patients with Chronic Obstructive Pulmonary Disease (COPD) and Chronic Bronchitis.
BACKGROUND We aimed to test the effectiveness of the pulmonary rehabilitation in a mountain environment on the pulmonary function, physical performance, dyspnea, affective factors, and quality of life (QoL) in patients with chronic obstructive pulmonary disease (COPD) and chronic bronchitis (CB), as well as to determine predictors of clinical improvement. MATERIAL AND METHODS 128 consecutive patients (90 diagnosed with COPD and 38 diagnosed with CB) underwent comprehensive pulmonary rehabilitation for a duration of 3 weeks in one of 3 mountain health resorts in the High Tatras. The examination included spirometry (FEV1 and FEV1/FVC), 6-minute walk test (6MWT), Borg scale of dyspnea, and assessment of depression (Zung score), anxiety (Beck score), and QoL using the SF-36 scales. RESULTS After the study intervention, all patients in both monitored groups demonstrated significant improvements in objective measurements in which large treatment effect was achieved (for FEV1 η²=0.218, for 6MWT η²=0.771). Similarly, in subjective measurements a large effect was achieved (for the Beck score: η²=0.599, for the Zung score: η²=0.536). QoL improved after the intervention in all the monitored SF-36 scales in both groups (P<0.001 for all). In patients with COPD, the improvement of exercise capacity was positively correlated with baseline 6MWT and FEV1, and negatively with the Beck anxiety score and the Borg dyspnea score, whereas, only improvement in the mental summary component of QoL was negatively correlated with baseline 6MWT and FEV1 (P<0.05 for all). CONCLUSIONS Rehabilitation in a mountain environment has proven to be effective in both the reported diagnoses of COPD and CB. Improvements in both functional and subjective indicators were observed. These findings support the use of this treatment modality.


Aircore microstructure fibers with suppressed higher-order modes.
A strategy for suppressing higher-order modes in aircore bandgap fibers is proposed. Simulations confirm that significant suppression of unwanted modes is achieved by including index-matched air-guiding structures in the cladding. Suppressing higher-order modes offers to improve the fundamental loss limit in aircore fibers, addressing a key obstacle to the development of this technology.


Individualized selection of pacing algorithms for the prevention of recurrent atrial fibrillation: Results from the VIP registry.
The VIP registry investigated the efficacy of preventive pacing algorithm selection in reducing atrial fibrillation (AF) burden. There are few data identifying which patients might benefit most from which preventive pacing algorithms. Patients, with at least one documented AF episode and a conventional antibradycardia indication for pacemaker therapy, were enrolled. They received pacemakers with AF diagnostics and four preventive algorithms (Selection and PreventAF series, Vitatron). A 3-month Diagnostic Phase with conventional pacing identified a Substrate Group (>70% of AF episodes with <2 premature atrial contractions [PACs] before AF onset) and a Trigger Group (< or =70% of AF episodes with <2 PACs before AF onset). This was followed by a 3-month Therapeutic Phase where in the Trigger Group algorithms were enabled aimed at avoiding or preventing a PAC and in the Substrate Group continuous atrial overdrive pacing was enabled. One hundred and twenty-six patients were evaluated. In the Trigger Group (n = 73), there was a statistically significant 28% improvement in AF burden (median AF burden: 2.06 hours/day, Diagnostic Phase vs 1.49 hours/day, Therapy Phase; P = 0.03304 signed-rank test), and reduced PAC activity. There was no significant improvement in AF burden in the Substrate Group (median AF burden: 1.82 hours/day, Diagnostic Phase vs 2.38 hours/day, Therapy Phase; P = 0.12095 signed-rank test), and little change in PAC activity. We identified a subgroup of patients for whom the selection of appropriate pacing algorithms, based on individual diagnostic data, translated into a reduced AF burden. Trigger AF patients were more likely responders to preventive pacing algorithms as a result of PAC suppression.


Living in Limbo: Contested Narratives of Patients With Chronic Symptoms Following Lyme Disease.
Persistent, subjective symptoms of unknown etiology following treatment for Lyme disease have been termed post- treatment Lyme disease syndrome or chronic Lyme disease (PTLDS/CLD). The objective of this study was to give primacy to the patient experience of this medically contested condition by eliciting patient illness narratives and identifying emergent issues through semistructured interviews conducted among 29 participants. We used thematic narrative analysis to identify three predominant themes: (a) Physical and social limitations lead to a "new normal" characterized by fundamental shifts of ways of being in the world, (b) disease-specific factors contribute to symptom and illness invisibility that affects social support in nuanced ways, and (c) pervasive medical uncertainty regarding PTLDS/CLD promotes an increased sense of personal responsibility for care. Similar to other contested or medically unexplained syndromes, our findings suggest that the social sequelae of PTLDS/CLD can be equally protracted as the physical effects of this illness.


Tricyclic antidepressants and the incidence of certain cancers: a study using the GPRD.
Several studies suggest links between cancer and tricyclic antidepressant use. A case-control study using the General Practice Research Database examined whether previous tricyclic usage was associated with reduced incidence of brain (with glioma as a sub-category), breast, colorectal, lung and prostate cancers. Conditional logistic regression adjusted for age, gender, general practice, depression, smoking, body mass index, alcohol use and non-steroidal anti-inflammatory drug use. A total of 31 953 cancers were identified, each matched with up to two controls. We found a statistically significant reduction in tricyclic prescriptions compared with controls in glioma (odds ratio (OR) =0.59, 95% confidence interval (CI)=0.42-0.81) and colorectal cancer patients (OR=0.84, CI=0.75-0.94). These effects were dose-dependent (P-values for trend, glioma=0.0005, colorectal=0.001) and time-dependant (P-values for trend glioma=0.0005, colorectal=0.0086). The effects were cancer-type specific, with lung, breast and prostate cancers largely unaffected by antidepressant use. The biologically plausible, specific and dose- and time-dependant inverse association that we have found suggests that tricyclics may have potential for prevention of both colorectal cancer and glioma.


Development of a new extraction technique and HPLC method for the analysis of non-psychoactive cannabinoids in fibre-type Cannabis sativa L. (hemp).
The present work was aimed at the development and validation of a new, efficient and reliable technique for the analysis of the main non-psychoactive cannabinoids in fibre-type Cannabis sativa L. (hemp) inflorescences belonging to different varieties. This study was designed to identify samples with a high content of bioactive compounds, with a view to underscoring the importance of quality control in derived products as well. Different extraction methods, including dynamic maceration (DM), ultrasound-assisted extraction (UAE), microwave-assisted extraction (MAE) and supercritical-fluid extraction (SFE) were applied and compared in order to obtain a high yield of the target analytes from hemp. Dynamic maceration for 45min with ethanol (EtOH) at room temperature proved to be the most suitable technique for the extraction of cannabinoids in hemp samples. The analysis of the target analytes in hemp extracts was carried out by developing a new reversed-phase high-performance liquid chromatography (HPLC) method coupled with diode array (UV/DAD) and electrospray ionization-mass spectrometry (ESI-MS) detection, by using an ion trap mass analyser. An Ascentis Express C18 column (150mm×3.0mm I.D., 2.7μm) was selected for the HPLC analysis, with a mobile phase composed of 0.1% formic acid in both water and acetonitrile, under gradient elution. The application of the fused-core technology allowed us to obtain a significant improvement of the HPLC performance compared with that of conventional particulate stationary phases, with a shorter analysis time and a remarkable reduction of solvent usage. The analytical method optimized in this study was fully validated to show compliance with international requirements. Furthermore, it was applied to the characterization of nine hemp samples and six hemp-based pharmaceutical products. As such, it was demonstrated to be a very useful tool for the analysis of cannabinoids in both the plant material and its derivatives for pharmaceutical and nutraceutical applications.


Health as a Secondary Property.
In the literature on health, naturalism and normativism are typically characterized as espousing and rejecting, respectively, the view that health is objective and value-free. This article points out that there are two distinct dimensions of disagreement, regarding objectivity and value-ladenness, and thus arranges naturalism and normativism as diagonal opposites on a two-by-two matrix of possible positions. One of the remaining quadrants is occupied by value-dependent realism, holding that health facts are value-laden and objective. The remaining quadrant, which holds that they are non-objective but value-free, is unexplored. The article endorses a view in the latter quadrant, namely, the view that health is a secondary property. The article argues that a secondary property framework provides the resources to respond to the deepest objections to a broadly Boorsean account of natural function, and so preserves the spirit, though not the letter, of that account. Treating health as a secondary property permits a naturalistic explanation-specifically, an evolutionary explanation-of the health concept, in terms of the assistance such a concept might have provided to the survival and reproduction of those organisms that had it. (This approach is completely distinct from evolutionary and aetiological accounts of natural functions.) This provides the explanation, missing from Boorse's account, for the fact that function is determined with reference to the contribution to the goals of survival and reproduction, relative to the age of the sex of the species, rather than some other equally natural goals or reference classes. 1Introduction2Two Ways to Disagree about Health3Secondary Properties4Health as a Secondary Property5Conclusion.


The effects of accessory stimuli on information processing: evidence from electrophysiology and a diffusion model analysis.
People typically respond faster to a stimulus when it is accompanied by a task-irrelevant accessory stimulus presented in another perceptual modality. However, the mechanisms responsible for this accessory-stimulus effect are still poorly understood. We examined the effects of auditory accessory stimulation on the processing of visual stimuli using scalp electrophysiology (Experiment 1) and a diffusion model analysis (Experiment 2). In accordance with previous studies, lateralized readiness potentials indicated that accessory stimuli do not speed motor execution. Surface Laplacians over the motor cortex, however, revealed a bihemispheric increase in motor activation-an effect predicted by nonspecific arousal models. The diffusion model analysis suggested that accessory stimuli do not affect parameters of the decision process, but expedite only the nondecision component of information processing. Consequently, we conclude that accessory stimuli facilitate stimulus encoding. The visual P1 and N1 amplitudes on accessory-stimulus trials were modulated in a way that is consistent with multisensory energy integration, a possible mechanism for this facilitation.


Platypnea-Orthodeoxia Syndrome After Complicated Cholecystectomy: An Unsuspected Diagnosis.
A 65-year-old woman with no significant prior medical history presented, in the postoperative course of a complicated cholecystectomy, several episodes of arterial desaturation. Pulmonary embolism was repeatedly suspected, but there was no evidence of pulmonary thrombus on the chest computed tomography angiographies obtained. As these episodes were mainly induced by postural changes, a platypnea-orthodeoxia syndrome was suspected. A transthoracic echocardiogram was performed and revealed a patent foramen ovale. A transesophageal echocardiography confirmed the presence of a significant right-to-left shunt exacerbated by the Valsalva manouver. The defect was repaired using a percutaneous transcatheter technique with complete resolution of the condition.


Naïve orangutans (Pongo abelii and Pongo pygmaeus) individually acquire nut-cracking using hammer tools.
Nut-cracking with hammer tools (henceforth: nut-cracking) has been argued to be one of the most complex tool-use behaviors observed in nonhuman animals. So far, only chimpanzees, capuchins, and macaques have been observed using tools to crack nuts in the wild (Boesch and Boesch, 1990; Gumert et al., 2009; Mannu and Ottoni, 2009). However, the learning mechanisms behind this behavior, and the extent of nut-cracking in other primate species are still unknown. The aim of this study was two-fold. First, we investigated whether another great ape species would develop nut-cracking when provided with all the tools and appropriate conditions to do so. Second, we examined the mechanisms behind the emergence of nut-cracking by testing a naïve sample. Orangutans (Pongo abelii and Pongo pygmaeus) have the second most extensive tool-use repertoire among the great apes (after chimpanzees) and show flexible problem-solving capacities. Orangutans have not been observed cracking nuts in the wild, however, perhaps because their arboreal habits provide limited opportunities for nut-cracking. Therefore, orangutans are a valid candidate species for the investigation of the development of this behavior. Four nut-cracking-naïve orangutans at Leipzig zoo (P. abelii; Mage = 16; age range = 10-19; 4F; at the time of testing) were provided with nuts and hammers but were not demonstrated the nut-cracking behavioral form. Additionally, we report data from a previously unpublished study by one of the authors (Martina Funk) with eight orangutans housed at Zürich zoo (six P. abelii and two P. pygmaeus; Mage = 14; age range = 2-30; 5F; at the time of testing) that followed a similar testing paradigm. Out of the twelve orangutans tested, at least four individuals, one from Leipzig (P. abelii) and three from Zürich (P. abelii and P. pygmaeus), spontaneously expressed nut-cracking using wooden hammers. These results demonstrate that nut-cracking can emerge in orangutans through individual learning and certain types of non-copying social learning.


Fructose replacement of glucose or sucrose in food or beverages lowers postprandial glucose and insulin without raising triglycerides: a systematic review and meta-analysis.
Background: Conflicting evidence exists on the effects of fructose consumption in people with type 1 and type 2 diabetes mellitus. No systematic review has addressed the effect of isoenergetic fructose replacement of glucose or sucrose on peak postprandial glucose, insulin, and triglyceride concentrations.Objective: The objective of this study was to review the evidence for postprandial glycemic and insulinemic responses after isoenergetic replacement of either glucose or sucrose in foods or beverages with fructose.Design: We searched the Cochrane Library, MEDLINE, EMBASE, the WHO International Clinical Trials Registry Platform Search Portal, and clinicaltrials.gov The date of the last search was 26 April 2016. We included randomized controlled trials measuring peak postprandial glycemia after isoenergetic replacement of glucose, sucrose, or both with fructose in healthy adults or children with or without diabetes. The main outcomes analyzed were peak postprandial blood glucose, insulin, and triglyceride concentrations.Results: Replacement of either glucose or sucrose by fructose resulted in significantly lowered peak postprandial blood glucose, particularly in people with prediabetes and type 1 and type 2 diabetes. Similar results were obtained for insulin. Peak postprandial blood triglyceride concentrations did not significantly increase.Conclusions: Strong evidence exists that substituting fructose for glucose or sucrose in food or beverages lowers peak postprandial blood glucose and insulin concentrations. Isoenergetic replacement does not result in a substantial increase in blood triglyceride concentrations.


Nutraceutical agents with anti-inflammatory properties prevent dietary saturated-fat induced disturbances in blood-brain barrier function in wild-type mice.
Emerging evidence suggests that disturbances in the blood-brain barrier (BBB) may be pivotal to the pathogenesis and pathology of vascular-based neurodegenerative disorders. Studies suggest that heightened systemic and central inflammations are associated with BBB dysfunction. This study investigated the effect of the anti-inflammatory nutraceuticals garlic extract-aged (GEA), alpha lipoic acid (ALA), niacin, and nicotinamide (NA) in a murine dietary-induced model of BBB dysfunction. C57BL/6 mice were fed a diet enriched in saturated fatty acids (SFA, 40% fat of total energy) for nine months to induce systemic inflammation and BBB disturbances. Nutraceutical treatment groups included the provision of either GEA, ALA, niacin or NA in the positive control SFA-group and in low-fat fed controls. Brain parenchymal extravasation of plasma derived immunoglobulin G (IgG) and large macromolecules (apolipoprotein (apo) B lipoproteins) measured by quantitative immunofluorescent microscopy, were used as markers of disturbed BBB integrity. Parenchymal glial fibrillar acidic protein (GFAP) and cyclooxygenase-2 (COX-2) were considered in the context of surrogate markers of neurovascular inflammation and oxidative stress. Total anti-oxidant status and glutathione reductase activity were determined in plasma. Brain parenchymal abundance of IgG and apoB lipoproteins was markedly exaggerated in mice maintained on the SFA diet concomitant with significantly increased GFAP and COX-2, and reduced systemic anti-oxidative status. The nutraceutical GEA, ALA, niacin, and NA completely prevented the SFA-induced disturbances of BBB and normalized the measures of neurovascular inflammation and oxidative stress. The anti-inflammatory nutraceutical agents GEA, ALA, niacin, or NA are potent inhibitors of dietary fat-induced disturbances of BBB induced by systemic inflammations.


Experience of Chicagoland acute care hospitals in preparing for Ebola virus disease, 2014-2015.
During the 2014-2015 Ebola Virus Disease (EVD) outbreak, hospitals in the United States selected personal protective equipment (PPE) and trained healthcare personnel (HCP) in anticipation of receiving EVD patients. To improve future preparations for high-consequence infectious diseases, it was important to understand factors that affected PPE selection and training in the context of the EVD outbreak. Semistructured interviews were conducted with HCP involved with decision-making during EVD preparations at acute care hospitals in the Chicago, IL area to gather information about the PPE selection and training process. HCP who received training were surveyed about elements of training and their perceived impact and overall experience by email invitation. A total of 28 HCP from 15 hospitals were interviewed, and 55 HCP completed the survey. Factors affecting PPE selection included: changing guidance, vendor supply, performance evaluations, and perceived risk and comfort for HCP. Cost did not affect selection. PPE acquisition challenges were mitigated by: sharing within hospital networks, reusing PPE during training, and improvising with existing PPE stock. Selected PPE ensembles were similar across sites. Training included hands-on activities with trained observers, instructional videos, and simulations/drills, which were felt to increase HCP confidence. Many felt refresher training would be helpful. Hands-on training was perceived to be effective, but there is a need to establish the appropriate frequency of refresher training frequency to maintain competence. Lacking confidence in the CDC guidance, interviewed trainers described turning to other sources of information and developing independent PPE evaluation and selection. Response to emerging and/or high consequence infectious diseases would be enhanced by transparent, risk-based guidance for PPE selection and training that addresses protection level, ease of use, ensembles, and availability.


Analysis of the Plasmodium and Anopheles transcriptomes during oocyst differentiation.
Understanding the life cycle of the malaria parasite in its mosquito vector is essential for developing new strategies to combat this disease. Subtractive hybridization cDNA libraries were constructed that are enriched for Plasmodium berghei and Anopheles stephensi genes expressed during oocyst differentiation on the midgut. Sequencing of 1485 random clones led to the identification of 1137 unique expressed sequence tags. Of the 608 expressed sequence tags with data base hits, 320 (53%) had significant matches to the non-redundant protein data base, whereas 288 (47%) with matches only to genomic data bases represent novel Plasmodium and Anopheles genes. Transcription of six novel parasite genes and two previously identified asexual stage genes was up-regulated during oocyst differentiation. In addition, the mRNA for an Anopheles fibrinogen domain gene was induced on day 2 after an infectious blood meal, at the time of ookinete to oocyst differentiation. The subcellular distribution of MAEBL, a sporozoite surface protein, is developmentally regulated from presumed storage organelles in day 15 oocysts to uniform distribution on the surface in day 22 oocysts. This redistribution may reflect a sporozoite maturation program in preparation for salivary gland invasion. Furthermore, apical membrane antigen 1, another parasite surface molecule, is translationally regulated late in sporozoite development, suggesting a role during infection of the vertebrate host. The present results and those of an accompanying report (Abraham, E. G., Islam, S., Srinivasan, P., Ghosh, A. K., Valenzuela, J., Ribeiro, J. M., Kafatos, F. C., Dimopoulos, G., & Jacobs-Lorena, M. (2003) J. Biol. Chem. 279, 5573-5580) provide the foundation for studies seeking to understand at the molecular level Plasmodium development and its interactions with the mosquito.


Effect of garlic on atherosclerosis and its factors.
Dietary patterns in the Mediterranean, characterized by high consumption of fruits and vegetables, especially garlic, are believed to be beneficial to the regional patterns of atherosclerotic disease. Garlic and many of its preparations have been widely recognized as effective in the prevention and treatment of atherosclerosis and other risk factors for cardiovascular disease. This review article examines the evidence from numerous scientific studies that have utilized various formulations of garlic and its preparations with varying results. It highlights the need for standardization of available garlic products to allow for better comparison of research findings in drawing conclusions about the beneficial effects of garlic on atherosclerosis.


Mother-Youth Acculturation Gaps and Health-Risking/Emotional Problems among Latin-American Adolescents.
Second-generation Latin-American adolescents tend to show higher levels of various health-risking behaviors and emotional problems than first-generation Latin-American adolescents. This cross-sectional study of 40 mother-adolescent dyads examined the association of mother-youth acculturation gaps to youth adjustment problems. Intergenerational acculturation gaps were assessed as a bidimensional self-report component and a novel observational measurement component. The Latin-American adolescents were predominantly second-generation of Mexican descent (M age = 13.42 years, SD = 0.55). Most of the mothers were born in Mexico (M age = 39.18 years, SD = 5.17). Data were collected from mothers, adolescents, and coders, using questionnaires, structured interviews, and videotaped mother-youth interaction tasks. Findings revealed generally weak support for the acculturation gap-distress hypothesis. In addition, stronger relative adherence to their heritage culture by the adolescents was significantly (p < .05, ES = 0.15) related to less engagement in early health-risking sexual behaviors, possibly reflecting selective acculturation processes. Mother-youth acculturation gaps in orientation to the heritage culture were the most salient dimension, changing the focus on the original formulation of the acculturation gap-distress hypothesis.


Interaction of the Ubc9 human homologue with c-Jun and with the glucocorticoid receptor.
Glucocorticoid hormones convert the glucocorticoid receptor (GR) from an inactive cytosolic complex to a nuclear form that regulates transcription. Binding of GR to palindromic DNA-recognition sites (hormone response elements) leads to activated target gene transcription. GR also exerts negative actions on transcription, e.g., by interfering with the function of several other transcription factors such as AP-1, NK-kappa B, CREB, and Oct-1. Physical interactions of GR with AP-1 subunits are readily detectable but do not seem sufficient since nonrepressing GR mutants still interact in vitro, so that specific conformational changes and/or interactions with additional partner proteins may be required for negative action. In an attempt to find such partner proteins, we defined regions of c-Jun and GR essential for mutual interference and used in those a yeast two-hybrid screen for interacting proteins. Repeatedly we isolated overlapping cDNA sequences of one protein interaction with both c-Jun and GR. This protein does not interact with c-Fos or a non-repressing GR mutant and expressed in mammalian cells does not substantially affect AP-1 or GR activity. Interestingly, however, the protein rescues yeast cells from the toxic effects of the GR fragment used for screening. The protein represents the human homologue of the yeast E2 ubiquitin-conjugating enzyme, Ubc9; its specific interactions with both GR and c-Jun, but not mutant GR, suggest that it may exert physiologic regulatory functions.


The Evolution of Silicon Transport in Eukaryotes.
Biosilicification (the formation of biological structures from silica) occurs in diverse eukaryotic lineages, plays a major role in global biogeochemical cycles, and has significant biotechnological applications. Silicon (Si) uptake is crucial for biosilicification, yet the evolutionary history of the transporters involved remains poorly known. Recent evidence suggests that the SIT family of Si transporters, initially identified in diatoms, may be widely distributed, with an extended family of related transporters (SIT-Ls) present in some nonsilicified organisms. Here, we identify SITs and SIT-Ls in a range of eukaryotes, including major silicified lineages (radiolarians and chrysophytes) and also bacterial SIT-Ls. Our evidence suggests that the symmetrical 10-transmembrane-domain SIT structure has independently evolved multiple times via duplication and fusion of 5-transmembrane-domain SIT-Ls. We also identify a second gene family, similar to the active Si transporter Lsi2, that is broadly distributed amongst siliceous and nonsiliceous eukaryotes. Our analyses resolve a distinct group of Lsi2-like genes, including plant and diatom Si-responsive genes, and sequences unique to siliceous sponges and choanoflagellates. The SIT/SIT-L and Lsi2 transporter families likely contribute to biosilicification in diverse lineages, indicating an ancient role for Si transport in eukaryotes. We propose that these Si transporters may have arisen initially to prevent Si toxicity in the high Si Precambrian oceans, with subsequent biologically induced reductions in Si concentrations of Phanerozoic seas leading to widespread losses of SIT, SIT-L, and Lsi2-like genes in diverse lineages. Thus, the origin and diversification of two independent Si transporter families both drove and were driven by ancient ocean Si levels.


Functional outcomes of severe bicondylar tibial plateau fractures treated with dual incisions and medial and lateral plates.
Plate fixation of comminuted bicondylar tibial plateau fractures remains controversial. This retrospective study was performed to evaluate the perioperative results and functional outcomes of medial and lateral plate stabilization, through anterolateral and posteromedial surgical approaches, of comminuted bicondylar tibial plateau fractures. Over a seventy-seven-month period, eighty-three AO/OTA type-41-C3 bicondylar tibial plateau fractures were treated with medial and lateral plate fixation through two exposures. Injury radiographs were rank-ordered according to fracture severity. Immediate biplanar postoperative radiographs were evaluated to assess the quality of the reduction. The Musculoskeletal Function Assessment (MFA) questionnaire was used to evaluate functional outcome. Twenty-three male and eighteen female patients (average age, forty-six years) who completed the MFA questionnaire were included in the study group. The mean duration of follow-up was fifty-nine months. Two patients had a deep wound infection. Complete radiographic information was available for thirty-one patients. Seventeen (55%) of those patients had a satisfactory articular reduction (< or =2-mm step or gap), twenty-eight patients (90%) had satisfactory coronal plane alignment (medial proximal tibial angle of 87 degrees +/- 5 degrees ), twenty-one patients (68%) demonstrated satisfactory sagittal plane alignment (posterior proximal tibial angle of 9 degrees +/- 5 degrees ), and all thirty-one patients demonstrated satisfactory tibial plateau width (0 to 5 mm). Patient age and polytrauma were associated with a higher (worse) MFA score (p = 0.034 and p = 0.039, respectively). When these variables were accounted for, regression analysis demonstrated that a satisfactory articular reduction was significantly associated with a better MFA score (p = 0.029). Rank-order fracture severity was also predictive of MFA outcome (p < 0.001). No association was identified between rank-order severity and a satisfactory articular reduction (p = 0.21). The patients in this series demonstrated significant residual dysfunction (p < 0.0001), compared with normative data, with the leisure, employment, and movement MFA domains displaying the worst scores. Medial and lateral plate stabilization of comminuted bicondylar tibial plateau fractures through medial and lateral surgical approaches is a useful treatment method; however, residual dysfunction is common. Accurate articular reduction was possible in about half of our patients and was associated with better outcomes within the confines of the injury severity.


Role of the saturated nonesterified fatty acid palmitate in beta cell dysfunction.
Sustained elevated levels of saturated free fatty acids, such as palmitate, contribute to beta cell dysfunction, a phenomenon aggravated by high glucose levels. The aim of this study was to investigate the mechanisms of palmitate-induced beta cell dysfunction and death, combined or not with high glucose. Protein profiling of INS-1E cells, exposed to 0.5 mmol/L palmitate and combined or not with 25 mmol/L glucose, for 24 h was done by 2D-DIGE, both on full cell lysate and on an enriched endoplasmic reticulum (ER) fraction. Eighty-three differentially expressed proteins (P < 0.05) were identified by MALDI-TOF/TOF mass spectrometry and proteomic results were confirmed by functional assays. 2D-DIGE analysis of whole cell lysates and ER enriched samples revealed a high number of proteins compared to previous reports. Palmitate induced beta cell dysfunction and death via ER stress, hampered insulin maturation, generation of harmful metabolites during triglycerides synthesis and altered intracellular trafficking. In combination with high glucose, palmitate induced increased shunting of excess glucose, increased mitochondrial reactive oxygen species production and an elevation in many transcription-related proteins. This study contributes to a better understanding and revealed novel mechanisms of palmitate-induced beta cell dysfunction and death and may provide new targets for drug discovery.


Maturity assessment of compost from municipal solid waste through the study of enzyme activities and water-soluble fractions.
In this work the dynamics of biochemical (enzymatic activities) and chemical (water-soluble fraction) parameters during 100 days of municipal solid wastes composting were studied to evaluate their suitability as tools for compost characterization. The hydrolase (protease, urease, cellulase, beta-glucosidase) and dehydrogenase activities were characterized by significant changes during the first 2 weeks of composting, because of the increase of easily decomposable organic compounds. After the 4th week a "maturation phase" was identified in which the enzymatic activities tended to gently decrease, suggesting the stabilisation of organic matter. Also the water-soluble fractions (water-soluble carbon, nitrogen, carbohydrates and phenols), which are involved in many degradation processes, showed major fluctuations during the first month of composting. The results obtained showed that the hydrolytic activities and the water-soluble fractions did not vary statistically during the last month of composting. Significant correlations between the enzymatic activities, as well as between enzyme activities and water-soluble fractions, were also highlighted. These results highlight the suitability of both enzymatic activities and water soluble fractions as suitable indicators of the state and evolution of the organic matter during composting. However, since in the literature the amount of each activity or fraction at the end of composting depends on the raw material used for composting, single point determinations appear inadequate for compost characterization. This emphasizes the importance of the characterization of the dynamics of enzymatic activities and water-soluble fractions during the process.


Optical needle endoscope for safe and precise stereotactically guided biopsy sampling in neurosurgery.
Proper treatment of deep seated brain tumors requires correct histological diagnosis which unambiguously necessitates biopsy sampling. Stereotactically guided sampling of biopsies is widely used but bears the danger of incorrect sampling locations and damage to intracerebral blood vessels. Here, we present a minimally invasive contact endoscopic probe that can be inserted into the tissue inside a standard biopsy needle and allows for fluorescence detection of both tumorous tissue and intracerebral blood vessels. Outer diameter of our contact probe is smaller than 1.5 mm, field-of-view in the range of several hundred microns; the optical design allows for simultaneous detection and visualization of tissue autofluorescence and selective fluorescence signals from deep seated brain tumors and vasculature as shown on in vivo animal models. We demonstrate the tumor detection capability during stereotactic needle insertion in a clinical pilot trial. Using our probe, we expect stereotactic interventions to become safer and more precise and the technology might ultimately be used also for various other kinds of applications.


Robust, frequency-stable and accurate mid-IR laser spectrometer based on frequency comb metrology of quantum cascade lasers up-converted in orientation-patterned GaAs.
We demonstrate a robust and simple method for measurement, stabilization and tuning of the frequency of cw mid-infrared (MIR) lasers, in particular of quantum cascade lasers. The proof of principle is performed with a quantum cascade laser at 5.4 µm, which is upconverted to 1.2 µm by sum-frequency generation in orientation-patterned GaAs with the output of a standard high-power cw 1.5 µm fiber laser. Both the 1.2 µm and the 1.5 µm waves are measured by a standard Er:fiber frequency comb. Frequency measurement at the 100 kHz-level, stabilization to sub-10 kHz level, controlled frequency tuning and long-term stability are demonstrated.


Effects of diltiazem on the calcium paradox in isolated rat hearts.
Effects of diltiazem (10(-5) M) on the calcium paradox were studied in isolated, perfused rat hearts. After 4 min of calcium-free perfusion, the hearts were reperfused with medium containing 2.5 mM calcium for 15 min at 37 degrees C. During this perfusion, the coronary flow rate was maintained either high (10 ml/min) to produce severe tissue injury of calcium paradox or low (5 ml/min) to produce mild injury. In the high flow rate group, administration of diltiazem during the calcium-free period and calcium-repletion period failed to reduce the overall level of tissue injury caused by calcium-repletion. In the low coronary flow rate group, diltiazem markedly prevented the development of the calcium paradox, in terms of calcium-induced creatine kinase release, recovery of contractile tension development, tissue high-energy phosphate stores and tissue calcium accumulation. These events were irrespective of whether the drug was administered only during the calcium-free period, the calcium-free period and initial 2 min of the calcium-repletion period or the calcium-free period and totality of the calcium-repletion period. Thus, diltiazem appears to exert its protective effect against the mild calcium paradox phenomenon by regulating the ionic environment of myocardial cells during the calcium-free period.


Control and placement of intracranial microcatheters.
Balloon-tipped microcatheters allow flow-guided entry into small vessels and permit selective angiography, selective drug infusion, temporary or permanent vessel occlusion, and controlled deposition of tissue adhesives. However, active directive techniques are not usually successful with balloon microcatheters, and more passive flow-directed maneuvering must be learned. Three conditions may be encountered. In the first, the vessel to be entered is large and exits at a small angle from the parent vessel. Flow and momentum carry the microcatheter toward the goal. In the second, the abnormal vessel exists at a large angle but is larger than the continuing vessel. Inflating the balloon until it is larger than the continuing vessel will cause the flow to carry it around even sharp bends. In the third, the abnormal vessel is small and also exits at a large angle. Two balloons must then be used. The first occludes the larger mainline continuing vessel, while a second is injected; flow then carries the second around the bend.


Endogenous neural stem cells in the adult brain.
Despite progress in our understanding molecular mechanisms of neuronal cell death in many central nervous system (CNS) diseases, widely effective treatments remain elusive. Recent studies have shown that neural stem cells (NSCs) are present in the subventricular zone (SVZ) lining the lateral ventricles and the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) in adult mouse, rat, nonhuman primate, and human brain. Newly generated cells in the SGZ can differentiate into mature, functional neurons and integrate into the DG as granule cells, which are involved in memory formation. In addition, many CNS diseases can stimulate the proliferation of neuronal stem/progenitor cells located in the SVZ and SGZ of the adult rodent brain, and the resulting newborn cells migrate into damaged brain regions, where they express mature neuronal markers. Therefore, it might be possible for damaged cells to be replaced from endogenous neural stem cell pools. However, the capacity of self-repair is obviously not enough. Proliferation, migration, and neuronal differentiation of endogenous NSCs could be manipulated by pharmaceutical tools to reach the adequate benefits for the treatment of CNS diseases.


Mapping the needs and psychological outcomes of Slovenian adolescent and young adult cancer patients: An exploratory mixed-method study.
With improving survival rates, it is becoming increasingly important to understand the psychological aspect and needs of young cancer patients and survivors. Our goal was to describe the self-reported levels of psychological distress, subjective illness experience and needs of young Slovenian cancer patients and survivors. Seventy-nine participants, aged 19-39 years, answered questionnaires about anxiety, depression, mental defeat, cancer worry and their experience of learning the diagnosis and being treated. We used visualisations to demonstrate the relationship between anxiety and depression. The qualitative responses were summarised using a content analysis approach. Twenty-eight (35%) participants scored in the clinical range for anxiety and fifteen (19%) for depression. Cancer-related worry was common (85% reported at least one worry). Mental defeat was positively associated with measures of psychological distress. Those who felt negative about learning their diagnosis emphasised the need for more time, empathy and dignity. Psychological support during illness was seen as crucial. Anxiety and depression remain a problem for a subset of patients. Medical professionals working with young people with cancer should encourage a warm atmosphere as they attend to patients' needs and concerns.


Efficacy and safety of autologous bone marrow-derived stem cell transplantation in patients with type 2 diabetes mellitus: a randomized placebo-controlled study.
There is a growing interest in cell-based therapies in T2DM as β-cell failure is progressive and inexorable with the advancing duration of disease. This prospective, randomized, single-blinded placebo-controlled study evaluates the efficacy and safety of autologous bone marrow-derived stem cell transplantation (ABMSCT) in T2DM. Twenty-one patients with triple oral antidiabetic drug failure and requiring insulin ≥0.4 IU per kg per day with HbA1c <7.5% were randomly assigned to an intervention (n = 11) and control group (n = 10) and followed for 12 months. Patients in the intervention group received ABMSCT through a targeted approach, and after 12 weeks, a second dose of stem cells was administered through the antecubital vein after mobilization with G-CSF, while the control group underwent a sham procedure. The primary end point was a reduction in insulin requirement by ≥50% from baseline while maintaining HbA1c <7%. Nine out of the 11 (82%) patients in the intervention group achieved the primary end point, whereas none of the patients in the control group did over the study period (p = 0.002). The insulin requirement decreased by 66.7% in the intervention group from 42.0 (31.0‐64.0) IU per day to 14.0 (0.0‐30.0) IU per day (p = 0.011), while in controls it decreased by 32.1% from 40.5 (31.8‐44.3) IU per day to 27.5 (23.5‐33.3) IU per day (p = 0.008) at 12 months. The reduction in insulin requirement was significantly more in the intervention group compared to controls at both 6 (p = 0.001) and 12 months (p = 0.004). There was a modest but nonsignificant increase in HbA1c (%) in cases from 6.9% (6.4‐7.2%) to 7.1% (6.6‐7.5%) as well as in controls from 6.9% (6.2‐7.0%) to 7.0% (6.9‐7.5%). Ten out of 11 (91%) patients could maintain HbA1c <7% in the intervention group, whereas 6 out of 10 did (60%) in the control group (p = 0.167). The glucagon-stimulated C-peptide significantly increased in treated cases compared to controls (p = 0.036). The decrease in insulin requirement positively correlated with stimulated C-peptide (r = 0.8, p = 0.001). In conclusion, ABMSCT results in a significant decrease in the insulin dose requirement along with an improvement in the stimulated C-peptide levels in T2DM. However, a greater number of patients with a longer duration of follow-up are required to substantiate these observations.


Cognitive and neural facets of dissociation in a traumatized population.
Dissociative phenomena are frequently experienced by psychologically traumatized people. However, little is known about the cognitive profiles of highly dissociative traumatized individuals, and corresponding patterns of neural connectivity when attentional networks are engaged in the context of emotion. One hundred seventeen traumatized women completed the multiscale dissociation inventory (MDI) and neuropsychological testing; MDI scores were used to classify high- and low-dissociative participants. Forty-six participants also underwent fMRI during performance of an attentional control task that incorporates emotionally distracting images (Affective Number Stroop; ANS). Compared to low-dissociative participants, high-dissociative participants demonstrated better performance on an executive functioning task (F1,111 = 4.64, p = .03), worse performance on a task of visual memory (F1,111 = 9.52, p = .003), and similar performance on all other neuropsychological measures. In addition, dissociative symptoms were negatively correlated with functional connectivity between the amygdala and right anterior insula in response to trauma-related ANS trials. These findings indicate that highly dissociative traumatized people experience difficulties with attentional control in the context of emotionally evocative stimuli, but in a neutral context, their overall cognitive profiles are similar to low-dissociative people. Highly dissociative participants also demonstrated weaker connectivity between the amygdala and insula in response to trauma-relevant images. Evocative, trauma-relevant stimuli appear to disrupt neutral networks involved with attention to salient cues and interoception in highly dissociative traumatized individuals. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Specialised early intervention teams for recent-onset psychosis.
Psychosis is an illness characterised by the presence of hallucinations and delusions that can cause distress or a marked change in an individual's behaviour (e.g. social withdrawal, flat or blunted effect). A first episode of psychosis (FEP) is the first time someone experiences these symptoms that can occur at any age, but the condition is most common in late adolescence and early adulthood. This review is concerned with first episode psychosis (FEP) and the early stages of a psychosis, referred to throughout this review as 'recent-onset psychosis.' Specialised early intervention (SEI) teams are community mental health teams that specifically treat people who are experiencing, or have experienced a recent-onset psychosis. The purpose of SEI teams is to intensively treat people with psychosis early in the course of the illness with the goal of increasing the likelihood of recovery and reducing the need for longer-term mental health treatment. SEI teams provide a range of treatments including medication, psychotherapy, psychoeducation, and occupational, educational and employment support, augmented by assertive contact with the service user and small caseloads. Treatment is time limited, usually offered for two to three years, after which service users are either discharged to primary care or transferred to a standard adult community mental health team. A previous Cochrane Review of SEI found preliminary evidence that SEI may be superior to standard community mental health care (described as 'treatment as usual (TAU)' in this review) but these recommendations were based on data from only one trial. This review updates the evidence for the use of SEI services. To compare specialised early intervention (SEI) teams to treatment as usual (TAU) for people with recent-onset psychosis. On 3 October 2018 and 22 October 2019, we searched Cochrane Schizophrenia's study-based register of trials, including registries of clinical trials. We selected all randomised controlled trials (RCTs) comparing SEI with TAU for people with recent-onset psychosis. We entered trials meeting these criteria and reporting useable data as included studies. We independently inspected citations, selected studies, extracted data and appraised study quality. For binary outcomes we calculated the risk ratios (RRs) and their 95% confidence intervals (CIs). For continuous outcomes we calculated the mean difference (MD) and their 95% CIs, or if assessment measures differed for the same construct, we calculated the standardised mean difference (SMD) with 95% CIs. We assessed risk of bias for included studies and created a 'Summary of findings' table using the GRADE approach. We included three RCTs and one cluster-RCT with a total of 1145 participants. The mean age in the trials was between 23.1 years (RAISE) and 26.6 years (OPUS). The included participants were 405 females (35.4%) and 740 males (64.6%). All trials took place in community mental healthcare settings. Two trials reported on recovery from psychosis at the end of treatment, with evidence that SEI team care may result in more participants in recovery than TAU at the end of treatment (73% versus 52%; RR 1.41, 95% CI 1.01 to 1.97; 2 studies, 194 participants; low-certainty evidence). Three trials provided data on disengagement from services at the end of treatment, with fewer participants probably being disengaged from mental health services in SEI (8%) in comparison to TAU (15%) (RR 0.50, 95% CI 0.31 to 0.79; 3 studies, 630 participants; moderate-certainty evidence). There was low-certainty evidence that SEI may result in fewer admissions to psychiatric hospital than TAU at the end of treatment (52% versus 57%; RR 0.91, 95% CI 0.82 to 1.00; 4 studies, 1145 participants) and low-certainty evidence that SEI may result in fewer psychiatric hospital days (MD -27.00 days, 95% CI -53.68 to -0.32; 1 study, 547 participants). Two trials reported on general psychotic symptoms at the end of treatment, with no evidence of a difference between SEI and TAU, although this evidence is very uncertain (SMD -0.41, 95% CI -4.58 to 3.75; 2 studies, 304 participants; very low-certainty evidence). A different pattern was observed in assessment of general functioning with an end of trial difference that may favour SEI (SMD 0.37, 95% CI 0.07 to 0.66; 2 studies, 467 participants; low-certainty evidence). It was uncertain whether the use of SEI resulted in fewer deaths due to all-cause mortality at end of treatment (RR 0.21, 95% CI 0.04 to 1.20; 3 studies, 741 participants; low-certainty evidence). There was low risk of bias for random sequence generation and allocation concealment in three of the four included trials; the remaining trial had unclear risk of bias. Due to the nature of the intervention, we considered all trials at high risk of bias for blinding of participants and personnel. Two trials had low risk of bias and two trials had high risk of bias for blinding of outcomes assessments. Three trials had low risk of bias for incomplete outcome data, while one trial had high risk of bias. Two trials had low risk of bias, one trial had high risk of bias, and one had unclear risk of bias for selective reporting. There is evidence that SEI may provide benefits to service users during treatment compared to TAU. These benefits probably include fewer disengagements from mental health services (moderate-certainty evidence), and may include small reductions in psychiatric hospitalisation (low-certainty evidence), and a small increase in global functioning (low-certainty evidence) and increased service satisfaction (moderate-certainty evidence). The evidence regarding the effect of SEI over TAU after treatment has ended is uncertain. Further evidence investigating the longer-term outcomes of SEI is needed. Furthermore, all the eligible trials included in this review were conducted in high-income countries, and it is unclear whether these findings would translate to low- and middle-income countries, where both the intervention and the comparison conditions may be different.


Characterisation and comparison of lactating mouse and bovine mammary gland miRNomes.
The mammary gland is a dynamic organ that undergoes important physiological changes during reproductive cycles. Until now, data regarding the characterisation of miRNA in the mammary gland have been scarce and mainly focused on their abnormal expression in breast cancer. Our goal was to characterise the microRNA (miRNA) involved in mechanisms regulating the mammary function, with particular focus on the lactation stage. Using high-throughput sequencing technology, the exhaustive repertoires of miRNA expressed (miRNome) in mouse and bovine mammary glands during established lactation were identified, characterized and compared. Furthermore, in order to obtain more information on miRNA loading in the RNA-induced silencing complex (RISC), the miRNome was compared with that obtained from RNA associated with the AGO2 protein (AGO2-miRNome) in mouse lactating mammary gland. This study enabled the identification of 164 and 167 miRNA in mouse and bovine, respectively. Among the 30 miRNA most highly expressed in each species, 24 were common to both species and six of them were preferentially highly expressed in lactating than non-lactating mammary gland. The potential functional roles of these 24 miRNA were deduced using DIANA-miRPath software, based on miRNA/mRNA interactions. Moreover, seven putative novel miRNA were identified. Using DAVID analysis, it was concluded that the predicted targets of two of these putative novel miRNA are involved in mammary gland morphogenesis. Our study provides an overview of the characteristics of lactating mouse and bovine mammary gland miRNA expression profiles. Moreover, species-conserved miRNA involved in this fundamental biological function were identified. These miRNomes will now be used as references for further studies during which the impact of animal breeding on the miRNA expression will be analysed.


Verifying performance characteristics of quantitative analytical systems: calibration verification, linearity, and analytical measurement range.
Both the regulations in the Clinical Laboratory Improvement Amendments of 1988 (CLIA) and the checklists of the College of American Pathologists (CAP) Laboratory Accreditation Program require clinical laboratories to verify performance characteristics of quantitative test systems. Laboratories must verify performance claims when introducing an unmodified, US Food and Drug Administration-cleared or approved test system, and they must comply with requirements for periodic calibration and calibration verification for existing test systems. They must also periodically verify the analytical measurement range of many quantitative test systems. To provide definitions for many of the terms used in these regulations, to describe a set of basic analyses that laboratories may adapt to demonstrate compliance with both CLIA and the CAP Laboratory Accreditation Program checklists for performing calibration verification and for verifying the analytical measurement range of test systems, to review some of the recommended procedures for establishing performance goals, and to provide data illustrating the performance goals used in some of the CAP's calibration verification and linearity surveys. The CAP's calibration verification and linearity survey programs, the CLIA regulations, the Laboratory Accreditation Program requirements, and published literature were used to meet these objectives. Calibration verification and linearity and analytical measurement range verification should be performed using suitable materials with assessment of results using well-defined evaluation protocols. We describe the CAP's calibration verification and linearity programs that may be used for these purposes.


Azidothymidine and cisplatin increase p14ARF expression in OVCAR-3 ovarian cancer cell line.
p14(ARF) tumor suppressor protein regulates p53 by interfering with mdm2-p53 interaction. p14(ARF) is activated in response to oncogenic stimuli but little is known of the responses of endogenous p14(ARF) to different types of cellular stress or DNA damage. Azidothymidine (AZT) is being tested in several clinical trials as an enhancer of anticancer chemotherapy. However, the knowledge of the relationship between AZT and cellular pathways, e.g. p53 pathway, is very limited. In this study, we show that AZT, cisplatin (CDDP) and docetaxel (DTX) all induce unique molecular responses in OVCAR-3 ovarian carcinoma cells carrying a mutated p53, while in A2780, ovarian carcinoma and MCF-7 breast carcinoma cells with wild type p53, all of these drugs cause similar p53 responses. We found that endogenous p14(ARF) protein in OVCAR-3 cells is down-regulated by DTX but induced by AZT and a short CDDP pulse treatment. In HT-29 colon carcinoma cells with a mutated p53, all treatments down-regulated p14(ARF) protein. Both CDDP and AZT increased the expression of p14ARF mRNA in OVCAR-3 cells. Differences in cell death induced by these drugs did not explain the differences in protein and mRNA expressions. No increase in the level of either c-Myc or H-ras oncoproteins was seen in OVCAR-3 cells after AZT or CDDP-treatment. These results suggest that p14(ARF) can respond to DNA damage without oncogene activation in cell lines without functional p53.