High maternal mortality in rural south-west Ethiopia: estimate by using the sisterhood method.
Estimation of maternal mortality is difficult in developing countries without complete vital registration. The indirect sisterhood method represents an alternative in places where there is high fertility and mortality rates. The objective of the current study was to estimate maternal mortality indices using the sisterhood method in a rural district in south-west Ethiopia. We interviewed 8,870 adults, 15-49 years age, in 15 randomly selected rural villages of Bonke in Gamo Gofa. By constructing a retrospective cohort of women of reproductive age, we obtained sister units of risk exposure to maternal mortality, and calculated the lifetime risk of maternal mortality. Based on the total fertility for the rural Ethiopian population, the maternal mortality ratio was approximated. We analyzed 8503 of 8870 (96%) respondents (5262 [62%] men and 3241 ([38%] women). The 8503 respondents reported 22,473 sisters (average = 2.6 sisters for each respondent) who survived to reproductive age. Of the 2552 (11.4%) sisters who had died, 819 (32%) occurred during pregnancy and childbirth. This provided a lifetime risk of 10.2% from pregnancy and childbirth with a corresponding maternal mortality ratio of 1667 (95% CI: 1564-1769) per 100,000 live births. The time period for this estimate was in 1998. Separate analysis for male and female respondents provided similar estimates. The impoverished rural area of Gamo Gofa had very high maternal mortality in 1998. This highlights the need for strengthening emergency obstetric care for the Bonke population and similar rural populations in Ethiopia.


Information sources and their use by parents of children with ophthalmic disorders.
Parents' input is critical to clinical management in pediatric ophthalmology. The importance of providing parents with appropriate information to enable them to participate effectively is recognized. However, little is known about the range of sources parents use to learn about their child's ophthalmic condition, which sources they find most useful, and how this relates to their understanding. Cross-sectional survey of the parents or usual caregivers of children with diverse ophthalmic disorders, diagnosed at least 1 year earlier, who attended pediatric ophthalmology clinics at Great Ormond Street Hospital, London, during 1 week in August 2001. Eighty-nine percent (n = 58) of parents with eligible children participated. Most parents received information from more than one source, with ophthalmologists (79%) and family practitioners (42%) being the two most frequently reported. Family support groups and voluntary organizations (29%) and the Internet (23%) were less commonly cited than anticipated. Parents reported receiving verbal information much more frequently than written information from professionals working with their children. Although 72% (n = 42) of parents could correctly name their child's diagnosis, only 46% (n = 27) were able to describe correctly the nature and impact of the disorder(s). Ophthalmologists were ranked as the most important source overall. The findings emphasize the key role of ophthalmic professionals in improving parental education directly, as well their responsibilities and opportunities to do so through supporting and shaping information provision through other sources, especially colleagues in primary care and the Internet.


No effect of 6-month intake of glucosamine sulfate on Modic changes or high intensity zones in the lumbar spine: sub-group analysis of a randomized controlled trial.
The underlying pathology and natural course of Modic changes (MC) in the vertebral body marrow and high intensity zones (HIZs) in the annulus fibrosus is not completely clarified. These findings on magnetic resonance imaging (MRI) have initiated different treatments with little or unclear effect. In a randomized trial (n=250), glucosamine sulfate (GS) had no effect on low back pain related disability. GS could still have an effect on MC and HIZ. In this sub-study, 45 patients from the trial who had MC and/or HIZ at pre-treatment underwent follow-up MRI. The aim was to examine the course of MC and HIZ and to compare this course between groups treated with 6-month intake of oral GS versus placebo. Of 141 pre-treatment MC in 42 (of 45) patients, 29 (20.6%) MC in 18 patients had altered type and 14 MC in 9 patients had altered size (decreased for 1 MC) 6-18 months later: odds ratio (OR) for type vs. size alterations 4.0; 95% confidence interval (CI) 1.2-17.7. No MC resolved. HIZ vanished from 3 of 23 discs in 3 of 21 patients with pre-treatment HIZ. Ten new MC (all type I or I/II) occurred in 8 patients and 2 new HIZs in 2 patients. The GS group (n=19) and placebo group (n=26) did not differ in proportions of MC with decreased (OR 1.6; 95% CI 0.4-6.1) or increased type I dominance at follow-up (OR placebo:GS 2.4; 95% CI 0.6-9.7), or with increased size (OR 1.0; 95% CI 0.2-4.7). HIZ vanished from 1 of 8 discs in 1 of 8 patients in the GS group vs. 2 of 15 discs in 2 of 13 patients in the placebo group (OR 0.8; 95% CI 0.02-12.2). In this sub-group analysis of a placebo-controlled trial, the effect of GS on MC and HIZs was no different from the effect of the placebo intervention. MC and HIZs remained mostly unchanged during the 6-18 months study period. Some short term changes did occur and MC more often altered type than size. NCT00404079 at http://www.clinicaltrial.gov.


CD24 staining of mouse mammary gland cells defines luminal epithelial, myoepithelial/basal and non-epithelial cells.
Breast cancer is thought to arise in mammary epithelial stem cells. There is, therefore, a large amount of interest in identifying these cells. The breast is a complex tissue consisting of two epithelial layers (an outer myoepithelial/basal layer and an inner luminal epithelial layer) as well as a large non-epithelial component (fibroblasts, endothelial cells, lymphocytes, adipocytes, neurons and myocytes). The definitive identification of a mammary epithelial stem cell population is critically dependent on its purity. To date, this has been hampered by the lack of suitable markers to separate out the two epithelial layers, and to remove contaminating non-epithelial cells. Mouse mammary glands were dissociated and stained with CD24. Cells were sorted into separate populations based on CD24 expression and assessed for luminal epithelial and myoepithelial/basal markers by direct fluorescent microscopy and real time PCR. The stem/progenitor potential of these cell populations was assessed in vivo by cleared mammary fat pad transplantation. Three populations of CD24 expressing cells were identified: CD24Negative, CD24Low and CD24High. Staining of these cells with cytokeratin markers revealed that these populations correspond to non-epithelial, myoepithelial/basal and luminal epithelial cells, respectively. Cell identities were confirmed by quantitative PCR. Cleared mammary fat pad transplantation of these cell populations revealed that extensive mammary fat pad repopulation capacity segregates with the CD24Low cells, whilst CD24High cells have limited repopulation capacity. Differential staining of mammary epithelial cells for CD24 can be used to simultaneously isolate pure populations of non-epithelial, myoepithelial/basal and luminal epithelial cells. Furthermore, mammary fat pad repopulation capacity is enriched in the CD24Low population. As separation is achieved using a single marker, it will be possible to incorporate additional markers to further subdivide these populations. This will considerably facilitate the further analysis of mammary epithelial subpopulations, whilst ensuring high purity, which is key for understanding mammary epithelial stem cells in normal tissue biology and carcinogenesis.


Tyrosine depletion attenuates the behavioural stimulant effects of amphetamine and cocaine in rats.
Neurochemical studies show that a tyrosine-free amino acid mixture depletes brain tyrosine and decreases dopamine synthesis and release. Here, we tested whether such a mixture would reduce the behavioural effects of amphetamine and other psychostimulants. A tyrosine-free amino acid mixture decreased the behavioural activation induced by both D-amphetamine (2 mg/kg s.c.) and cocaine (2 mg/kg s.c.). In contrast, the activation induced by the dopamine agonist, apomorphine (0.75 and 5 mg/kg s.c.), or the 5-hydroxytryptamine releasing agent, p-chloroamphetamine (2 mg/kg s.c.) was not altered. These findings provide behavioural evidence that tyrosine-free amino acid mixtures reduce presynaptic dopamine function in the brain.


Operating from the other side of the table: control dynamics and the surgeon educator.
Critical moments in operations cause the surgeon to transition from a relatively "automatic" mode of operating to a more attentive mode-previously referred to as "slowing down when you should." Using this framework, this study explored how academic surgeons manage and balance the often competing responsibilities of patient safety and education during the slowing-down moments. This study used a constructivist approach to grounded theory methodology to explore an emergent theme of control among academic surgeons. Twenty-eight surgeons were interviewed across 4 academic teaching hospitals, and 5 general (hepato-pancreatico-biliary) surgeons were observed. Thematic analysis of the transcripts and field notes was conducted and iteratively elaborated and refined as data collection progressed with all team members. A reflexive approach was adopted throughout. An interesting control dynamic emerged as surgeons discussed the need to maintain a sense of control of an operation regardless of how much manual control they had. A dual responsibility to education and patient safety was apparent, with surgeons describing and demonstrating numerous strategies for negotiating manual control with the trainee during the critical slowing-down moments. An assessment of the trainee was implicit in the negotiation process. Numerous complications of control were identified ("bargaining," "skidding") as a product of this control dynamic. Operating from the "other side of the table" sets up a control dynamic that requires manipulation and negotiation on the part of the academic surgeon. Understanding these issues informs surgeons in their supervisory role, offering avenues for optimizing surgical training.


What Is the Role of Vitamin D Supplementation in Acute Fracture Patients? A Systematic Review and Meta-Analysis of the Prevalence of Hypovitaminosis D and Supplementation Efficacy.
The objectives of this systematic review and meta-analyses are (1) to estimate the prevalence of hypovitaminosis D in fracture patients and (2) to summarize the available evidence on the efficacy of vitamin D supplementation in fracture patients. A comprehensive search of the MEDLINE, Embase, PubMed, and Cochrane Central Register of Controlled Trials databases was conducted. Conference abstracts from relevant meetings were also searched. We included studies that investigate vitamin D insufficiency or examine the effect of vitamin D supplementation on 25-hydroxy-vitamin D (25(OH)D) serum levels in fracture patients. Two authors independently extracted data using a predesigned form. We performed a pooled analysis to determine the prevalence of postfracture hypovitaminosis D and mean postfracture 25(OH)D levels. We present detailed summaries of each of the studies evaluating the impact of vitamin D supplementation. The weighted pooled prevalence of hypovitaminosis D was 70.0% (95% confidence interval: 63.7%-76.0%, I = 97.7). The mean postfracture serum 25(OH)D was 19.5 ng/mL. The studies that evaluated the efficacy of vitamin D supplementation suggest that vitamin D supplementation safely increases serum 25(OH)D levels. Only 1 meeting abstract showed a trend toward reduced risk of nonunion after a single large loading dose of vitamin D. This review found a high prevalence of hypovitaminosis D in fracture patients and that vitamin D supplementation at a range of doses safely increases 25(OH)D serum levels. To date, only 1 pilot study published as a meeting abstract has demonstrated a trend toward improved fracture healing with vitamin D supplementation. Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.


Pediatric invasive pneumococcal disease in Taiwan following a national catch-up program with the 13-valent pneumococcal conjugate vaccine.
Seven-valent pneumococcal conjugate vaccine (PCV) has been available in Taiwan since late 2005. A national catch-up program was launched in Taiwan in 2013, providing 1 dose of 13-valent PCV to children aged 2-5 years. Here, we report the epidemiology of invasive pneumococcal disease (IPD) in children aged ≤5 years in this setting. We collected demographic and clinical information for pediatric patients (≤5 years) with IPD between 2008 and 2013. The incidence of IPD was estimated. The logs for PCV import into Taiwan were obtained to evaluate the impact of PCV usage on IPD epidemiology. The overall incidence of IPD in children aged ≤5 years was 15.9 cases per 100,000 person-years. The IPD incidence caused by 7-valent PCV serotypes decreased significantly from 10.0 cases per 100,000 person-years in 2008 to 2.3 cases per 100,000 person-years in 2013. The incidence of IPD caused by serotype 19A increased substantially from 1.7 cases per 100,000 person-years in 2008 to 10.3 cases per 100,000 person-years in 2012, followed by a significant decrease to 5.6 cases per 100,000 person-years in 2013. The significant decrease in the incidence of serotype 19A IPD occurred primarily in children aged 2-5 years. The 13-valent PCV catch-up program was associated with a significant decrease in serotype 19A IPD incidence in 2013, primarily in children eligible for the 13-valent PCV immunization. Continued surveillance is necessary to assess the further impact of the national catch-up program on pediatric IPD epidemiology in Taiwan.


Doubling the spatial frequency with cavity resonance lithography.
We describe the theory and report the first experimental demonstration of Cavity Resonance Lithography (CRL); a double pattering (DP) technique that can generate patterns on a photoresist 1) with twice the spatial frequency of that of the diffraction limited lithography mask, and 2) at an offset distance that is in the far field of the mask. CRL requires only a single exposure and development step and does not require any additional processes. With commercially available photoresists (PR) and developers, we have recorded a 32.5 nm half-pitch pattern (which is well below the diffraction limit) at an offset distance of 180 nm (which is well beyond the evanescent decay length scales) using 193 nm illumination. We also discuss strategies to improve the minimum feature size and potential implementation schemes.


Infection control in delivery care units, Gujarat state, India: a needs assessment.
Increasingly, women in India attend health facilities for childbirth, partly due to incentives paid under government programs. Increased use of health facilities can alleviate the risks of infections contracted in unhygienic home deliveries, but poor infection control practices in labour and delivery units also cause puerperal sepsis and other infections of childbirth. A needs assessment was conducted to provide information on procedures and practices related to infection control in labour and delivery units in Gujarat state, India. Twenty health care facilities, including private and public primary health centres and referral hospitals, were sampled from two districts in Gujarat state, India. Three pre-tested tools for interviewing and for observation were used. Data collection was based on existing infection control guidelines for clean practices, clean equipment, clean environment and availability of diagnostics and treatment. The study was carried out from April to May 2009. Seventy percent of respondents said that standard infection control procedures were followed, but a written procedure was only available in 5% of facilities. Alcohol rubs were not used for hand cleaning and surgical gloves were reused in over 70% of facilities, especially for vaginal examinations in the labour room. Most types of equipment and supplies were available but a third of facilities did not have wash basins with "hands-free" taps. Only 15% of facilities reported that wiping of surfaces was done immediately after each delivery in labour rooms. Blood culture services were available in 25% of facilities and antibiotics are widely given to women after normal delivery. A few facilities had data on infections and reported rates of 3% to 5%. This study of current infection control procedures and practices during labour and delivery in health facilities in Gujarat revealed a need for improved information systems, protocols and procedures, and for training and research. Simply incentivizing the behaviour of women to use health facilities for childbirth via government schemes may not guarantee safe delivery.


Hand: Clinical Anatomy and Regional Approaches with Injectable Fillers.
Cosmetic physicians are more and more frequently asked for hand rejuvenation. They commonly propose the same techniques as for the face. The authors undertook an anatomical study of the hand dorsum to understand the optimal location for an injected filler and to design the safest technique of placement. The first part of the study included dissections of 19 fresh cadaveric hands and duplex ultrasounds investigation of 28 healthy hands. A technique of injection specifically designed from anatomical findings was then tested on 8 fresh cadaveric hands using magnetic resonance imaging and dissection in comparison with 3 other commonly used techniques of rejuvenating injections. Between the dermis and the tendons, the thickness of the fascial plane was measured from 0.3 to 2.2 mm. Because of numerous fibrous septa, the entire plane was found as a 3-dimensional sponge-like framework. Veins could be located in all levels of this framework. There was no predefined free space. The optimal place for the deposition of a filler was found to be the undersurface of the dermis. The specific technique named Scrape Skin Threading Technique and using a cannula scraping the deep side of the dermis was checked as the only technique which could give a perfect placement of product restricted to the fascial layer. The Scrape Skin Threading Technique was designed to inject safely and accurately any kind of injectable in contact with the undersurface of the dermis, which appeared anatomically as the optimal location of a filler for enhancing the outer appearance of the dorsum of hands.


A joint cross-border investigation of a cluster of multidrug-resistant tuberculosis in Austria, Romania and Germany in 2014 using classic, genotyping and whole genome sequencing methods: lessons learnt.
Molecular surveillance of multidrug-resistant tuberculosis (MDR-TB) using 24-loci MIRU-VNTR in the European Union suggests the occurrence of international transmission. In early 2014, Austria detected a molecular MDR-TB cluster of five isolates. Links to Romania and Germany prompted the three countries to investigate possible cross-border MDR-TB transmission jointly. We searched genotyping databases, genotyped additional isolates from Romania, used whole genome sequencing (WGS) to infer putative transmission links, and investigated pairwise epidemiological links and patient mobility. Ten isolates from 10 patients shared the same 24-loci MIRU-VNTR pattern. Within this cluster, WGS defined two subgroups of four patients each. The first comprised an MDR-TB patient from Romania who had sought medical care in Austria and two patients from Austria. The second comprised patients, two of them epidemiologically linked, who lived in three different countries but had the same city of provenance in Romania. Our findings strongly suggested that the two cases in Austrian citizens resulted from a newly introduced MDR-TB strain, followed by domestic transmission. For the other cases, transmission probably occurred in the same city of provenance. To prevent further MDR-TB transmission, we need to ensure universal access to early and adequate therapy and collaborate closely in tuberculosis care beyond administrative borders.


Microdevices for separation, accumulation, and analysis of biological micro- and nanoparticles.
Microfabrication and performance of a novel microsystem for separation, accumulation and analysis of biological micro- and nanoparticles is reported. Versatile chip functions based on dielectrophoresis and microfluidics were integrated to isolate particles from complex sample solutions such as serum. A bead-based assay for virus detection is proposed. Separation of micro- and sub-mum beads employing dielectrophoretic deflector and bandpass structures is demonstrated. Individual antibody coated beads with hepatitis A virus bound to their surface were trapped by negative dielectrophoresis in a field cage and analysed by fluorescence microscopy.


Defective DNA repair and neurodegenerative disease.
Defects in cellular DNA repair processes have been linked to genome instability, heritable cancers, and premature aging syndromes. Yet defects in some repair processes manifest themselves primarily in neuronal tissues. This review focuses on studies defining the molecular defects associated with several human neurological disorders, particularly ataxia with oculomotor apraxia 1 (AOA1) and spinocerebellar ataxia with axonal neuropathy 1 (SCAN1). A picture is emerging to suggest that brain cells, due to their nonproliferative nature, may be particularly prone to the progressive accumulation of unrepaired DNA lesions.


DNA methylation and evolution of duplicate genes.
The evolutionary mechanisms underlying duplicate gene maintenance and divergence remain highly debated. Epigenetic modifications, such as DNA methylation, may contribute to duplicate gene evolution by facilitating tissue-specific regulation. However, the role of epigenetic divergence on duplicate gene evolution remains little understood. Here we show, using comprehensive data across 10 diverse human tissues, that DNA methylation plays critical roles in several aspects of duplicate gene evolution. We first demonstrate that duplicate genes are initially heavily methylated, before gradually losing DNA methylation as they age. Within each pair, DNA methylation divergence between duplicate partners increases with evolutionary age. Importantly, tissue-specific DNA methylation of duplicates correlates with tissue-specific expression, implicating DNA methylation as a causative factor for functional divergence of duplicate genes. These patterns are apparent in promoters but not in gene bodies, in accord with the complex relationship between gene-body DNA methylation and transcription. Remarkably, many duplicate gene pairs exhibit consistent division of DNA methylation across multiple, divergent tissues: For the majority (73%) of duplicate gene pairs, one partner is always hypermethylated compared with the other. This is indicative of a common underlying determinant of DNA methylation. The division of DNA methylation is also consistent with their chromatin accessibility profiles. Moreover, at least two sequence motifs known to interact with the Sp1 transcription factor mark promoters of more hypomethylated duplicate partners. These results demonstrate critical roles of DNA methylation, as well as complex interaction between genome and epigenome, on duplicate gene evolution.


Proteases as antimalarial targets: strategies for genetic, chemical, and therapeutic validation.
Malaria is a devastating parasitic disease affecting half of the world's population. The rapid emergence of resistance against new antimalarial drugs, including artemisinin-based therapies, has made the development of drugs with novel mechanisms of action extremely urgent. Proteases are enzymes proven to be well suited for target-based drug development due to our knowledge of their enzymatic mechanisms and active site structures. More importantly, Plasmodium proteases have been shown to be involved in a variety of pathways that are essential for parasite survival. However, pharmacological rather than target-based approaches have dominated the field of antimalarial drug development, in part due to the challenge of robustly validating Plasmodium targets at the genetic level. Fortunately, over the last few years there has been significant progress in the development of efficient genetic methods to modify the parasite, including several conditional approaches. This progress is finally allowing us not only to validate essential genes genetically, but also to study their molecular functions. In this review, I present our current understanding of the biological role proteases play in the malaria parasite life cycle. I also discuss how the recent advances in Plasmodium genetics, the improvement of protease-oriented chemical biology approaches, and the development of malaria-focused pharmacological assays, can be combined to achieve a robust biological, chemical and therapeutic validation of Plasmodium proteases as viable drug targets.


Phase I trial of a ligand fusion-protein (DAB389IL-2) in lymphomas expressing the receptor for interleukin-2.
The purpose of this study was to evaluate the safety, tolerability, pharmacokinetics, and possible antitumor activity of a ligand fusion-protein, DAB389IL-2, in a phase I trial. This was a multicenter, open-label, dose-escalation trial. Patients with preserved organ function and histologically confirmed relapsed cutaneous T-cell lymphoma (CTCL), other non-Hodgkin's lymphomas (NHL), or Hodgkin's disease (HD) were eligible if their cancer was shown to express the interleukin (IL)-2 receptor by an immunohistochemical assay for the p55 or the p75 subunit. Patients received up to eight courses of DAB389IL-2 given as a short intravenous infusion daily for 5 days with subsequent courses every 21 days. The maximum tolerated dose (MTD) and tumor response was determined according to standard criteria. Seventy-three patients (44 men/29 women), aged 16 to 81 years (mean, 50.7) with CTCL (n = 35), NHL (n = 17), and HD (n = 21) were enrolled. The patients were extensively treated, failing 0 to 15 previous therapies (median, 4). Patients received one to six courses (mean, 3.3) of DAB389IL-2 over a range of 3 to 31 micrograms/kg/day. The dose-limiting toxicity was asthenia, establishing the maximum tolerated dose of 27 micrograms/kg/day. Approximately half of all patients had significant titers of antibody to diphtheria toxin or to DAB389IL-2 at the time of enrollment compared with 92% with titers at the end of treatment. The presence of antibody did not preclude clinical response. There were five complete (CR) and eight partial (PR) remissions in patients with CTCL with one CR and two PR occurring in NHL. The median time to response was 2 months and the duration of response was 2 to 39+ months. No responses were documented in patients with HD. DAB389IL-2 is well tolerated with an MTD of 27 micrograms/kg/day. This ligand fusion-protein showed antitumor effects in patients with IL-2 receptor expressing CTCL and NHL. Additional trials in these diseases are warranted.


Intranasal glyphosate-based herbicide administration alters the redox balance and the cholinergic system in the mouse brain.
Pesticide exposure is associated with cognitive and psychomotor disorders. Glyphosate-based herbicides (GlyBH) are among the most used agrochemicals, and inhalation of GlyBH sprays may arise from frequent aerial pulverizations. Previously, we described that intranasal (IN) administration of GlyBH in mice decreases locomotor activity, increases anxiety, and impairs recognition memory. Then, the aim of the present study was to investigate the mechanisms involved in GlyBH neurotoxicity after IN administration. Adult male CF-1 mice were exposed to GlyBH IN administration (equivalent to 50 mg/kg/day of Gly acid, 3 days a week, during 4 weeks). Total thiol content and the activity of the enzymes catalase, acetylcholinesterase and transaminases were evaluated in different brain areas. In addition, markers of the cholinergic and the nigrostriatal pathways, as well as of astrocytes were evaluated by fluorescence microscopy in coronal brain sections. The brain areas chosen for analysis were those seen to be affected in our previous study. GlyBH IN administration impaired the redox balance of the brain and modified the activities of enzymes involved in cholinergic and glutamatergic pathways. Moreover, GlyBH treatment decreased the number of cholinergic neurons in the medial septum as well as the expression of the α7-acetylcholine receptor in the hippocampus. Also, the number of astrocytes increased in the anterior olfactory nucleus of the exposed mice. Taken together, these disturbances may contribute to the neurobehavioural impairments reported previously by us after IN GlyBH administration in mice.


Effects of Citalopram on Sutural and Calvarial Cell Processes.
The use of selective serotonin reuptake inhibitors (SSRIs) for the treatment of depression during pregnancy is suggested to increase the incidence of craniofacial abnormalities including craniosynostosis. Little is known about this mechanism, however based on previous data we propose a mechanism that affects cell cycle. Excessive proliferation, and reduction in apoptosis may lead to hyperplasia within the suture that may allow for differentiation, bony infiltration, and fusion. Here we utilized in vivo and in vitro analysis to investigate this proposed phenomenon. For in vivo analysis we used C57BL-6 wild-type breeders treated with a clinical dose of citalopram during the third trimester of pregnancy to produce litters exposed to the SSRI citalopram in utero. At post-natal day 15 sutures were harvested from resulting pups and subjected to histomorphometric analysis for proliferation (PCNA) and apoptosis (TUNEL). For in vitro studies, we used mouse calvarial pre-osteoblast cells (MC3T3-E1) to assess proliferation (MTS), apoptosis (Caspase 3/7-activity), and gene expression after exposure to titrated doses of citalopram. In vivo analysis for PCNA suggested segregation of effect by location, with the sagittal suture, showing a statistically significant increase in proliferative response. The coronal suture was not similarly affected, however there was a decrease in apoptotic activity at the dural edge as compared to the periosteal edge. No differences in apoptosis by suture or area due to SSRI exposure were observed. In vitro results suggest citalopram exposure increased proliferation and proliferative gene expression, and decreased apoptosis of the MC3T3-E1 cells. Decreased apoptosis was not confirmed in vivo however, an increase in proliferation without a concomitant increase in apoptosis is still defined as hyperplasia. Thus prenatal SSRI exposure may exert a negative effect on post-natal growth through a hyperplasia effect at the cranial growth sites perhaps leading to clinically significant craniofacial abnormalities.


Reciprocal transcriptional regulation of metabolic and signaling pathways correlates with disease severity in heart failure.
Systolic heart failure (HF) is a complex systemic syndrome that can result from a wide variety of clinical conditions and gene mutations. Despite phenotypic similarities, characterized by ventricular dilatation and reduced contractility, the extent of common and divergent gene expression between different forms of HF remains a matter of intense debate. Using a meta-analysis of 28 experimental (mouse, rat, dog) and human HF microarray studies, we demonstrate that gene expression changes are characterized by a coordinated and reciprocal regulation of major metabolic and signaling pathways. In response to a wide variety of stressors in animal models of HF, including ischemia, pressure overload, tachypacing, chronic isoproterenol infusion, Chagas disease, and transgenic mouse models, major metabolic pathways are invariably downregulated, whereas cell signaling pathways are upregulated. In contrast to this uniform transcriptional pattern that recapitulates a fetal gene expression program in experimental animal models of HF, human HF microarray studies displayed a greater heterogeneity, with some studies even showing upregulation of metabolic and downregulation of signaling pathways in end-stage human hearts. These discrepant results between animal and human studies are due to a number of factors, prominently cardiac disease and variable exposure to cold cardioplegic solution in nonfailing human samples, which can downregulate transcripts involved in oxidative phosphorylation (OXPHOS), thus mimicking gene expression patterns observed in failing samples. Additionally, β-blockers and ACE inhibitor use in end-stage human HF was associated with higher levels of myocardial OXPHOS transcripts, thus partially reversing the fetal gene expression pattern. In human failing samples, downregulation of metabolism was associated with hemodynamic markers of disease severity. Irrespective of the etiology, gene expression in failing myocardium is characterized by downregulation of metabolic transcripts and concomitant upregulation of cell signaling pathways. Gene expression changes along this metabolic-signaling axis in mammalian myocardium are a consistent feature in the heterogeneous transcriptional response observed in phenotypically similar models of HF.


Determination of the recovered-fiber content in paperboard samples by applying mid-infrared spectroscopy.
Paperboard is widely used in different applications, such as packaging and graphic printing, among others. Consumption of recycled paper is growing, which has led the paper-mill packaging industry to apply strict quality controls. This means that it is very important to develop methods to test the quality of recycled products. In this article, we focus on determining the recovered-fiber content of paperboard samples by applying Fourier transform mid-infrared (FT-MIR) spectroscopy in combination with multivariate statistical methods. To this end, two very fast, nondestructive approaches were applied: classification and quantification. The first approach is based on classifying unknown paperboard samples into two groups: high and low recovered-fiber content. Conversely, under the quantification approach, the content of recovered fiber in the incoming paperboard samples is determined. The experimental results presented in this article show that the classification approach, which classifies unknown incoming paperboard samples, is highly accurate and that the quantification approach has a root mean square error of prediction of about 4.1.


Femoroacetabular Impingement Randomised controlled Trial (FIRST) - a multi-centre randomized controlled trial comparing arthroscopic lavage and arthroscopic osteochondroplasty on patient important outcomes and quality of life in the treatment of young adult (18-50 years) femoroacetabular impingement: a statistical analysis plan.
The research objectives of the Femoroacetabular Impingement Randomised controlled Trial (FIRST) are to assess whether surgical correction of the hip impingement morphology (arthroscopic osteochondroplasty) with or without labral repair, in adults aged 18-50 years diagnosed with non-arthritic femoroacetabular impingement (FAI), provides decreased pain and improved health-related quality of life at 12 months compared to arthroscopic lavage of the hip joint. This article describes the statistical analysis plan for the FIRST trial. FIRST is an ongoing multi-centre, blinded randomised controlled trial of 220 patients who have been diagnosed with FAI and are optimized for surgical intervention. This article describes the overall analysis principles, including how participants will be included in each analysis, the presentation of the results, adjustments for covariates, the primary and secondary outcomes and their respective analyses. In addition, we will present the planned sensitivity and subgroup analyses. Our rationale for FIRST is based upon (1) an epidemic of FAI surgery with resultant increased healthcare costs over that last decade, (2) worldwide disparity in perceptions about its utility, and (3) consensus that definitive evidence for or against surgical approaches is lacking. ClinicalTrials.gov, NCT01623843 . Registered on 20 June 2012.


Systematic Evaluation of Diagnostic Delay in Pediatric Inflammatory Bowel Disease.
We evaluated the diagnostic delay (time from first symptoms to diagnosis) in 100 pediatric patients with Crohn disease (CD) and 75 patients with ulcerative colitis (UC). Median (interquartile range) diagnostic delay in patients with CD was 4 (2-8) (range 0-82) months compared with 2 (1-7) (range 0-52) months in patients with UC (P = 0.003). The time interval from first physician visit to inflammatory bowel disease diagnosis was longer in patients with CD and UC when compared to the time interval from symptom onset to first physician visit (CD: median 3 vs 1 months, P < 0.001; UC: median 2 vs 0 months, P < 0.001). No specific risk factors were identified for the length of diagnostic delay. Measures should be taken to reduce diagnostic delay.


Phylogeny and Classification of Yersinia pestis Through the Lens of Strains From the Plague Foci of Commonwealth of Independent States.
The established phylogeny of the etiological agent of plague, Yersinia pestis, is not perfect, as it does not take into account the strains from numerous natural foci of Commonwealth of Independent States (CIS). We have carried out PCR and SNP typing of 359 strains and whole genome sequencing of 51 strains from these plague foci and determined the phylogenetic diversity of the strains circulating here. They belong to 0.ANT3, 0.ANT5, 2.ANT3, 4.ANT branches of antique biovar, 2.MED0, 2.MED1 branches of medieval biovar and to 0.PE2, 0.PE4a. 0.PE4h, 0.PE4t branches. Based on the studies of 178 strains from 23 plague foci of CIS countries, it was determined that the population structure of 2.MED strains is subdivided into Caucasian-Caspian and Central Asian-Chinese branches. In Central-Caucasian high-mountain plague foci in the Russian Federation (RF) the most deeply diverged branch of medieval biovar, 2.MED0, has been found. With the data obtained, the current population structure of Y. pestis species has been refined. New subspecies classification is developed, comprising seven subspecies: pestis, caucasica (0.PE2), angolica (0.PE3), central asiatica (0.PE4), tibetica (0.PE7), ulegeica (0.PE5), and qinghaica (0.PE10).


Effects of water management on greenhouse gas emissions from farmers' rice fields in Bangladesh.
Alternate wetting and drying (AWD) irrigation in lowland rice cultivation increases water use efficiency and could reduce greenhouse gas (GHG) emissions compared to the farmers' practice of continuous flooding (CF). However, there is a dearth of studies on the impacts of water management on methane (CH4) and nitrous oxide (N2O) emissions in Bangladesh. Multi-location field experiments were conducted during the dry seasons of 2018 and 2019 to determine the baseline emissions of CH4 and N2O from rice fields and compare the emissions from AWD irrigation and CF. CH4 and N2O emissions were measured using the closed chamber technique and their concentrations were determined using a gas chromatograph. CH4 and N2O emissions varied across water management schemes and sites. AWD irrigation significantly (p < 0.05) reduced cumulative CH4 emissions (37%, average across sites) without affecting grain yields compared to CF. The CH4 emission factor for AWD was lower (1.39 kg ha-1 day-1) compared to CF (2.21 kg ha-1 day-1). Although AWD irrigation increased seasonal cumulative N2O emissions by 46%, it did not offset reduced CH4 emissions. AWD reduced the total global warming potential (GWP) by 36% compared to CF. Similarly, GHG intensity (GHGI) in AWD was 34% smaller compared to that in CF. Emissions varied across sites and the magnitudes of seasonal cumulative CH4 and N2O emissions were higher at the Gazipur site compared to the Mymensingh site. AWD, which saves irrigation water without any yield penalty, could be considered a promising strategy to mitigate GHG emissions from rice fields in Bangladesh.


COZOID: contact zone identifier for visual analysis of protein-protein interactions.
Studying the patterns of protein-protein interactions (PPIs) is fundamental for understanding the structure and function of protein complexes. The exploration of the vast space of possible mutual configurations of interacting proteins and their contact zones is very time consuming and requires the proteomic expert knowledge. In this paper, we propose a novel tool containing a set of visual abstraction techniques for the guided exploration of PPI configuration space. It helps proteomic experts to select the most relevant configurations and explore their contact zones at different levels of detail. The system integrates a set of methods that follow and support the workflow of proteomics experts. The first visual abstraction method, the Matrix view, is based on customized interactive heat maps and provides the users with an overview of all possible residue-residue contacts in all PPI configurations and their interactive filtering. In this step, the user can traverse all input PPI configurations and obtain an overview of their interacting amino acids. Then, the models containing a particular pair of interacting amino acids can be selectively picked and traversed. Detailed information on the individual amino acids in the contact zones and their properties is presented in the Contact-Zone list-view. The list-view provides a comparative tool to rank the best models based on the similarity of their contacts to the template-structure contacts. All these techniques are interactively linked with other proposed methods, the Exploded view and the Open-Book view, which represent individual configurations in three-dimensional space. These representations solve the high overlap problem associated with many configurations. Using these views, the structural alignment of the best models can also be visually confirmed. We developed a system for the exploration of large sets of protein-protein complexes in a fast and intuitive way. The usefulness of our system has been tested and verified on several docking structures covering the three major types of PPIs, including coiled-coil, pocket-string, and surface-surface interactions. Our case studies prove that our tool helps to analyse and filter protein-protein complexes in a fraction of the time compared to using previously available techniques.


Quantification of mortality risk after abdominal aortic aneurysm repair.
The study was designed to evaluate the Acute Physiology And Chronic Health Evaluation (APACHE) II risk scoring system in abdominal aortic aneurysm (AAA) surgery. The aim was to create an APACHE-based risk stratification model for postoperative death. Prospective postoperative APACHE II data were collected from patients undergoing AAA repair over a 9-year interval from 24 intensive care units (ICUs) in the Thames region. A multilevel logistic regression model (APACHE-AAA) for in-hospital mortality was developed to adjust for both case mix and the variation in outcome between ICUs. A total of 1896 patients were studied. The in-hospital mortality rate among the 1289 patients who had elective AAA repair was 9.6 (95 per cent confidence interval (c.i.) 8.0 to 11.2) per cent and that among the 605 patients who had an emergency repair was 46.9 (95 per cent c.i. 43.0 to 50.9) per cent. Four independent predictors of death were identified: age (odds ratio (OR) 1.05 (95 per cent c.i. 1.03 to 1.07) per year increase), Acute Physiology Score (OR 1.14 (95 per cent c.i. 1.12 to 1.17) per unit increase), emergency operation (OR 4.86 (95 per cent c.i. 3.64 to 6.52)) and chronic health dysfunction (OR 1.43 (95 per cent c.i. 1.04 to 1.97)). The APACHE-AAA model was internally valid, as shown by calibration (Hosmer-Lemeshow C statistic: chi(2) = 6.14, 8 d.f., P = 0.632), discrimination properties (area under receiver-operator characteristic curve 0.845) and subgroup analysis. There was no significant variation in outcome between hospitals. APACHE-AAA was shown to be an accurate risk-stratification model that could be used to quantify the risk of death after AAA surgery. It might also be used to determine the relative impact of ICU over high-dependency unit care.


Is Diagnosis of Low-Grade Urothelial Carcinoma Possible in Urine Cytology?
Urine cytology is a useful modality, primarily for the diagnosis and follow-up surveillance of high-grade urothelial carcinoma (HGUC). Its utility in diagnosing low-grade urothelial carcinoma (LGUC) remains controversial because of low reported sensitivity compared to cystoscopy. To study the cytomorphology of LGUC in voided urine samples and analyze its utility in diagnosis. This is a retrospective study of one year, including 48 voided urine samples in cases which were confirmed as LGUC on subsequent histology. Urine cytology smears of these cases, originally stained with Papanicolaou stain were reviewed, critically analyzed and the specific cytomorphologic and cystoscopic findings were documented. On review 18 samples were re-categorized as LGUC which included 10 samples initially diagnosed as Negative for HGUC, 2 as Atypical Urothelial Cells - Not Otherwise Specified (AUC-NOS) and 6 as Suspicious for Carcinoma. In addition, another 3 samples with initial diagnosis of LGUC remained as LGUC on review. Thus, a total of 21 LGUC samples were identified after the review. 26 (54%) samples with a diagnosis of negative for HGUC remained negative even after review, as the tumor cells were not identified either due to sampling error or unrecognizable morphology. One (2%) samples of AUC-NOS remained the same on review due to very scant atypical cells. In 21 LGUC samples, cytology showed a dual population of benign differentiated urothelial cells and small urothelial cells with subtle nuclear atypia such as irregular and thickened nuclear membrane with increased nuclear cytoplasmic ratio. In 12 false negative LGUC samples, the diagnostic cells were camouflaged by their subtle nuclear atypia coupled with an overwhelming background of differentiated benign urothelial cells as both appeared almost similar in morphology. Papillary fragments were identified only in 2 samples. Diagnosis of LGUC on cytology is challenging and depends on the presence of diagnostic cells, pick up of diagnostic cells on screening and accurate interpretation. Special attention to papillary fragments and aforementioned nuclear atypia should be paid as tumor cells may resemble normal urothelial cells and can be easily missed.


Flexible logic circuits based on top-gate thin film transistors with printed semiconductor carbon nanotubes and top electrodes.
In this report printed thin film transistors and logic circuits on flexible substrates are reported. The top-gate thin film transistors were made of the sorted semiconducting single-walled carbon nanotubes (sc-SWCNTs) ink as channel material and printed silver lines as top electrodes and interconnect. 5 nm HfOx thin films pre-deposited on PET substrates by atomic layer deposition (ALD) act as the adhesion layers to significantly improve the immobilization efficiency of sc-SWCNTs and environmental stability. The immobilization mechanism was investigated in detail. The flexible partially-printed top-gate SWCNT TFTs display ambipolar characteristics with slightly strong p-type when using 50 nm HfO(x) thin films as dielectric layer, as well as the encapsulation layer by atomic layer deposition (ALD) at 120 °C. The hole mobility, on/off ratio and subthreshold swing (SS) are ∼ 46.2 cm(2) V(-1) s(-1), 10(5) and 109 mV per decade, respectively. Furthermore, partially-printed TFTs show small hysteresis, low operating voltage (2 V) and high stability in air. Flexible partially-printed inverters show good performance with voltage gain up to 33 with 1.25 V supply voltage, and can work at 10 kHz. The frequency of flexible partially-printed five-stage ring oscillators can reach 1.7 kHz at supply voltages of 2 V with per stage delay times of 58.8 μs. This work paves a way to achieve printed SWCNT advanced logic circuits and systems on flexible substrates.


Power relations and contrasting conceptions of evidence in patient-involvement processes used to inform health funding decisions in Australia.
We collected and analysed views of key stakeholders on the processes used to involve patient organisations in health care funding decision making in Australia. We conducted 12 semi-structured interviews with patient organisation representatives and members of Advisory Committees that provide advice to the Australian Department of Health and employ Health Technology Assessment (HTA) as an evaluation framework. Using two theoretical frameworks, we analysed structural and contextual elements pertaining to the involvement processes. The findings reported in this article relate to interviewees' perspectives on contextual elements, analysed using a Foucauldian lens. These elements include: the perspectives of marginalised voices; the diversity of views on what ought to be considered valid evidence in a HTA setting; and the relationships between stakeholders, along with how these relationships impact on involvement processes and the outcomes of those processes. The findings demonstrate that the involvement processes currently used are deemed inadequate by both patient organisation representatives and Advisory Committee members, but for different reasons connected to how different stakeholders conceptualise evidence. Advisory Committee members viewed evidence as encompassing clinical outcomes and patient preferences, whereas patient organisation representatives tended to view evidence as encompassing aspects not directly related to a disease entity, such as the social and emotional aspects of patients' experiences in living with illness. Patient organisation representatives reported interacting with other stakeholders (especially industry) to increase the influence of their conception of evidence on decision making. The use of this strategy by interviewees illustrates how power struggles occur in government decision-making processes which involve both medical expertise and patients' accounts. Such struggles, and the power differentials they reflect, need to be considered by those responsible for designing and implementing meaningful public- and patient-involvement processes.


Measurement of changes in antihypertensive drug utilisation following primary care educational interventions.
To measure changes in drug utilisation following a national general practice education program aimed at improving prescribing for hypertension. A series of nationally implemented, multifaceted educational interventions using social marketing principles focusing on prescribing for hypertension, was commenced in October 1999, and repeated in September 2001 and August 2003. The target group was all primary care prescribers in Australia and interventions were both active (voluntary) and passive. Newsletter and prescribing feedback was mailed in October 1999, September 2001 (newsletter only) and August 2003. Approximately a third of general practitioners (GPs) in Australia undertook at least one active educational activity (clinical audit, educational visit or case study) during the period October 1999-April 2004. National dispensing data from 1996 to 2004 were analysed using time series methodology with a decay term for intervention effect, to assess trends in prescribing of various classes of antihypertensives. In particular, the program aimed to increase the prescribing of thiazide diuretics and beta blockers. Consistent with key intervention messages, the program achieved an increase in low-dose thiazide and beta blocker prescribing. The rate of prescribing of low-dose thiazides doubled from 1.1 per 1000 consultations in October 1999 to 2.4 per 1000 in October 2003. Beta-blocker utilisation showed a more modest but significant increase over the time of the study, with the change in observed versus expected rate of prescribing increasing by 8% by April 2004. Therapeutic options for treating hypertension changed markedly in the time of the study with the advent of ACE inhibitor/Angiotensin II receptor antagonists and thiazide combination products. It is important, therefore, to interpret the results in light of these changes. A national education program aimed at GPs was successful in improving prescribing for hypertension. Lessons learned will be applied in evaluation of future NPS programs and are also applicable to analysis of other interventions aimed at influencing prescribing behaviour.


Intra-fraction motion gating during frameless Gamma Knife® Icon™ therapy: The relationship between cone beam CT assessed intracranial anatomy displacement and infrared-tracked nose marker displacement.
Gamma Knife Icon™'s high-definition motion management (HDMM) system gates treatment delivery should intra-fraction displacement of a nose marker exceed some user-defined threshold. A method, previously-validated with a phantom, is used to relate intra-fractional displacements of the nose marker to displacements of patient targets. Additionally, novel analysis is performed to ascertain the relationship between nose marker displacement and displacement of a 3D grid of coordinates throughout stereotactic space. This spatial information is used to retrospectively review HDMM threshold levels based upon real target locations. For 41 targets from 22 patients, the mean(standard deviation) and maximum target-to-nose displacement ratio was 0.54(0.32) and 1.65, respectively. On average, displacements typically exceed those of the nose only for coordinates at the most extreme peripheral corner of the investigated 3D grid of points. Allowing target displacement of up to a maximum of 0.8mm, retrospective review indicated that at the locations of the 41 targets a median(range) HDMM threshold of 1.4(1.0-1.9) mm could have been adopted, compared to our standard threshold of 1.0mm. Intracranial targets typically displace by a magnitude around half that of the nose. Novel analysis to determine the spatial variation of target-to-nose displacement ratio suggests, for our 41 targets, HDMM threshold could have been increased from our standard. Cases for which HDMM threshold could be safely increased would minimise treatment gating events and expedite treatment delivery to offer patient comfort benefits.


Generalized Structured Component Analysis with Uniqueness Terms for Accommodating Measurement Error.
Generalized structured component analysis (GSCA) is a component-based approach to structural equation modeling (SEM), where latent variables are approximated by weighted composites of indicators. It has no formal mechanism to incorporate errors in indicators, which in turn renders components prone to the errors as well. We propose to extend GSCA to account for errors in indicators explicitly. This extension, called GSCAM, considers both common and unique parts of indicators, as postulated in common factor analysis, and estimates a weighted composite of indicators with their unique parts removed. Adding such unique parts or uniqueness terms serves to account for measurement errors in indicators in a manner similar to common factor analysis. Simulation studies are conducted to compare parameter recovery of GSCAM and existing methods. These methods are also applied to fit a substantively well-established model to real data.


Anaesthesia and airway management in mucopolysaccharidosis.
This paper provides a detailed overview and discussion of anaesthesia in patients with mucopolysaccharidosis (MPS), the evaluation of risk factors in these patients and their anaesthetic management, including emergency airway issues. MPS represents a group of rare lysosomal storage disorders associated with an array of clinical manifestations. The high prevalence of airway obstruction and restrictive pulmonary disease in combination with cardiovascular manifestations poses a high anaesthetic risk to these patients. Typical anaesthetic problems include airway obstruction after induction or extubation, intubation difficulties or failure [can't intubate, can't ventilate (CICV)], possible emergency tracheostomy and cardiovascular and cervical spine issues. Because of the high anaesthetic risk, the benefits of a procedure in patients with MPS should always be balanced against the associated risks. Therefore, careful evaluation of anaesthetic risk factors should be made before the procedure, involving evaluation of airways and cardiorespiratory and cervical spine problems. In addition, information on the specific type of MPS, prior history of anaesthesia, presence of cervical instability and range of motion of the temporomandibular joint are important and may be pivotal to prevent complications during anaesthesia. Knowledge of these risk factors allows the anaesthetist to anticipate potential problems that may arise during or after the procedure. Anaesthesia in MPS patients should be preferably done by an experienced (paediatric) anaesthetist, supported by a multidisciplinary team (ear, nose, throat surgeon and intensive care team), with access to all necessary equipment and support.


Cavernous hemangioma of the liver: factors affecting disease progression in general hepatology practice.
Although for asymptomatic hepatic hemangiomas conservative management is generally recommended, factors affecting the disease course are still not very well understood. To determine disease characteristics of cavernous hemangioma and factors affecting its progression in patients from a general hepatology clinic in Tehran, Iran. We reviewed medical records of 198 patients with cavernous hemangioma of the liver visiting a large private hepatology clinic in Tehran from 1997 to 2007. Of a total of 198 cases, 129 could be followed up for a period of 3.2 ± 2.5 years, and 80 of these had 1-5 repeated sonographies. Patients were between 27 and 84 years old (mean age: 44.3 ± 10.9 years), and 131 (66.2%) were female. Thirty-six patients (18.2%) had giant hemangiomas. Abdominal pain was the primary reason for evaluation in 100 (50.5%) patients. Abdominal pain at the beginning of the follow-up was significantly associated with having irritable bowel syndrome [odds ratio (OR)=8.3; 95% confidence interval (CI): 3.1-28.7] or other gastrointestinal diseases (OR=3.9; 95% CI: 2.6-10.2), but not with hemangioma size, number, or location. During follow-up, having a single giant lesion at the time of diagnosis, adjusted for age, sex, and presence of irritable bowel syndrome, was a strong predictor of persistent pain during follow-up (OR=11.1; 95% CI: 3.2-38.6). In repeated sonographies, 35% showed an increased size, which was significantly associated only with having a single lesion (P=0.04). Many symptoms in hepatic hemangioma are attributable to accompanying gastrointestinal diseases. Patients with a single giant lesion are more likely to have persistent pain, and single lesions are more likely to grow in size.


Naive Bayesian classifier for rapid assignment of rRNA sequences into the new bacterial taxonomy.
The Ribosomal Database Project (RDP) Classifier, a naïve Bayesian classifier, can rapidly and accurately classify bacterial 16S rRNA sequences into the new higher-order taxonomy proposed in Bergey's Taxonomic Outline of the Prokaryotes (2nd ed., release 5.0, Springer-Verlag, New York, NY, 2004). It provides taxonomic assignments from domain to genus, with confidence estimates for each assignment. The majority of classifications (98%) were of high estimated confidence (> or = 95%) and high accuracy (98%). In addition to being tested with the corpus of 5,014 type strain sequences from Bergey's outline, the RDP Classifier was tested with a corpus of 23,095 rRNA sequences as assigned by the NCBI into their alternative higher-order taxonomy. The results from leave-one-out testing on both corpora show that the overall accuracies at all levels of confidence for near-full-length and 400-base segments were 89% or above down to the genus level, and the majority of the classification errors appear to be due to anomalies in the current taxonomies. For shorter rRNA segments, such as those that might be generated by pyrosequencing, the error rate varied greatly over the length of the 16S rRNA gene, with segments around the V2 and V4 variable regions giving the lowest error rates. The RDP Classifier is suitable both for the analysis of single rRNA sequences and for the analysis of libraries of thousands of sequences. Another related tool, RDP Library Compare, was developed to facilitate microbial-community comparison based on 16S rRNA gene sequence libraries. It combines the RDP Classifier with a statistical test to flag taxa differentially represented between samples. The RDP Classifier and RDP Library Compare are available online at http://rdp.cme.msu.edu/.


Depression and anxiety in women with early breast cancer: five year observational cohort study.
To examine the prevalence of, and risk factors for, depression and anxiety in women with early breast cancer in the five years after diagnosis. Observational cohort study. NHS breast clinic, London. 222 women with early breast cancer: 170 (77%) provided complete interview data up to either five years after diagnosis or recurrence. Prevalence of clinically important depression and anxiety (structured psychiatric interview with standardised diagnostic criteria) and clinical and patient risk factors, including stressful life experiences (Bedford College life events and difficulties schedule). Nearly 50% of the women with early breast cancer had depression, anxiety, or both in the year after diagnosis, 25% in the second, third, and fourth years, and 15% in the fifth year. Point prevalence was 33% at diagnosis, falling to 15% after one year. 45% of those with recurrence experienced depression, anxiety, or both within three months of the diagnosis. Previous psychological treatment predicted depression, anxiety, or both in the period around diagnosis (one month before diagnosis to four months after diagnosis). Longer term depression and anxiety, were associated with previous psychological treatment, lack of an intimate confiding relationship, younger age, and severely stressful non-cancer life experiences. Clinical factors were not associated with depression and anxiety, at any time. Lack of intimate confiding support also predicted more protracted episodes of depression and anxiety. Increased levels of depression, anxiety, or both in the first year after a diagnosis of early breast cancer highlight the need for dedicated service provision during this time. Psychological interventions for women with breast cancer who remain disease free should take account of the broader social context in which the cancer occurs, with a focus on improving social support.


Racial disparities in emergency department length of stay for admitted patients in the United States.
Recent studies have demonstrated the adverse effects of prolonged emergency department (ED) boarding times on outcomes. The authors sought to examine racial disparities across U.S. hospitals in ED length of stay (LOS) for admitted patients, which may serve as a proxy for boarding time in data sets where the actual time of admission is unavailable. Specifically, the study estimated both the within- and among-hospital effects of black versus non-black race on LOS for admitted patients. The authors studied 14,516 intensive care unit (ICU) and non-ICU admissions in 408 EDs in the National Hospital Ambulatory Medical Care Survey (NHAMCS; 2003-2005). The main outcomes were ED LOS (triage to transfer to inpatient bed) and proportion of patients with prolonged LOS (>6 hours). The effects of black versus non-black race on LOS were decomposed to distinguish racial disparities between patients at the same hospital (within-hospital component) and between hospitals that serve higher proportions of black patients (among-hospital component). In the unadjusted analyses, ED LOS was significantly longer for black patients admitted to ICU beds (367 minutes vs. 290 minutes) and non-ICU beds (397 minutes vs. 345 minutes). For admissions to ICU beds, the within-hospital estimates suggested that blacks were at higher risk for ED LOS of >6 hours (odds ratio [OR] = 1.42, 95% confidence interval [CI] = 1.01 to 2.01), while the among-hospital differences were not significant (OR = 1.08 for each 10% increase in the proportion of black patients, 95% CI = 0.96 to 1.23). By contrast, for non-ICU admissions, the within-hospital racial disparities were not significant (OR = 1.12, 95% CI = 0.94 to 1.23), but the among-hospital differences were significant (OR = 1.13, 95% CI = 1.04 to 1.22) per 10% point increase in the percentage of blacks admitted to a hospital. Black patients who are admitted to the hospital through the ED have longer ED LOS compared to non-blacks, indicating that racial disparities may exist across U.S. hospitals. The disparity for non-ICU patients might be accounted for by among-hospital differences, where hospitals with a higher proportion of blacks have longer waits. The disparity for ICU patients is better explained by within-hospital differences, where blacks have longer wait times than non-blacks in the same hospital. However, there may be additional unmeasured clinical or socioeconomic factors that explain these results.


Homeobox D10 induces phenotypic reversion of breast tumor cells in a three-dimensional culture model.
Homeobox (Hox) genes are master regulatory genes that direct organogenesis and maintain differentiated tissue function. We previously reported that HoxD10 helps to maintain a quiescent, differentiated phenotype in endothelial cells by suppressing expression of genes involved in remodeling the extracellular matrix and cell migration. Here we investigated whether HoxD10 could also promote or maintain a differentiated phenotype in epithelial cells. We observed that HoxD10 expression is progressively reduced in epithelial cells as malignancy increases in both breast and endometrial tumors. Retroviral gene transfer to restore expression of HoxD10 in the malignant breast tumor cells MDA-MB-231 significantly impaired migration, and when these cells were cultured in a three-dimensional laminin-rich basement membrane (3DlrBM) model, they formed polarized, acinar structures. This phenotypic reversion was accompanied by decreased alpha3 integrin expression and reduced proliferation. Importantly, expression of HoxD10 in the MDA-MB-231 cells inhibited their ability to form tumors in mouse xenografts. Taken together, our results suggest that HoxD10 has tumor-suppressive functions for mammary epithelial cells.


Expression of the Na-K-2Cl cotransporter by macula densa and thick ascending limb cells of rat and rabbit nephron.
Sodium and chloride transport by the macula densa and thick ascending limb of Henle's loop participates importantly in extracellular fluid volume homeostasis, urinary concentration and dilution, control of glomerular filtration, and control of renal hemodynamics. Transepithelial Na and Cl transport across the apical membrane of thick ascending limb (TALH) cells is mediated predominantly by a loop diuretic sensitive Na-K-2Cl cotransport pathway. The corresponding transport protein has recently been cloned. Functional studies suggest that the cotransporter is expressed by macula densa cells as well as by TALH cells. The current studies were designed to identify sites of Na-K-2Cl cotransporter expression along distal nephron in rabbit and rat. Non-isotopic high-resolution in situ hybridization, using an antisense probe for the apical form of the Na-K-2Cl cotransporter identified expression throughout the TALH, from the junction between inner and outer medulla to the transition to distal convoluted tubule. Expression by macula densa cells was confirmed by colocalization using markers specific for macula densa cells. First, Na-K-2Cl cotransporter mRNA was detected in macula densa cells that did not stain with anti-Tamm-Horsfall protein antibodies. Second, Na-K-2Cl cotransporter mRNA was detected in macula densa cells that show positive NADPH-diaphorase reaction, indicating high levels of constitutive nitric oxide synthase activity. In rat, levels of Na-K-2Cl cotransporter mRNA expression were similar in TALH and macula densa cells. In rabbit, expression levels were higher in macula densa cells than in surrounding TALH cells. The present data provide morphological support for a previously established functional concept that Na-K-2Cl cotransport at the TALH is accomplished by the expression of a well-defined cotransporter. At the macula densa, this transporter may establish a crucial link between tubular salt load and glomerular vascular regulation.


Preference for conspecifics evolves earlier in males than females in a sexually dimorphic radiation of fishes.
Speciation by sexual selection is generally modeled as the coevolution of female preferences and elaborate male ornaments leading to behavioral (sexual) reproductive isolation. One prediction of these models is that female preference for conspecific males should evolve earlier than male preference for conspecific females in sexually dimorphic species with male ornaments. We tested that prediction in darters, a diverse group of freshwater fishes with sexually dimorphic ornamentation. Focusing on the earliest stages of divergence, we tested preference for conspecific mates in males and females of seven closely related species pairs. Contrary to expectation, male preference for conspecific females was significantly greater than female preference for conspecific males. Males in four of the 14 species significantly preferred conspecific females; whereas, females in no species significantly preferred conspecific males. Relationships between the strength of preference for conspecifics and genetic distance revealed no difference in slope between males and females, but a significant difference in intercept, also suggesting that male preference evolves earlier than females'. Our results are consistent with other recent studies in darters and suggest that the coevolution of female preferences and male ornaments may not best explain the earliest stages of behavioral isolation in this lineage.


Mimicking plasmonic nanolaser emission by selective extraction of electromagnetic near-field from photonic microcavity.
Plasmonic nanolasers have attracted significant attention owing to their ability to generate a coherent optical field in the deep subwavelength region, and they exhibit promising applications in integrated photonics, bioimaging and sensing. However, the demonstration of lasing in individual metallic nanoparticles with 3D subwavelength confinement represents a significant challenge and is yet to be realized. Herein, we propose to mimic a plasmonic nanolaser via selective scattering off the evanescent tail of a lasing photonic nanobelt using a single silver nanorod (24 nm × 223 nm). The nanorod acts as an optical antenna that selectively extracts the near-field component along the rod axis. The light output from the silver nanorod mimics the emission of a plasmonic nanolaser in its localized near-field and polarization dependence, except for the lasing wavelength and linewidth, which are inherited from the photonic laser. The realization of localized coherent light sources provides promising nanoscale lighting that shows potential in background-suppressed illumination, biosensing and imaging.


Effects of inulin-type fructans on lipid metabolism in man and in animal models.
Studies in rodents show that inulin and oligofructose can reduce the plasma levels of cholesterol and triacylglycerols (TG). In addition, they can oppose TG accumulation in liver and have favourable effects on hepatic steatosis. The hypotriglyceridaemic effect is due to a reduction in hepatic re-esterification of fatty acids, but mainly in the expression and activity of liver lipogenesis, resulting in lower hepatic secretion rate of TG. This repression of lipogenesis is not observed in adipose tissue. The effect on liver lipogenesis can be explained by reduced insulin/glucose levels or by a selective exposure of the liver to increased amounts of propionic acid produced in the large intestine during fermentation of non-digestible carbohydrates. The decrease in plasma cholesterol could also be due to inhibition of cholesterol synthesis by propionic acid or to modifications in the bile acid metabolism. Studies in man yield more conflicting results with a decrease or no effects on plasma lipid levels, and, when a decrease is observed, more marked effects on TG than on cholesterol and more consistent action of inulin than of oligofructose. Besides the difference in the dose of inulin or oligofructose used, differences in metabolic status could play a role in this discrepancy between man and animals since reduction in plasma TG is observed in man mainly in a situation of increased liver lipogenesis (high-carbohydrate diet, obesity, hypertriglyceridaemia). The effects on plasma cholesterol appear also more marked in hyperlipidaemic subjects than in healthy controls, suggesting that inulin and oligofructose have beneficial effects in these types of subjects.


The use of immobilised metal affinity chromatography (IMAC) to compare expression of copper-binding proteins in control and copper-exposed marine microalgae.
Toxicity of metals to aquatic organisms is dependent on both external factors, such as exposure concentration and water quality parameters, and intracellular processes including specific metal-binding sites and detoxification. Current models used to predict copper toxicity in microalgae do not adequately consider these intracellular processes. This study compared the copper-binding proteins from four species of marine microalgae, Dunaliella tertiolecta, Tetraselmis sp., Phaedactylum tricornutum and Ceratoneis closterium, in controls (no added copper) and following a 72-h exposure to copper (sufficient to inhibit growth by approximately 50%). Cells were lysed by sonication, which was optimised to obtain 54-94% cell rupture for the different algae. Cell lysates were processed by immobilised metal affinity chromatography (IMAC) using Cu(2+) as the bound metal (i.e. Cu-IMAC). Bound proteins were subsequently analysed by SDS-PAGE, comparing proteins recovered from algae that were exposed to copper versus untreated control cells. Individual proteins for which copper exposure resulted in changes to proteins present were excised from gels and further analysed by nano LC ESI-MS/MS; proteins were identified using the Mascot database. Proteins identified in this way included heat-shock proteins, rubisco, α- and β-tubulins and ATP synthase (β subunit). The results established that Cu-IMAC is a useful approach to identify proteins involved in copper binding in algae. This study identified several proteins that may play an active role in responses to copper toxicity in marine microalgae.


The sorption behaviour of amine micropollutants on polyethylene microplastics - impact of aging and interactions with green seaweed.
Microplastics are ubiquitous in the environment. Due to still rising global production, the emission of polymers into the environment and the abundance of microplastics have increased accordingly. Due to the long mineralization processes of microplastics, distribution in all compartments can be found. The hydrophobic surfaces of the particles can sorb chemical pollutants, therefore providing a potential pathway to accumulation by organisms within the food web. However, little is known about how long-term aging and degradation processes of microplastics can affect the sorption behaviours of organic pollutants on the particles. In this study, important industrial additives of emerging environmental concern, such as hydrophobic aromatic amines, were studied in relation to their sorption behaviour on high-density polyethylene and low-density polyethylene microplastics. Diphenylamine (log POW (logarithmic octanol-water partition coefficient) = 3.5) showed strong sorption, carbamazepine (log POW = 2.5) showed moderate sorption, and aniline (log POW = 0.9) showed no detectable sorption behaviour. Artificially aged particles exposed to photochemical aging and long-term mechanical treatment in water were compared to pristine microplastics. While mechanically aged microplastics promoted the sorption of aromatic amines, photochemically aged particles showed a decrease in sorption capacity due to changed surface chemistry. Importantly, the sorption capacity increased with increasing salinity, leading to strong implications for ocean systems, as an elevated uptake of pollutants could occur under marine conditions. Moreover, our study demonstrates that the ecotoxicological effects of diphenylamine on the growth of the seaweed Ulva (sea lettuce, Chlorophyta) were reduced in the presence of microplastics. As the plastic particles withdrew enough contaminants from solution, even toxic levels of diphenylamine (c = 10-4 M) became tolerable for the algae. However, the pollutants initially sorbed on the microplastics can be released again at a later point in the ageing process, thus having delayed pollution potential.


Role of Oculoproprioception in Coding the Locus of Attention.
The most common neural representations for spatial attention encode locations retinotopically, relative to center of gaze. To keep track of visual objects across saccades or to orient toward sounds, retinotopic representations must be combined with information about the rotation of one's own eyes in the orbits. Although gaze input is critical for a correct allocation of attention, the source of this input has so far remained unidentified. Two main signals are available: corollary discharge (copy of oculomotor command) and oculoproprioception (feedback from extraocular muscles). Here we asked whether the oculoproprioceptive signal relayed from the somatosensory cortex contributes to coding the locus of attention. We used continuous theta burst stimulation (cTBS) over a human oculoproprioceptive area in the postcentral gyrus (S1EYE). S1EYE-cTBS reduces proprioceptive processing, causing ∼1° underestimation of gaze angle. Participants discriminated visual targets whose location was cued in a nonvisual modality. Throughout the visual space, S1EYE-cTBS shifted the locus of attention away from the cue by ∼1°, in the same direction and by the same magnitude as the oculoproprioceptive bias. This systematic shift cannot be attributed to visual mislocalization. Accuracy of open-loop pointing to the same visual targets, a function thought to rely mainly on the corollary discharge, was unchanged. We argue that oculoproprioception is selective for attention maps. By identifying a potential substrate for the coupling between eye and attention, this study contributes to the theoretical models for spatial attention.


Characterizing the topology of probabilistic biological networks.
Biological interactions are often uncertain events, that may or may not take place with some probability. This uncertainty leads to a massive number of alternative interaction topologies for each such network. The existing studies analyze the degree distribution of biological networks by assuming that all the given interactions take place under all circumstances. This strong and often incorrect assumption can lead to misleading results. In this paper, we address this problem and develop a sound mathematical basis to characterize networks in the presence of uncertain interactions. Using our mathematical representation, we develop a method that can accurately describe the degree distribution of such networks. We also take one more step and extend our method to accurately compute the joint-degree distributions of node pairs connected by edges. The number of possible network topologies grows exponentially with the number of uncertain interactions. However, the mathematical model we develop allows us to compute these degree distributions in polynomial time in the number of interactions. Our method works quickly even for entire protein-protein interaction (PPI) networks. It also helps us find an adequate mathematical model using MLE. We perform a comparative study of node-degree and joint-degree distributions in two types of biological networks: the classical deterministic networks and the more flexible probabilistic networks. Our results confirm that power-law and log-normal models best describe degree distributions for both probabilistic and deterministic networks. Moreover, the inverse correlation of degrees of neighboring nodes shows that, in probabilistic networks, nodes with large number of interactions prefer to interact with those with small number of interactions more frequently than expected. We also show that probabilistic networks are more robust for node-degree distribution computation than the deterministic ones. all the data sets used, the software implemented and the alignments found in this paper are available at http://bioinformatics.cise.ufl.edu/projects/probNet/.


Open mesh versus non-mesh for repair of femoral and inguinal hernia.
Inguinal hernia repair is the most frequent operation in general surgery. Until recently the standard procedure has been open musculo-aponeurotic repair using sutures under tension to close the defect but 'tension-free' repair using prosthetic mesh is becoming increasingly common in many countries. The purpose of this review is to evaluate open mesh techniques in comparison with open non-mesh techniques for the surgical repair of groin hernia. Electronic databases were searched and further trials were sought from the reference lists of reports of known trials. Through the EU Hernia Trialists Collaboration authors of identified randomised controlled trials were asked for information on any other trials known to them. There was no language restriction. Studies were eligible for inclusion if they were randomised or quasi-randomised trials comparing either a) open mesh with open non-mesh repair of groin hernia or b) open flat mesh repair with plug and mesh repair of groin hernia. For each outcome the results were derived using data from the best available source. The majority of data for this review came from individual patient data (IPD) supplied by the trialists. When these were unavailable data came from additional aggregated information or from published trial reports. All trials were analysed using the 'intention to treat' principle. Twenty trials comparing open mesh with open non-mesh repair were identified. Open mesh methods, on average, took 7-10 minutes less to perform than Shouldice procedures, but took 1-4 minutes longer than other non-mesh methods. There were no clear differences between mesh and non-mesh groups for haematomas, seromas or wound/superficial infections. Three serious operative complications were reported after open mesh repair and three following non-mesh repair. Overall, those in the mesh groups had a shorter length of hospital stay and quicker return to usual activities, but this pattern was not observed for all trials. There was a suggestion that persisting pain was less frequent after mesh repair than after non-mesh repair but this result was dependent on one trial and data were not available for 11 trials. There was no evidence of a difference between the groups with respect to persisting numbness. Fewer hernia recurrences were reported after mesh repair (Peto OR: 0.37, 95% CI: 0.26 to 0.51). There were too few data to reliably address differential effects for patients with recurrent, bilateral or femoral hernias. Two trials comparing flat mesh with plug and mesh were identified. There was no clear evidence of differences between the groups. There is evidence that the use of open mesh repair is associated with a reduction in the risk of recurrence of between 50% and 75%. Although the trials were heterogeneous there is also some evidence of quicker return to work and of lower rates of persisting pain following mesh repair.


Impact of Bioactive Peptide Motifs on Molecular Structure, Charging, and Nonfouling Properties of Poly(ethylene oxide) Brushes.
Polymer layers capable of suppressing protein adsorption from biological media while presenting extracellular matrix-derived peptide motifs offer valuable new options for biomimetic surface engineering. Herein, we provide detailed insights into physicochemical changes induced in a nonfouling poly(ethylene oxide) (PEO) brush/polydopamine (PDA) system by incorporation of adhesion ligand (RGD) peptides. Brushes with high surface chain densities (σ ≥ 0.5 chains·nm-2) and pronounced hydrophilicity (water contact angles ≤ 10°) were prepared by end-tethering of heterobifunctional PEOs ( Mn ≈ 20 000 g·mol-1) to PDA-modified surfaces from a reactive melt. Using alkyne distal end group on the PEO chains, azidopentanoic-bearing peptides were coupled through a copper-catalyzed Huisgen azide-alkyne "click" cycloaddition reaction. The surface concentration of RGD was tuned from complete saturation of the PEO surface with peptides (1.7 × 105 fmol·cm-2) to values which may induce distinct differences in cell adhesion (<6.0 × 102 fmol·cm-2). Infrared reflection-absorption and X-ray photoelectron spectroscopies proved the PDA-PEO layers covalent structure and the immobilization of RGD peptides. The complete reconstruction of experimental electrohydrodynamics data utilizing mean-field theory predictions further verified the attained brush structure of the end-tethered PEO chains which provided hydrodynamic screening of the PDA anchor. Increasing the surface concentration of immobilized RGD peptides led to increased interfacial charging. Supported by simulations, this observation was attributed to the ionization of functional groups in the amino acid sequence and to the pH-dependent adsorption of water ions (OH- > H3O+) from the electrolyte. Despite the distinct differences observed in the electrokinetic analysis of the surfaces bearing different amounts of RGD, it was found that the peptide presence on PEO(20 000)-PDA layers does not have a significant effect on the nonfouling properties of the system. Notably, the presented PEO(20 000)-PDA layers bearing RGD peptides in the surface concentration range 5.9 to 1.7 × 105 fmol·cm-2 reduced the protein adsorption from fetal bovine serum to less than 30 ng·cm-2, that is, values comparable to the ones obtained for pristine PEO(20 000)-PDA layers.


Life-history strategies of Australian lizards: a comparison between the tropics and the temperate zone.
Previous studies have suggested that tropical and temperate-zone lizards may differ fundamentally in life histories. We tested the applicability of this idea to Australian species by comparing temperate-zone species of agamid and scincid lizards with their congeners from the seasonal tropics. Data were derived from dissection of 1,941 specimens and from published information. Clutch size and egg size were positively correlated with mean maternal body size in most lizard species from both climatic zones. Mean body size of the lizards studies did not differ between the tropics and the temperate zone, nor did egg or hatchling size. However, tropical skinks showed considerably (approximately 20%) lower clutch size and relative clutch mass than did temperate-zone skinks. This difference was partly due to the higher incidence of species with low, invariant clutch size in the tropical lizard fauna (as seen in other continents as well), but primarily due to a trend for lineages (especially genera) with relatively high fecundity to be more common in the temperate zone than in the tropics. In contrast to studies on African lizards, our data suggested that modification of clutch size between areas has not occurred within genera: congeneric species from the tropics and temperate zone did not differ in clutch size. Production of more than one clutch per annum by individual females was common in both climatic zones. Tropical lizards may differ from temperate-zone species in showing higher reproductive frequencies, more rapid growth and earlier maturation. However, most of these effects may be due to phenotypic responses to environmental conditions (especially longer annual activity season), rather than to genetically based lifehistory adaptations.


Evaluation of Pochonia chlamydosporia and Purpureocillium lilacinum for Suppression of Meloidogyne enterolobii on Tomato and Banana.
Meloidogyne enterolobii is one of the most important root-knot nematode in tropical regions, due to its ability to overcome resistance mechanisms of a number of host plants. The lack of new and safe active ingredients against this nematode has restricted control alternatives for growers. Egg-parasitic fungi have been considered as potential candidates for the development of bionematicides. In tissue culture plates, Pochonia chlamydosporia (var. catenulata and chlamydosporia) and Purpureocillium lilacinum strains were screened for their ability to infect eggs of the root-knot nematode M. enterolobii on water-agar surfaces. Reduction in the hatching of J2 varied from 13% to 84%, depending on strain. The more efficacious strains reduced hatchability of J2 by 57% to 84% when compared to untreated eggs, but average reductions were only 37% to 55% when the same strains were applied to egg masses. Combinations of fungal isolates (one of each species) did not increase the control efficacy in vitro. In experiments in which 10,000 nematode eggs were inoculated per plant, reductions in the number of eggs after 12 months were seen in three of four treatments in banana plants, reaching 34% for P. chlamydosporia var. catenulata. No significant reductions were seen in tomato plants after 3 mon. In another experiment with tomato plants using either P. chlamydosporia var. catenulata or P. lilacinum, the number of eggs was reduced by 34% and 44%, respectively, when initial infestation level was low (500 nematode eggs per plant), but tested strains were not effective under a moderate infestation level (5,000 eggs per plant). Under all infestation levels tested in this work, gall and egg mass indexes (MI) did not differ from the untreated controls, bringing concerns related to the practical adoption of this control strategy by farmers. In our opinion, if the fungi P. chlamydosporia and P. lilacinum are to be used as biocontrol tools toward M. entorolobii, they should focus on agricultural settings with low soil infestation levels and within an IPM approach.


Executive summary of the report by the WPA section on pharmacopsychiatry on general and comparative efficacy and effectiveness of antidepressants in the acute treatment of depressive disorders.
Current gold standard in the treatment of depression includes pharmacotherapeutic and psychotherapeutic strategies together with social support. Due to the actually discussed controversies concerning the differential efficacy of antidepressants, a contribution to a comprehensive clarification seems to be necessary to avert further deterioration and uncertainty from patients, relatives, and their treating psychiatrists and general practitioners. Both efficacy and clinical effectiveness of antidepressants in the treatment of depressive disorders can be confirmed. Clinically meaningful antidepressant treatment effects were confirmed in different types of studies. Methodological issues of randomized controlled studies, meta-analyses, and effectiveness studies will be discussed. Furthermore, actual data about the differential efficacy and effectiveness of antidepressants with distinct pharmacodynamic properties and about outcome differences in studies using antidepressants and/or psychotherapy are discussed. This is followed by a clinically oriented depiction-the differential clinical effectiveness of different pharmacodynamic modes of action of antidepressants in different subtypes of depressive disorders. It can be summarized that the spectrum of different antidepressant treatments has broadened during the last decades. The efficacy and clinical effectiveness of antidepressants is statistically significant and clinically relevant and proven repeatedly. For further optimizing antidepressant treatment plans, clearly structured treatment algorithms and the implementation of psychotherapy seem to be useful. A modern individualized antidepressant treatment in most cases is a well-tolerated and efficacious tool to minimize the negative impact of the otherwise devastating and life-threatening outcome of depressive disorders.


Distribution of polarization-entangled photonpairs produced via spontaneous parametric down-conversion within a local-area fiber network: theoretical model and experiment.
We present a theoretical model for the distribution of polarization-entangled photon-pairs produced via spontaneous parametric down-conversion within a local-area fiber network. This model allows an entanglement distributor who plays the role of a service provider to determine the photon-pair generation rate giving highest two-photon interference fringe visibility for any pair of users, when given user-specific parameters. Usefulness of this model is illustrated in an example and confirmed in an experiment, where polarization-entangled photon-pairs are distributed over 82 km and 132 km of dispersion-managed optical fiber. Experimentally observed visibilities and entanglement fidelities are in good agreement with theoretically predicted values.


Simulation of diffusion in a crowded environment.
We performed extensive and systematic simulation studies of two-dimensional fluid motion in a complex crowded environment. In contrast to other studies we focused on cooperative phenomena that occurred if the motion of particles takes place in a dense crowded system, which can be considered as a crude model of a cellular membrane. Our main goal was to answer the following question: how do the fluid molecules move in an environment with a complex structure, taking into account the fact that motions of fluid molecules are highly correlated. The dynamic lattice liquid (DLL) model, which can work at the highest fluid density, was employed. Within the frame of the DLL model we considered cooperative motion of fluid particles in an environment that contained static obstacles. The dynamic properties of the system as a function of the concentration of obstacles were studied. The subdiffusive motion of particles was found in the crowded system. The influence of hydrodynamics on the motion was investigated via analysis of the displacement in closed cooperative loops. The simulation and the analysis emphasize the influence of the movement correlation between moving particles and obstacles.


Comparative genome and phenotypic analysis of Clostridium difficile 027 strains provides insight into the evolution of a hypervirulent bacterium.
The continued rise of Clostridium difficile infections worldwide has been accompanied by the rapid emergence of a highly virulent clone designated PCR-ribotype 027. To understand more about the evolution of this virulent clone, we made a three-way genomic and phenotypic comparison of an 'historic' non-epidemic 027 C. difficile (CD196), a recent epidemic and hypervirulent 027 (R20291) and a previously sequenced PCR-ribotype 012 strain (630). Although the genomes are highly conserved, the 027 genomes have 234 additional genes compared to 630, which may contribute to the distinct phenotypic differences we observe between these strains relating to motility, antibiotic resistance and toxicity. The epidemic 027 strain has five unique genetic regions, absent from both the non-epidemic 027 and strain 630, which include a novel phage island, a two component regulatory system and transcriptional regulators. A comparison of a series of 027 isolates showed that some of these genes appeared to have been gained by 027 strains over the past two decades. This study provides genetic markers for the identification of 027 strains and offers a unique opportunity to explain the recent emergence of a hypervirulent bacterium.


The peroxisome proliferator-activated receptor alpha (PPARalpha) agonist ciprofibrate inhibits apolipoprotein B mRNA editing in low density lipoprotein receptor-deficient mice: effects on plasma lipoproteins and the development of atherosclerotic lesions.
Low density lipoprotein receptor (LDLR)-deficient mice fed a chow diet have a mild hypercholesterolemia caused by the abnormal accumulation in the plasma of apolipoprotein B (apoB)-100- and apoB-48-carrying intermediate density lipoproteins (IDL) and low density lipoproteins (LDL). Treatment of LDLR-deficient mice with ciprofibrate caused a marked decrease in plasma apoB-48-carrying IDL and LDL but at the same time caused a large accumulation of triglyceride-depleted apoB-100-carrying IDL and LDL, resulting in a significant increase in plasma cholesterol levels. These plasma lipoprotein changes were associated with an increase in the hepatic secretion of apoB-100-carrying very low density lipoproteins (VLDL) and a decrease in the secretion of apoB-48-carrying VLDL, accompanied by a significant decrease in hepatic apoB mRNA editing. Hepatic apobec-1 complementation factor mRNA and protein abundance were significantly decreased, whereas apobec-1 mRNA and protein abundance remained unchanged. No changes in apoB mRNA editing occurred in the intestine of the treated animals. After 150 days of treatment with ciprofibrate, consistent with the increased plasma accumulation of apoB-100-carrying IDL and LDL, the LDLR-deficient mice displayed severe atherosclerotic lesions in the aorta. These findings demonstrate that ciprofibrate treatment decreases hepatic apoB mRNA editing and alters the pattern of hepatic lipoprotein secretion toward apoB-100-associated VLDL, changes that in turn lead to increased atherosclerosis.