Poly-alpha-glutamic acid synthesis using a novel catalytic activity of RimK from Escherichia coli K-12.
Poly-L-α-amino acids have various applications because of their biodegradable properties and biocompatibility. Microorganisms contain several enzymes that catalyze the polymerization of L-amino acids in an ATP-dependent manner, but the products from these reactions contain amide linkages at the side residues of amino acids: e.g., poly-γ-glutamic acid, poly-ε-lysine, and cyanophycin. In this study, we found a novel catalytic activity of RimK, a ribosomal protein S6-modifying enzyme derived from Escherichia coli K-12. This enzyme catalyzed poly-α-glutamic acid synthesis from unprotected L-glutamic acid (Glu) by hydrolyzing ATP to ADP and phosphate. RimK synthesized poly-α-glutamic acid of various lengths; matrix-assisted laser desorption ionization-time of flight-mass spectrometry showed that a 46-mer of Glu (maximum length) was synthesized at pH 9. Interestingly, the lengths of polymers changed with changing pH. RimK also exhibited 86% activity after incubation at 55°C for 15 min, thus showing thermal stability. Furthermore, peptide elongation seemed to be catalyzed at the C terminus in a stepwise manner. Although RimK showed strict substrate specificity toward Glu, it also used, to a small extent, other amino acids as C-terminal substrates and synthesized heteropeptides. In addition, RimK-catalyzed modification of ribosomal protein S6 was confirmed. The number of Glu residues added to the protein varied with pH and was largest at pH 9.5.


Regulation of intestinal growth in response to variations in energy supply and demand.
The growth of the intestine requires energy, which is known to be met by catabolism of ingested nutrients. Paradoxically, during whole body energy deficit including calorie restriction, the intestine grows in size. To understand how and why this happens, we reviewed data from several animal models of energetic challenge. These were bariatric surgery, cold exposure, lactation, dietary whey protein intake and calorie restriction. Notably, these challenges all reduced the adipose tissue mass, altered hypothalamic neuropeptide expression and increased intestinal size. Based on these data, we propose that the loss of energy in the adipose tissue promotes the growth of the intestine via a signalling mechanism involving the hypothalamus. We discuss possible candidates in this pathway including data showing a correlative change in intestinal (ileal) expression of the cyclin D1 gene with adipose tissue mass, adipose derived-hormone leptin and hypothalamic expression of leptin receptor and the pro-opiomelanocortin gene. The ability of the intestine to grow in size during depletion of energy stores provides a mechanism to maximize assimilation of ingested energy and in turn sustain critical functions of tissues important for survival.


Dopamine: release from the brain in vivo by amantadine.
After dopamine stores in the caudate nucleus of cats were labeled with [(3)H]dopamine, the ventricular system was perfused with artificial cerebrospinal fluid. The addition of amantadine to the perfusing fluid caused a doserelated increase in the concentrations of [(3)H]dopamine appearing in the perfusion effluent. Subthreshold concentrations of amantadine also enhanced the efflux of [(3)H]dopamine induced by electrical stimulation of the caudate nucleus.


Immunomodulation by macrolides: therapeutic potential for critical care.
Critical illness is associated with immune dysregulation, characterised by concurrent hyperinflammation and immune suppression. Hyperinflammation can result in collateral tissue damage and organ failure, whereas immune suppression has been implicated in susceptibility to secondary infections and reactivation of latent viruses. Macrolides are a class of bacteriostatic antibiotics that are used in the intensive care unit to control infections or to alleviate gastrointestinal dysmotility. Yet macrolides also have potent and wide-ranging immunomodulatory properties, which might have the potential to correct immune dysregulation in patients who are critically ill without affecting crucial antimicrobial defences. In this Review, we provide an overview of preclinical and clinical studies that point to the beneficial effects of macrolides in acute diseases relevant to critical care, and we discuss the possible underlying mechanisms of their immunomodulatory effects. Further studies are needed to explore the therapeutic potential of macrolides in critical illness, to identify subgroups of patients who might benefit from treatment, and to develop novel non-antibiotic macrolide derivatives with improved immunomodulatory properties.


Analysis of strain and regional variation in gene expression in mouse brain.
We performed a statistical analysis of a previously published set of gene expression microarray data from six different brain regions in two mouse strains. In the previous analysis, 24 genes showing expression differences between the strains and about 240 genes with regional differences in expression were identified. Like many gene expression studies, that analysis relied primarily on ad hoc 'fold change' and 'absent/present' criteria to select genes. To determine whether statistically motivated methods would give a more sensitive and selective analysis of gene expression patterns in the brain, we decided to use analysis of variance (ANOVA) and feature selection methods designed to select genes showing strain- or region-dependent patterns of expression. Our analysis revealed many additional genes that might be involved in behavioral differences between the two mouse strains and functional differences between the six brain regions. Using conservative statistical criteria, we identified at least 63 genes showing strain variation and approximately 600 genes showing regional variation. Unlike ad hoc methods, ours have the additional benefit of ranking the genes by statistical score, permitting further analysis to focus on the most significant. Comparison of our results to the previous studies and to published reports on individual genes show that we achieved high sensitivity while preserving selectivity. Our results indicate that molecular differences between the strains and regions studied are larger than indicated previously. We conclude that for large complex datasets, ANOVA and feature selection, alone or in combination, are more powerful than methods based on fold-change thresholds and other ad hoc selection criteria.


Ab Initio Molecular Dynamics Calculations versus Quantum-State-Resolved Experiments on CHD3 + Pt(111): New Insights into a Prototypical Gas-Surface Reaction.
The dissociative chemisorption of methane on metal surfaces is of fundamental and practical interest, being a rate-limiting step in the steam reforming process. The reaction is best modeled with quantum dynamics calculations, but these are currently not guaranteed to produce accurate results because they rely on potential energy surfaces based on untested density functionals and on untested dynamical approximations. To help overcome these limitations, here we present for the first time statistically accurate reaction probabilities obtained with ab initio molecular dynamics (AIMD) for a polyatomic gas-phase molecule reacting with a metal surface. Using a general purpose density functional, the AIMD reaction probabilities are in semiquantitative agreement with new quantum-state-resolved experiments on CHD3 + Pt(111). The comparison suggests the use of the sudden approximation for treating the rotations even though CHD3 has large rotational constants and yields an estimated reaction barrier of 0.9 eV for CH4 + Pt(111).


Guidelines concordance of maintenance treatment in euthymic patients with bipolar disorder: Data from the national bipolar mania pathway survey (BIPAS) in mainland China.
Although the treatment guidelines of bipolar disorders (BPD) have spread more than a decade, the concordance with evidence-based guidelines was typically low in routine clinical practice. This study is to present the data on the maintenance treatment of BPD in mainland China. One thousand and twenty-three patients who had experienced a euthymia were eligible for entry into this survey on the maintenance treatment of BPD. Guidelines disconcordance was determined by comparing the medication(s) that patients were prescribed with the recommendations in the guidelines of the Canadian Network for Mood and Anxiety Treatments. Three hundred and sixty-four patients (35.6%) had not been prescribed with the maintenance treatment as guidelines recommendations, and 208 patients (20.3%) were prescribed with the antidepressants. A longer duration of BPD, a depressive episode at first onset, and a recent depressive or mixed episode significantly increased the risk for guidelines disconcordance and prescribing antidepressant. In contrast, a hospitalization history due to manic episode was associated with a significant decrease in the risk for guidelines disconcordance and prescribing antidepressant. This study was a cross-sectional and retrospective investigation based on medical records. Considering the potentially hazardous effects of inappropriate treatment, individualized psychoeducational strategies for subjects with BPD are necessary to enhance treatment adherence and close the gap between guidelines and clinical practice in mainland China.


Tropical forests are not flat: how mountains affect herbivore diversity.
Ecologists debate whether tropical insect diversity is better explained by higher plant diversity or by host plant species specialization. However, plant-herbivore studies are primarily based in lowland rainforests (RF) thus excluding topographical effects on biodiversity. We examined turnover in Eois (Geometridae) communities across elevation by studying elevational transects in Costa Rica and Ecuador. We found four distinct Eois communities existing across the elevational gradients. Herbivore diversity was highest in montane forests (MF), whereas host plant diversity was highest in lowland RF. This was correlated with higher specialization and species richness of Eois/host plant species we found in MF. Based on these relationships, Neotropical Eois richness was estimated to range from 313 (only lowland RF considered) to 2034 (considering variation with elevation). We conclude that tropical herbivore diversity and diet breadth covary significantly with elevation and urge the inclusion of montane ecosystems in host specialization and arthropod diversity estimates.


RSV 2010: Recent advances in research on respiratory syncytial virus and other pneumoviruses.
Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) are important causes of acute respiratory tract disease in infants, immunocompromised patients and the elderly. The Seventh International RSV symposium was held in Rotterdam, the Netherlands, from December 2-5, 2010. This symposium is the flagship event for leading investigators engaged in RSV and HMPV research around the world. The objective of the symposium was to provide a forum to review recent advances in research on RSV, HMPV and other pneumoviruses. More than 200 young and established investigators attended the meeting. Over a hundred papers were presented in 55 oral presentations and six poster sessions, providing all participants the opportunity to share and to discuss their work. The Chanock lecture, instituted in 2003 to acknowledge important contributors to RSV research, was presented by Peter Collins. As a preface to his lecture, he presented an in memoriam of the late Dr. Robert M. Chanock, who played a key role in the characterization of RSV as a human pathogen. The current report presents highlights of the meeting, covering topics from basic virology, pathogenesis and immunology to clinical studies, therapeutics and vaccine development.


Probing Interkingdom Signaling Molecules via Liquid Extraction Surface Analysis-Mass Spectrometry.
Previously, metabolites diffused or secreted from microbial samples have been analyzed via liquid chromatography-mass spectrometry (LC-MS) approaches following lengthy extraction protocols. Here, we present a model system for growing biofilms on discs before utilizing rapid and direct surface sampling MS, namely, liquid extraction surface analysis, to study the microbial exometabolome. One of the benefits of this approach is its surface-specific nature, enabling mimicking biofilm formation in a way that the study of planktonic liquid cultures cannot imitate. Even though Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), and Candida albicans (C. albicans) have been studied previously in isolation, very few studies consider the complexity of the interplay between these pathogens, which are commonly combined causative agents of infection. Our model system provides a route to investigate changes in the exometabolome, such as metabolites that become circulatory in the presence of multiple pathogens. Our results agree with previous reports showing that 2-alkyl-4(1H)-quinolone signal molecules produced by P. aeruginosa are important markers of infection and suggest that methods for monitoring levels of 2-heptyl-4-hydroxyquinoline and 2,4-dihydroxyquinoline, as well as pyocyanin, could be beneficial in the determination of causative agents in interkingdom infection including P. aeruginosa. Furthermore, studying changes in exometabolome metabolites between pqs quorum sensing antagonists in treated and nontreated samples suggests suppression of phenazine production by P. aeruginosa. Hence, our model provides a rapid analytical approach to gaining a mechanistic understanding of bacterial signaling.


Technology networks: the autocatalytic origins of innovation.
We analyse the autocatalytic structure of technological networks and evaluate its significance for the dynamics of innovation patenting. To this aim, we define a directed network of technological fields based on the International Patents Classification, in which a source node is connected to a receiver node via a link if patenting activity in the source field anticipates patents in the receiver field in the same region more frequently than we would expect at random. We show that the evolution of the technology network is compatible with the presence of a growing autocatalytic structure, i.e. a portion of the network in which technological fields mutually benefit from being connected to one another. We further show that technological fields in the core of the autocatalytic set display greater fitness, i.e. they tend to appear in a greater number of patents, thus suggesting the presence of positive spillovers as well as positive reinforcement. Finally, we observe that core shifts take place whereby different groups of technology fields alternate within the autocatalytic structure; this points to the importance of recombinant innovation taking place between close as well as distant fields of the hierarchical classification of technological fields.


Protection from photodamage by topical application of caffeine after ultraviolet irradiation.
Characterization of mechanisms that can reverse residual damage from prior skin exposure to ultraviolet (UV) would be of considerable biological and therapeutic interest. Topical caffeine application to mouse skin that had previously been treated with UV has been shown to inhibit the subsequent development of squamous cell carcinomas. We used an established mouse photodamage model to investigate other possible effects of topical caffeine application after UV. SKH-1 hairless mice were treated with ultraviolet B (UVB) followed immediately by topical application of caffeine or vehicle three times weekly for 11 weeks. Caffeine applied topically after UV treatment resulted in a significant decrease in UV-induced skin roughness/transverse rhytides as assessed by treatment-blinded examiners. Histologically, topical caffeine application after a single dose of UVB more than doubled the number of apoptotic keratinocytes as evaluated by sunburn cell formation, caspase 3 cleavage and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling (TUNEL) staining. A trend towards decreased solar elastosis was noted in the caffeine-treated group although this was not statistically significant. Other histological parameters including epidermal hyperplasia, solar elastosis and angiogenesis were increased in mice treated with UV but topical application of caffeine did not alter these particular UV effects. These findings support the concept that topical application of caffeine to mouse skin after UV irradiation promotes the deletion of DNA-damaged keratinocytes and may partially diminish photodamage as well as photocarcinogenesis.


The Use of an Informational Video to Improve Patient Satisfaction, Preparedness, Mood, and Empowerment.
Massage therapy is commonly used in Canada for the treatment of a wide range of health concerns. Massage therapy is changing to meet the health care needs of Canadians. Rapid changes to the profession may create a gap between patient expectations of massage therapy treatment based on historic views of the profession and their experience in today's practice. This gap could lead to patient confusion, dissatisfaction, or other negative outcomes. This study sought to understand whether patient satisfaction, preparedness, mood, and patient empowerment are improved when new patients who attend a student massage therapy clinic watch an informational video, compared to those who receive the standard paper information sheet. The study used a convenience sample of new patients who presented for their first massage therapy appointment to the Humber College Student Massage Therapy Clinic. Participants were randomized either to the intervention group (video and paper information) or the comparison group (paper information only). The outcomes of interest in this study were patient preparedness, satisfaction, mood, and empowerment. Data were collected using two questionnaires, one before treatment and one after. A total of 108 patients participated in the study (55 comparison group; 53 intervention group). Demographic and clinical characteristics were comparable between the two groups. A statistically significant difference was seen between the two groups when comparing their responses to the pre-appointment statement: "I know what will happen in my initial massage therapy appointment" (p < .001). There was no statistically significant difference seen when comparing the responses of the related post-appointment statement (p = .63). This study found that an informational video improved perceived knowledge as patients entered the massage therapy treatment, but did not have a significant effect on satisfaction, mood, or patient empowerment. Other student clinics should consider the addition of an informational video to their procedures to increase patient knowledge of what to expect.


Liquid based cytology improves the positive predictive value of glandular smears compared to conventional cytology.
To investigate whether the introduction of liquid-based cytology (LBC) in an urban setting decreases the diagnosis of glandular neoplasia (grade 6) and improves the positive predictive value (PPV) of cervical cytological screening. A retrospective database review was conducted identifying women with cervical cytological abnormalities including glandular neoplasia (grade 6) before and after the introduction of LBC. Following the introduction of LBC the rate of glandular neoplasia (grade 6) referrals fell from 1.08% to 0.69% of all cervical cytological abnormalities. There was a significant reduction in 'abnormal' cytological samples subsequently found to be associated with no invasive or preinvasive disease but no decrease in the number showing preinvasive or invasive disease. A significant decrease in number of patients having a final diagnosis of normal/inflammatory or wart changes was seen in those patients referred during the LBC period (p < 0.01). The introduction of LBC in an urban setting decreased cytological glandular neoplasia referrals but not at the expense of missing preinvasive and invasive cancers. It has also increased the PPV of cervical sampling to detect preinvasive and invasive cancer from 59.6% to 76.0%.


Activity of the novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 against T-cell acute lymphoblastic leukemia.
Recent findings have highlighted that constitutively active phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL), where it upregulates cell proliferation, survival, and drug resistance. These observations lend compelling weight to the application of PI3K/Akt/mTOR inhibitors in the therapy of T-ALL. Here, we have analyzed the therapeutic potential of the novel dual PI3K/mTOR inhibitor NVP-BEZ235, an orally bioavailable imidazoquinoline derivative, which has entered clinical trials for solid tumors, on both T-ALL cell lines and patient samples. NVP-BEZ235 was cytotoxic to a panel of T-ALL cell lines as determined by MTT assays. NVP-BEZ235 treatment resulted in cell cycle arrest and apoptosis. Western blots showed a dose- and time-dependent dephosphorylation of Akt and mTORC1 downstream targets in response to NVP-BEZ235. Remarkably, NVP-BEZ235 targeted the side population of both T-ALL cell lines and patient lymphoblasts, which might correspond to leukemia-initiating cells, and synergized with chemotherapeutic agents (cyclophosphamide, cytarabine, dexamethasone) currently used for treating T-ALL patients. NVP-BEZ235 reduced chemoresistance to vincristine induced in Jurkat cells by coculturing with MS-5 stromal cells, which mimic the bone marrow microenvironment. NVP-BEZ235 was cytotoxic to T-ALL patient lymphoblasts displaying pathway activation, where the drug dephosphorylated eukaryotic initiation factor 4E-binding protein 1, at variance with rapamycin. Taken together, our findings indicate that longitudinal inhibition at two nodes of the PI3K/Akt/mTOR network with NVP-BEZ235, either alone or in combination with chemotherapeutic drugs, may be an efficient treatment of those T-ALLs that have aberrant upregulation of this signaling pathway for their proliferation and survival.


The effect of a multifaceted ergonomic intervention program on reducing musculoskeletal disorders in dentists.
Background: Work-related musculoskeletal disorders (WMSDs) are the most common occupational injuries in dentists. These disorders occur due to the specific characteristics of dentistry occupation such as the use of tools and instruments and awkward posture. The present study aimed at evaluating the effect of multifaceted ergonomic program on reducing musculoskeletal disorders in dentists. Methods: One hundred-two male dentists who worked in dentistry clinics of Tehran's hospitals participated in this interventional study. Participants were randomly divided into control (n=50) and intervention (n=52) groups. Dentists in the intervention group (n=52) underwent multifaceted ergonomic intervention program for 8 weeks and dentists in the control group (n=50) only received the measurements. The prevalence of musculoskeletal disorders was evaluated in each of the 2 groups at 3 time points before the intervention, 3, and 6 months after the intervention using the Nordic Musculoskeletal Questionnaire (NMQ). Paired t-test was used to compare the prevalence of musculoskeletal disorders before and after the ergonomic intervention program at the end of 3 and 6 months. Results: The results revealed that the prevalence of musculoskeletal disorders was reduced after the intervention in the neck, shoulder, arm, wrist, back, thigh, knees, and feet (p<0.05). On the other hand, the prevalence of musculoskeletal disorders increased in the control group in the neck, shoulder, arm, wrist, thigh, and knee, respectively. The survey results revealed that 98% of the participants agreed with this intervention program. Conclusion: The results of this study revealed that the multifaceted ergonomic intervention program, which included improving working conditions, identifying ergonomic risk factors, regular exercise, and discussion group meetings, could decrease the prevalence of musculoskeletal disorders in dentists.


Accidental falls in the elderly and their relation with functional capacity.
This study aimed to determinate the prevalence of falls in the elderly and its relationship with the functional capacity. This is an epidemiological and cross-sectional study; a two-stage cluster sample of 240 male and female subjects aged over 60 years was used. Data were collected from November 2010 to February 2011. The following questionnaires were used: socio-demographic profile, assessment of falls, Functional Independence Measure, Lawton and Brody Scale. Significance was set at 0.05. To identify the occurrence of falls and their relation with functional capacity, the prevalence ratio and prevalence odds ratios were used, as well as multiple logistic regression. Average age was 73.5 years (±8.4); 25% 80 years or more, with preponderance of female gender; 48.8% attended school between 1-4 years. The average was 1.33 falls (±0.472), with prevalence in women and elderly between 60 and 79 years old; the most frequently sites were the backyard and bathroom. Strong correlation between the level of functional independence and instrumental activities and age was found, but no relation between elderly victims of falls and the gender and age variables. Women who suffered falls related to functional independence were predominant, which can be prevented through elderly health promotion strategies, a policy that serves to offer living conditions to people in the aging process.


Development of risk prediction models to predict urine culture growth for adults with suspected urinary tract infection in the emergency department: protocol for an electronic health record study from a single UK university hospital.
Urinary tract infection (UTI) is a leading cause of hospital admissions and is diagnosed based on urinary symptoms and microbiological cultures. Due to lags in the availability of culture results of up to 72 h, and the limitations of routine diagnostics, many patients with suspected UTI are started on antibiotic treatment unnecessarily. Predictive models based on routinely collected clinical information may help clinicians to rule out a diagnosis of bacterial UTI in low-risk patients shortly after hospital admission, providing additional evidence to guide antibiotic treatment decisions. Using electronic hospital records from Queen Elizabeth Hospital Birmingham (QEHB) collected between 2011 and 2017, we aim to develop a series of models that estimate the probability of bacterial UTI at presentation in the emergency department (ED) among individuals with suspected UTI syndromes. Predictions will be made during ED attendance and at different time points after hospital admission to assess whether predictive performance may be improved over time as more information becomes available about patient status. All models will be externally validated for expected future performance using QEHB data from 2018/2019. Risk prediction models using electronic health records offer a new approach to improve antibiotic prescribing decisions, integrating clinical and demographic data with test results to stratify patients according to their probability of bacterial infection. Used in conjunction with expert opinion, they may help clinicians to identify patients that benefit the most from early antibiotic cessation.


Contrasting bacterial strategies to coexist with a flagellate predator in an experimental microbial assemblage.
We studied predator-induced changes within a slowly growing mixed microbial assemblage that was sustained by algal exudates in a continuous cultivation system. In situ hybridization with fluorescent monolabeled oligonucleotide probes was used for a tentative community analysis. This method also allowed us to quantify the proportions of predators with ingested bacteria of different taxonomic groups. In addition, we determined grazing rates on bacteria with fluorescently labelled prey. Bacteria belonging to the alpha and beta subdivisions of the phylum Proteobacteria ((alpha)- and (beta)-Proteobacteria, respectively) showed very different responses to the addition of a bacterivorous flagellate, Bodo saltans. Within one day, filamentous protist-inedible bacteria developed; these belonged to the (beta)-Proteobacteria and constituted between 8.7 and 34% of bacteria from this subgroup. Total abundance of (beta)-Proteobacteria decreased from 3.05 x 10(sup6) to 0.23 x 10(sup6) cells ml(sup-1), and estimated cell division rates were low. Other morphologically inconspicuous protist-edible bacteria belonging to the (alpha)-Proteobacteria were found to respond to predation by an increase in growth rate. Although these bacteria were heavily grazed upon, as on average >85% of flagellate cells had ingested (alpha)-Proteobacteria, they numerically dominated after the addition of B. saltans (mean, 1.35 x 10(sup6) cells ml(sup-1)). It was thus mainly those fast-dividing strains of (alpha)-Proteobacteria that supported the growth of the flagellate population. We conclude that bacteria in mixed assemblages can adopt at least two distinct strategies as a reaction to intense flagellate predation: to outgrow predation pressure or to develop inedible, inactive filaments. Since these strategies occurred within 24 h after the addition of the flagellate, we hypothesize that chemical stimuli released by the predator may have triggered bacterial responses.


Review of the efficacy and safety of antidepressants in youth depression.
Depression in children and adolescents is a cause of substantial morbidity and mortality in this population. It is a common disorder that affects 2% of children and up to 6% of adolescents. Although antidepressants are used frequently for the treatment of this disorder, there has been recent controversy about the efficacy and safety of these medications in this population. This review examined the available evidence from clinical trials of antidepressants in adolescents and children with depression. Clinical trial data reviewed were obtained from published reports, including peer review journals and meeting abstracts, as well as unpublished data in the public domain. Clinical trials in this review included large RCTs of antidepressants in youth under the age of 19 with depression. Studies were identified in 2 stages: 1) all RCTs included in the 2004 FDA safety report were reviewed; and 2) to ensure that no additional studies not reported to the FDA were missed, MEDLINE and PSYCH Info were searched from inception until December 2004. A total of 8 published studies and 9 unpublished studies were identified and reviewed. Efficacy and safety results from each study are reviewed in detail. There are significant differences in remission and response rates between different antidepressants but also between placebo groups across studies. Adverse events are common in clinical trials involving children and adolescents with depression. Due to lack of access to full data sets, effect sizes could not be calculated. With the variability in trial methodology and the variation in the drug/placebo response rates within a single trial, clinicians need to be judicious in their interpretation of research data on pediatric antidepressant trials. Significant methodological issues may also have affected the efficacy and safety results from these clinical trials.


Retrograde supra-aortic stent placement combined with open carotid or subclavian artery revascularization.
To review the outcomes of retrograde supra-aortic vessel stent (RSAS) placement combined with open carotid or subclavian artery revascularization. Retrospective review of all consecutive patients between 1995 and 2010, excluding transfemoral procedures or isolated retrograde stent placement. There were 11 patients (9 females, mean age 65 years). Open revascularization included carotid endarterectomy in 6 patients, carotid-subclavian bypass in 3, and carotid-carotid bypass in 2 patients. There were no operative deaths or neurological events. All symptomatic patients improved. Over a mean follow-up of 24 months, One patient developed common carotid artery (CCA) in-stent dissection and symptomatic restenosis treated with subclavian-carotid bypass. Another 3 patients had asymptomatic restenosis of the carotid bifurcation but required no intervention. Retrograde stenting of the common carotid or innominate artery is a safe and effective method to provide inflow in selected patients with severe supra-aortic vessel disease who require concomitant open carotid or subclavian artery reconstructions.


Achievements and needs for the climate change scenario framework.
Long-term global scenarios have underpinned research and assessment of global environmental change for four decades. Over the past ten years, the climate change research community has developed a scenario framework combining alternative futures of climate and society to facilitate integrated research and consistent assessment to inform policy. Here we assess how well this framework is working and what challenges it faces. We synthesize insights from scenario-based literature, community discussions and recent experience in assessments, concluding that the framework has been widely adopted across research communities and is largely meeting immediate needs. However, some mixed successes and a changing policy and research landscape present key challenges, and we recommend several new directions for the development and use of this framework.


Flamingo regulates R8 axon-axon and axon-target interactions in the Drosophila visual system.
Photoreceptors (R cells) in the Drosophila retina connect to targets in three distinct layers of the optic lobe of the brain: R1-R6 connect to the lamina, and R7 and R8 connect to distinct layers in the medulla. In each of these layers, R axon termini are arranged in evenly spaced topographic arrays. In a genetic screen for mutants with abnormal R cell connectivity, we recovered mutations in flamingo (fmi). fmi encodes a seven-transmembrane cadherin, previously shown to function in planar cell polarity and in dendritic patterning. Here, we show that fmi has two specific functions in R8 axon targeting: it facilitates competitive interactions between adjacent R8 axons to ensure their correct spacing, and it promotes the formation of stable connections between R8 axons and their target cells in the medulla. The former suggests a general role for Fmi in establishing nonoverlapping dendritic and axonal target fields. The latter, together with the finding that N-Cadherin has an analogous role in R7 axon-target interactions, points to a cadherin-based system for target layer specificity in the Drosophila visual system.


A Refined Neuronal Population Measure of Visual Attention.
Neurophysiological studies of cognitive mechanisms such as visual attention typically ignore trial-by-trial variability and instead report mean differences averaged across many trials. Advances in electrophysiology allow for the simultaneous recording of small populations of neurons, which may obviate the need for averaging activity over trials. We recently introduced a method called the attention axis that uses multi-electrode recordings to provide estimates of attentional state of behaving monkeys on individual trials. Here, we refine this method to eliminate problems that can cause bias in estimates of attentional state in certain scenarios. We demonstrate the sources of these problems using simulations and propose an amendment to the previous formulation that provides superior performance in trial-by-trial assessments of attentional state.


Effect of disinfection/sterilization treatments on Gluma-mediated dentin shear bond strengths.
This in vitro study investigated Gluma-mediated dentin shear bond strengths after treatment by three commonly used disinfection/sterilization methods: 1) proprietary phenolated glutaraldehyde (Sporicidin); 2) 1% NaOCl and; 3) autoclaving. Varying numbers of bonds were too low to be measured, failing prior to, or early in testing. Failed bonds were scored as zero. When all attempted bonds were subjected to ANOVA, there was a significant difference between groups (P less than 0.0001) in bond strengths. These results demonstrate the significant differences were due to statistical management; that is, inclusion of zeros. When only measurable bonds were similarly analyzed, no significant differences in bond strength were found. When the measurable bonds were tested by Fisher's exact test, significant differences were detected among and between the experimental groups. Additionally, the experimental treatments probably altered or removed dentinal protein constituents. A plea is made for clarity and uniformity in statistical management and reporting of bonds which are too low to be measured.


Update in internal medicine.
More than 500,000 new medical articles are published every year and available time to keep updated is scarcer every day. Nowadays, the task of selecting useful, consistent, and relevant information for clinicians is a priority in many major medical journals. This review has the aim of gathering the results of the most important findings in clinical medicine in the last few years. It is focused on results from randomized clinical trials and well-designed observational research. Findings were included preferentially if they showed solid results, and we avoided as much as possible including only preliminary data, or results that included only non-clinical outcomes. Some of the most relevant findings reported here include the significant benefit of statins in patients with coronary artery disease even with mean cholesterol level. It also provides a substantial review of the most significant trials assessing the effectiveness of IIb/IIIa receptor blockers. In gastroenterology many advances have been made in the H. pylori eradication, and the finding that the cure of H. pylori infection may be followed by gastroesophageal reflux disease. Some new antivirals have shown encouraging results in patients with chronic hepatitis. In the infectious disease arena, the late breaking trials in anti-retroviral disease are discussed, as well as the new trends regarding antibiotic resistance. This review approaches also the role of leukotriene modifiers in the treatment of asthma and discusses the benefit of using methylprednisolone in patients with adult respiratory distress syndrome, among many other advances in internal medicine.


Hydromorphone Protects against CO2 Pneumoperitoneum-Induced Lung Injury via Heme Oxygenase-1-Regulated Mitochondrial Dynamics.
Various pharmacological agents and protective methods have been shown to reverse pneumoperitoneum-related lung injury, but identifying the best strategy is challenging. Herein, we employed lung tissues and blood samples from C57BL/6 mice with pneumoperitoneum-induced lung injury and blood samples from patients who received laparoscopic gynecological surgery to investigate the therapeutic role of hydromorphone in pneumoperitoneum-induced lung injury along with the underlying mechanism. We found that pretreatment with hydromorphone alleviated lung injury in mice that underwent CO2 insufflation, decreased the levels of myeloperoxidase (MPO), total oxidant status (TOS), and oxidative stress index (OSI), and increased total antioxidant status (TAS). In addition, after pretreatment with hydromorphone, upregulated HO-1 protein expression, reduced mitochondrial DNA content, and improved mitochondrial morphology and dynamics were observed in mice subjected to pneumoperitoneum. Immunohistochemical staining also verified that hydromorphone could increase the expression of HO-1 in lung tissues in mice subjected to CO2 pneumoperitoneum. Notably, in mice treated with HO-1-siRNA, the protective effects of hydromorphone against pneumoperitoneum-induced lung injury were abolished, and hydromorphone did not have additional protective effects on mitochondria. Additionally, in clinical patients who received laparoscopic gynecological surgery, pretreatment with hydromorphone resulted in lower serum levels of club cell secretory protein-16 (CC-16) and intercellular adhesion molecule-1 (ICAM-1), a lower prooxidant-antioxidant balance (PAB), and higher heme oxygenase-1 (HO-1) activity than morphine pretreatment. Collectively, our results suggest that hydromorphone protects against CO2 pneumoperitoneum-induced lung injury via HO-1-regulated mitochondrial dynamics and may be a promising strategy to treat CO2 pneumoperitoneum-induced lung injury.


Occurrence and properties of a thermostable protease secreted by sea-urchin embryos.
1. A trypsinogen-activating enzyme is distinct from the chorion-dissolving enzyme of the sea-urchin blastula, but is secreted with it. 2. This ;trypsinogenase' does not attack N-alpha-toluene-p-sulphonylarginine methyl ester, and is not inhibited by concentrations of di-isopropyl phosphorofluoridate or 7-amino-1-chloro-3-toluene-p-sulphonamidoheptan-2-one that are 98% effective against trypsin. It requires a small amount of Ca(2+) for activity, but is inhibited by more, from as little as 1mm. 3. Enzymic activity is associated with a wide range of particle weights, some apparently as high as 15x10(6). The mean particle weight can be decreased by sonication. 4. Fresh trypsinogenase in the higher range of particle weights appears to be remarkably stable to heating, e.g. retaining full activity after boiling for 15min.


Following the LINEs: an analysis of primate genomic variation at human-specific LINE-1 insertion sites.
The L1 Ta subfamily of long interspersed elements (LINEs) consists exclusively of human-specific L1 elements. Polymerase chain reaction-based screening in nonhuman primate genomes of the orthologous sites for 249 human L1 Ta elements resulted in the recovery of various types of sequence variants for approximately 12% of these loci. Sequence analysis was employed to capture the nature of the observed variation and to determine the levels of gene conversion and insertion site homoplasy associated with LINE elements. Half of the orthologous loci differed from the predicted sizes due to localized sequence variants that occurred as a result of common mutational processes in ancestral sequences, often including regions containing simple sequence repeats. Additional sequence variation included genomic deletions that occurred upon L1 insertion, as well as successive mobile element insertions that accumulated within a single locus over evolutionary time. Parallel independent mobile element insertions at orthologous loci in distinct species may introduce homoplasy into retroelement-based phylogenetic and population genetic data. We estimate the overall frequency of parallel independent insertion events at L1 insertion sites in seven different primate species to be very low (0.52%). In addition, no cases of insertion site homoplasy involved the integration of a second L1 element at any of the loci, but rather largely involved secondary insertions of Alu elements. No independent mobile element insertion events were found at orthologous loci in the human and chimpanzee genomes. Therefore, L1 insertion polymorphisms appear to be essentially homoplasy free characters well suited for the study of population genetics and phylogenetic relationships within closely related species.


EHR-based phenome wide association study in pancreatic cancer.
Pancreatic cancer is one of the most common causes of cancer-related deaths in the United States, it is difficult to detect early and typically has a very poor prognosis. We present a novel method of large-scale clinical hypothesis generation based on phenome wide association study performed using Electronic Health Records (EHR) in a pancreatic cancer cohort. The study population consisted of 1,154 patients diagnosed with malignant neoplasm of pancreas seen at The Froedtert & The Medical College of Wisconsin academic medical center between the years 2004 and 2013. We evaluated death of a patient as the primary clinical outcome and tested its association with the phenome, which consisted of over 2.5 million structured clinical observations extracted out of the EHR including labs, medications, phenotypes, diseases and procedures. The individual observations were encoded in the EHR using 6,617 unique ICD-9, CPT-4, LOINC, and RxNorm codes. We remapped this initial code set into UMLS concepts and then hierarchically expanded to support generalization into the final set of 10,164 clinical concepts, which formed the final phenome. We then tested all possible pairwise associations between any of the original 10,164 concepts and death as the primary outcome. After correcting for multiple testing and folding back (generalizing) child concepts were appropriate, we found 231 concepts to be significantly associated with death in the study population. With the abundance of structured EHR data, phenome wide association studies combined with knowledge engineering can be a viable method of rapid hypothesis generation.


Takayasu arteritis: Prevalence and clinical presentation in Switzerland.
Takayasu arteritis (TAK) is a rare immune-mediated vasculitis of the aorta and its branches. Aims were to calculate prevalence and incidence in Switzerland, to assess disease activity and performance of MR-Angiography (MRA). 31 patients were recorded in a database, 27 were followed prospectively up to 3 years. Prevalence was calculated based on data of the national statistical bureau. Disease activity was defined using the revised EULAR criteria. MRA depicted stenotic changes and aortic wall enhancement. A disease prevalence of 14.5/1.000.000 inhabitants and an incidence of 0.3/1.000.000 per year was calculated. Aortic wall enhancement was found in 10 patients while in clinical and serological remission. EULAR criteria missed 5 patients with disease activity with isolated elevations of ESR/CRP. Arterial stenosis did not change over time in 5 cases, it improved in 2 and increased in 7. At follow-up 16 patients were treated with tocilizumab, 11/16 in monotherapy, 5 patients were treatment-free, 25/27 stayed in remission. In addition to prevalence and incidence, our data show that MRA qualifies to detect subclinical disease activity, but, on the other hand, that EULAR criteria may miss disease activity in case of isolated elevation of ESR/CRP.


Hyperchloremic normal gap metabolic acidosis.
Metabolic acidosis is defined as a pathologic process that, when unopposed, increases the concentration of hydrogen ions (H+) in the body and reduces the bicarbonate (HCO3-) concentration. Metabolic acidosis can be of a kidney origin or an extrarenal cause. Assessment of urinary ammonium excretion by calculating the urine anion gap or osmolal gap is a useful method to distinguish between these two causes. Extrarenal processes include increased endogenous acid production and accelerated loss of bicarbonate from the body. Metabolic acidosis of renal origin is due to a primary defect in renal acidification with no increase in extrarenal hydrogen ion production. This situation can occur because either the renal input of new bicarbonate is insufficient to regenerate the bicarbonate lost in buffering endogenous acid as with distal renal tubular acidosis (RTA) or the RTA of renal insufficiency, or the filtered bicarbonate is lost by kidney wasting as in proximal RTA. In either condition, because of loss of either NaHCO3 (proximal RTA) or NaA (distal RTA), effective extracellular volume is reduced and as a result the avidity for chloride reabsorption derived from the diet is increased and results in a hyperchloremic normal gap metabolic acidosis. The RTA of renal insufficiency is also characterized by a normal gap acidosis, however, with severe reductions in the glomerular filtration rate an anion gap metabolic acidosis eventually develops.


Pro-inflammatory, IL-17 pathways dominate the architecture of the immunome in pediatric refractory epilepsy.
Drug refractory epilepsy (RE) is a chronic neurological disease with varied etiology that represents a group of patients whose seizures do not respond to anti-epileptic drugs. The immune system may have a role in seizure and epilepsy development, but the specific mechanisms of inflammation that lead to epileptogenesis and contribute to RE are unknown. Here, we used mass cytometry to comprehensively study the immune system of pediatric patients with RE and compared their immune profile and function with patients with age-matched autoimmune encephalitis (AIE) and healthy controls. Patients with RE and AIE displayed similar immune profiles overall, with changes in CD4+ and CD8+ T-cell subsets and an unbalance toward pro-inflammatory IL-17 production. In addition, patients with RE uniquely showed an altered balance in natural killer cell subsets. A systems level intercellular network analysis identified rewiring of the immune system leading to loss of inhibitory/regulatory intercellular connections and emergence of pro-inflammatory pathogenic functions in neuro-inflammatory immune-cell networks in patients with AIE and RE. These data underscore the contribution of systemic inflammation to the pathogenesis of seizures and epileptogenesis and have direct translational implications in advancing diagnostics and therapeutics design.


Talus fractures: evaluation and treatment.
Fractures of the talus are uncommon. The relative infrequency of these injuries in part accounts for the lack of useful and objective data to guide treatment. The integrity of the talus is critical to normal function of the ankle, subtalar, and transverse tarsal joints. Injuries to the head, neck, or body of the talus can interfere with normal coupled motion of these joints and result in permanent pain, loss of motion, and deformity. Outcomes vary widely and are related to the degree of initial fracture displacement. Nondisplaced fractures have a favorable outcome in most cases. Failure to recognize fracture displacement (even when minimal) can lead to undertreatment and poor outcomes. The accuracy of closed reduction of displaced talar neck fractures can be very difficult to assess. Operative treatment should, therefore, be considered for all displaced fractures. Osteonecrosis and malunion are common complications, and prompt and accurate reduction minimizes their incidence and severity. The use of titanium screws for fixation permits magnetic resonance imaging, which may allow earlier assessment of osteonecrosis; however, further investigation is necessary to determine the clinical utility of this information. Unrecognized medial talar neck comminution can lead to varus malunion and a supination deformity with decreased range of motion of the subtalar joint. Combined anteromedial and anterolateral exposure of talar neck fractures can help ensure anatomic reduction. Posttraumatic hindfoot arthrosis has been reported to occur in more than 90% of patients with displaced talus fractures. Salvage can be difficult and often necessitates extended arthrodesis procedures.


Sulphurous thermal water increases the release of the anti-inflammatory cytokine IL-10 and modulates antioxidant enzyme activity.
The beneficial effects of hot springs have been known for centuries and treatments with sulphurous thermal waters are recommended in a number of chronic pathologies as well as acute recurrent infections. However, the positive effects of the therapy are often evaluated in terms of subjective sense of wellbeing and symptomatic clinical improvements. Here, the effects of an S-based compound (NaSH) and of a specific sulphurous thermal water characterized by additional ions such as sodium chloride, bromine and iodine (STW) were investigated in terms of cytokine release and anti-oxidant enzyme activity in primary human monocytes and in saliva from 50 airway disease patients subjected to thermal treatments. In vitro, NaSH efficiently blocked the induction of pro-inflammatory cytokines and counterbalanced the formation of ROS. Despite STW not recapitulating these results, possibly due to the low concentration of S-based compounds reached at the minimum non-toxic dilution, we found that it enhanced the release of IL-10, a potent anti-inflammatory cytokine. Notably, higher levels of IL-10 were also observed in patients' saliva following STW treatment and this increase correlated positively with salivary catalase activity (r2 = 0.19, *p less than 0.01). To our knowledge, these results represent the first evidence suggesting that S-based compounds and STW may prove useful in facing chronic inflammatory and age-related illness due to combined anti-inflammatory and anti-oxidant properties.


Ascorbic acid may not be involved in cryptochrome-based magnetoreception.
Seventeen years after it was originally suggested, the photoreceptor protein cryptochrome remains the most probable host for the radical pair intermediates that are thought to be the sensors in the avian magnetic compass. Although evidence in favour of this hypothesis is accumulating, the intracellular interaction partners of the sensory protein are still unknown. It has been suggested that ascorbate ions could interact with surface-exposed tryptophan radicals in photoactivated cryptochromes, and so lead to the formation of a radical pair comprised of the reduced form of the flavin adenine dinucleotide cofactor, FAD•-, and the ascorbate radical, Asc•- This species could provide a more sensitive compass than a FAD-tryptophan radical pair. In this study of Drosophila melanogaster cryptochrome and Erithacus rubecula (European robin) cryptochrome 1a, we use molecular dynamics simulations to characterize the transient encounters of ascorbate ions with tryptophan radicals in cryptochrome in order to assess the likelihood of the [FAD•- Asc•-]-pathway. It is shown that ascorbate ions are expected to bind near the tryptophan radicals for periods of a few nanoseconds. The rate at which these encounters happen is low, and it is therefore concluded that ascorbate ions are unlikely to be involved in magnetoreception if the ascorbate concentration is only of the order of 1 mM or less.


Clinical advantages of image-free navigation system using surface-based registration in anatomical anterior cruciate ligament reconstruction.
To evaluate the clinical advantages of a navigation system developed with an emphasis on attaining an appropriate femoral tunnel length and posterior wall margin with no posterior wall blowout, as well as having accurate tunnel positioning, in anatomical anterior cruciate ligament reconstruction (ACLR). Ten freshly frozen human knees were transected at mid-femur and mid-tibia. Each knee specimen underwent arthroscopic single-bundle anterior cruciate ligament reconstruction using the outside-in technique, with two knees by manual ACLR (control group) and another eight knees by only the navigational ACLR without arthroscopic assistance (experimental group). The position/orientation information of tunnel entry point, tunnel length, and posterior wall distance of pre-, intra-, and postoperative tunnel were recorded, and the reliability and errors among them were evaluated. From comparison of the 3D models for preoperative planning and postoperative reconstruction, the mean differences for navigational femoral tunnelling and arthroscopic-assisted femoral tunnelling were recorded, respectively: (1) tunnel entry position, 1.4 mm (SD 0.3) versus 4.9 mm; (2) tunnel length, 0.7 mm (SD 0.2), similar to 0.6 mm in arthroscopic-assisted femoral tunnelling, and (3) posterior wall distance, 0.5 mm (SD 0.2), much smaller than 4.7 mm for arthroscopic-assisted femoral tunnelling. The intraclass correlation coefficients, calculated to determine the accuracy and reliability of navigational femoral tunnelling, showed excellent internal consistency that ranged from 0.965 to 0.989 for tunnel length and from 0.810 to 0.953 for posterior wall distance. Navigation systems with enhancement of the registration accuracy by the developed system are feasible in anatomical ACLR, in reducing surgical failures such as short tunnel length or posterior wall breakage of distal femur. The present study revealed that computer navigation could aid in avoiding major mistakes in exact positioning and posterior wall blowout and help in attaining appropriate length for femoral tunnelling in anatomical ACLR.


Is virtual endoscopy of the middle ear useful?
Virtual endoscopy is a relatively new imaging technology in otology, and therefore data on its efficacy in clinical situations are limited. We conducted a prospective study to evaluate the clinical relevance of radiologic diagnoses based on virtual endoscopy of the middle ear. Our patient population was made up of 30 adults who were scheduled to undergo surgery to correct conductive hearing loss of unknown etiology. Virtual endoscopy was performed on three-dimensional images that were constructed from images obtained with conventional two-dimensional computed tomography (CT). Findings on virtual endoscopy were then compared with the subsequent surgical findings. Virtual endoscopy suggested a middle ear pathology in 19 patients and a normal middle ear in 11 patients. Postoperatively, we found that the virtual diagnoses correlated moderately well with the surgical findings in the group of patients with predicted pathology; 13 of these 19 patients were found to have middle ear problems such as ossicular chain anomalies, otosclerosis, and cholesteatoma (positive predictive value: 68%). However, among the 11 patients whose middle ear structures were radiologically predicted to be normal, only 2 had negative middle ear findings on surgical exploration; of the remaining 9 patients, 8 had otosclerosis and 1 had malleus fixation (negative predictive value: 18%). Thus, the sensitivity and specificity of virtual endoscopy were 59 and 25%, respectively. Virtual endoscopy provides images from a surgeon's perspective, and so it has the potential to be useful in the preoperative evaluation of the middle ear cavity. With ongoing advancements in computer systems and imaging techniques, the cost, reliability, and efficacy of virtual endoscopy may improve. However, further clinical validation and cost-benefit analysis are required before we can determine if it has any additional advantages over conventional two-dimensional CT.


Selling sex in unsafe spaces: sex work risk environments in Phnom Penh, Cambodia.
The risk environment framework provides a valuable but under-utilised heuristic for understanding environmental vulnerability to HIV and other sexually transmitted infections among female sex workers. Brothels have been shown to be safer than street-based sex work, with higher rates of consistent condom use and lower HIV prevalence. While entertainment venues are also assumed to be safer than street-based sex work, few studies have examined environmental influences on vulnerability to HIV in this context. As part of the Young Women's Health Study, a prospective observational study of young women (15-29 years) engaged in sex work in Phnom Penh, we conducted in-depth interviews (n = 33) to explore vulnerability to HIV/STI and related harms. Interviews were conducted in Khmer by trained interviewers, transcribed and translated into English and analysed for thematic content. The intensification of anti-prostitution and anti-trafficking efforts in Cambodia has increased the number of women working in entertainment venues and on the street. Our results confirm that street-based sex work places women at risk of HIV/STI infection and identify significant environmental risks related to entertainment-based sex work, including limited access to condoms and alcohol-related intoxication. Our data also indicate that exposure to violence and interactions with the police are mediated by the settings in which sex is sold. In particular, transacting sex in environments such as guest houses where there is little or no oversight in the form of peer or managerial support or protection, may increase vulnerability to HIV/STI. Entertainment venues may also provide a high risk environment for sex work. Our results indicate that strategies designed to address HIV prevention among brothel-based FSWs in Cambodia have not translated well to street and entertainment-based sex work venues in which increasing numbers of women are working. There is an urgent need for targeted interventions, supported by legal and policy reforms, designed to reduce the environmental risks of sex work in these settings. Future research should seek to investigate sex work venues as risk environments, explore the role of different business models in mediating these environments, and identify and quantify exposure to risk in different occupational settings.


Autocatalytic cleavage of Clostridium difficile toxin B.
Clostridium difficile, the causative agent of nosocomial antibiotic-associated diarrhoea and pseudomembranous colitis, possesses two main virulence factors: the large clostridial cytotoxins A and B. It has been proposed that toxin B is cleaved by a cytosolic factor of the eukaryotic target cell during its cellular uptake. Here we report that cleavage of not only toxin B, but also all other large clostridial cytotoxins, is an autocatalytic process dependent on host cytosolic inositolphosphate cofactors. A covalent inhibitor of aspartate proteases, 1,2-epoxy-3-(p-nitrophenoxy)propane, completely blocked toxin B function on cultured cells and was used to identify its catalytically active protease site. To our knowledge this is the first report on a bacterial toxin that uses eukaryotic signals for induced autoproteolysis to deliver its toxic domain into the cytosol of target cells. On the basis of our data, we present an integrated model for the uptake and inositolphosphate-induced activation of toxin B.


Structural basis for the function of anti-idiotypic antibody in immune memory.
We had earlier proposed a hypothesis to explain the mechanism of perpetuation of immunological memory based on the operation of idiotypic network in the complete absence of antigen. Experimental evidences were provided for memory maintenance through anti-idiotypic antibody (Ab(2)) carrying the internal image of the antigen. In the present work, we describe a structural basis for such memory perpetuation by molecular modeling and structural analysis studies. A three-dimensional model of Ab(2) was generated and the structure of the antigenic site on the hemagglutinin protein H of Rinderpest virus was modeled using the structural template of hemagglutinin protein of Measles virus. Our results show that a large portion of heavy chain containing the CDR regions of Ab(2) resembles the domain of the hemagglutinin housing the epitope regions. The similarity demonstrates that an internal image of the H antigen is formed in Ab(2), which provides a structural basis for functional mimicry demonstrated earlier. This work brings out the importance of the structural similarity between a domain of hemagglutinin protein to that of its corresponding Ab(2). It provides evidence that Ab(2) is indeed capable of functioning as surrogate antigen and provides support to earlier proposed relay hypothesis which has provided a mechanism for the maintenance of immunological memory.


Early Changes in Cortical Emotion Processing Circuits after Mild Traumatic Brain Injury from Motor Vehicle Collision.
Mild traumatic brain injury (mTBI) patients frequently experience emotion dysregulation symptoms, including post-traumatic stress. Although mTBI likely affects cortical activation and structure, resulting in cognitive symptoms after mTBI, early effects of mTBI on cortical emotion processing circuits have rarely been examined. To assess early mTBI effects on cortical functional and structural components of emotion processing, we assessed cortical activation to fearful faces within the first 2 weeks after motor vehicle collision (MVC) in survivors who did and did not experience mTBI. We also examined the thicknesses of cortical regions with altered activation. MVC survivors with mTBI (n = 21) had significantly less activation in left superior parietal gyrus (SPG) (-5.9, -81.8, 33.8; p = 10-3.623), left medial orbitofrontal gyrus (mOFG) (-4.7, 36.1, -19.3; p = 10-3.231), and left and right lateral orbitofrontal gyri (lOFG) (left: -16.0, 41.4, -16.6; p = 10-2.573; right: 18.7, 22.7, -17.7; p = 10-2.764) than MVC survivors without mTBI (n = 23). SPG activation in mTBI survivors within 2 weeks after MVC was negatively correlated with subsequent post-traumatic stress symptom severity at 3 months (r = -0.68, p = 0.03). Finally, the SPG region was thinner in the mTBI survivors than in the non-mTBI survivors (F = 11.07, p = 0.002). These results suggest that early differences in activation and structure in cortical emotion processing circuits in trauma survivors who sustain mTBI may contribute to the development of emotion-related symptoms.


Targeted tissue proteomic analysis of human astrocytomas.
Complicating proteomic analysis of whole tissues is the obvious problem of cell heterogeneity in tissues, which often results in misleading or confusing molecular findings. Thus, the coupling of tissue microdissection for tumor cell enrichment with capillary isotachophoresis-based selective analyte concentration not only serves as a synergistic strategy to characterize low abundance proteins, but it can also be employed to conduct comparative proteomic studies of human astrocytomas. A set of fresh frozen brain biopsies were selectively microdissected to provide an enriched, high quality, and reproducible sample of tumor cells. Despite sharing many common proteins, there are significant differences in the protein expression level among different grades of astrocytomas. A large number of proteins, such as plasma membrane proteins EGFR and Erbb2, are up-regulated in glioblastoma. Besides facilitating the prioritization of follow-on biomarker selection and validation, comparative proteomics involving measurements in changes of pathways are expected to reveal the molecular relationships among different pathological grades of gliomas and potential molecular mechanisms that drive gliomagenesis.


Attenuation of Bleomycin-Induced Pulmonary Fibrosis in Rats with S-Allyl Cysteine.
Pulmonary fibrosis is a complex disease with high mortality and morbidity. As there are currently no effective treatments, development of new strategies is essential for improving therapeutic outcomes. S-allyl cysteine (SAC) is a constituent of aged garlic extract that has demonstrated efficacy as an antioxidant and anti-inflammatory agent. The current study examines the effects of SAC on pulmonary fibrosis induced by a single intratracheal instillation of bleomycin (2.5 mg/kg). SAC was administered to rats as 0.15% SAC-containing diet from seven days prior to instillation up until the conclusion of the experiment (14 days post-instillation). SAC significantly reduced collagen mRNA expression and protein deposition (33.3 ± 2.7 μg/mg and 28.2 ± 2.1 μg/mg tissue in vehicle- and SAC-treated rats, respectively), and decreased fibrotic area, as assessed histologically. In the rats' lungs, SAC also attenuated the increased expression of transforming growth factor-β1 (TGF-β1), a central regulator of myofibroblast recruitment, activation, and differentiation. While bleomycin instillation increased the number of myofibroblasts within the lung mesenchymal area, this change was significantly reduced by SAC treatment. SAC may exert efficacy as an anti-fibrotic by attenuating myofibroblast differentiation through TGF-β1-mediated fibroproliferative processes. Thus, our results indicate SAC may be useful for the prevention or treatment of pulmonary fibrosis.


Levels, trends & predictors of infant & child mortality among Scheduled Tribes in rural India.
The level of infant and child mortality is high among Scheduled Tribes particularly those living in rural areas. This study examines levels, trends and socio-demographic factors associated with infant and child mortality among Scheduled Tribes in rural areas. Data from the three rounds of the National Family Health Survey (NFHS) of India from 1992 to 2006 were analysed to assess the levels and trends of infant and child mortality. Univariate and multivariate Cox proportional hazard model were used to understand the socio-economic and demographic factors associated with mortality during 1992-2006. Significant change was observed in infant and child mortality over the time period from 1992-2006 among Scheduled Tribes in rural areas. After controlling for other factors, birth interval, household wealth, and region were found to be significantly associated with infant and child mortality. Hazard of infant mortality was highest among births to mothers aged 30 yr or more (HR=1.3, 95% CI=1.1-1.7) as compared with births to the mother's aged 20-29 yr. Hazard of under-five mortality was 42 per cent (95% CI=1.3-1.6) higher among four or more birth order compared with the first birth order. The risk of infant dying was higher among male children (HR = 1.2, 95% CI=1.1-1.4) than among female children while male children were at 30 per cent (HR=0.7, 95% CI=0.6-0.7) less hazard of child mortality than female children. Literate women were at 40 per cent (HR=0.6, 95% CI=0.50-0.76) less hazard of child death than illiterate women. Mortality differentials by socio-demographic and economic factors were observed over the time period (1992-2006) among Scheduled Tribes (STs) in rural India. Findings support the need to focus on age at first birth and spacing between two births.


Growth hormone in sports: detecting the doped or duped.
Doping with growth hormone (GH) is banned; however, there is anecdotal evidence that it is widely abused. GH is reportedly often used in combination with anabolic steroids at high doses for several months. Development of a robust test for detecting GH has been challenging since recombinant human 22-kDa GH used in doping is indistinguishable analytically from endogenous GH and there are wide physiological fluctuations in circulating GH concentrations. One approach to GH testing is based on measurement of different circulating GH isoforms using immunoassays that differentiate between 22-kDa and other GH isoforms. Administration of 22-kDa GH results in a change in its abundance relative to other endogenous pituitary GH isoforms. The differential isoform method is, however, limited by its short time window of detection. A second approach that extends the time window of detection is based on detection of increased levels of circulating GH-responsive proteins, such as the insulin-like growth factor (IGF) axis and collagen peptides. As age and gender are the major determinants of variability for IGF-I and the collagen markers, a test based on these markers must take these factors into account. Extensive data now validate the GH-responsive marker approach, and implementation is largely dependent on establishing an assured supply of standardized assays. Robust tests are available to detect GH and enforce the ban on its abuse in sports. Novel approaches that include gene expression and proteomic profiling must continue to be pursued to expand the repertoire of testing approaches available and to maintain deterrence of GH doping.


Patient classification as an outlier detection problem: an application of the One-Class Support Vector Machine.
Pattern recognition approaches, such as the Support Vector Machine (SVM), have been successfully used to classify groups of individuals based on their patterns of brain activity or structure. However these approaches focus on finding group differences and are not applicable to situations where one is interested in accessing deviations from a specific class or population. In the present work we propose an application of the one-class SVM (OC-SVM) to investigate if patterns of fMRI response to sad facial expressions in depressed patients would be classified as outliers in relation to patterns of healthy control subjects. We defined features based on whole brain voxels and anatomical regions. In both cases we found a significant correlation between the OC-SVM predictions and the patients' Hamilton Rating Scale for Depression (HRSD), i.e. the more depressed the patients were the more of an outlier they were. In addition the OC-SVM split the patient groups into two subgroups whose membership was associated with future response to treatment. When applied to region-based features the OC-SVM classified 52% of patients as outliers. However among the patients classified as outliers 70% did not respond to treatment and among those classified as non-outliers 89% responded to treatment. In addition 89% of the healthy controls were classified as non-outliers.


Band structure and quantum conductance of nanostructures from maximally localized Wannier functions: the case of functionalized carbon nanotubes.
We have combined large-scale, tau-point electronic-structure calculations with the maximally localized Wannier functions approach to calculate efficiently the band structure and the quantum conductance of complex systems containing thousands of atoms while maintaining full first-principles accuracy. We have applied this approach to study covalent functionalizations in metallic single-walled carbon nanotubes. We find that the band structure around the Fermi energy is much less dependent on the chemical nature of the ligands than on the sp(3) functionalization pattern disrupting the conjugation network. Common aryl functionalizations are more stable when paired with saturating hydrogens; even when paired, they still act as strong scattering centers that degrade the ballistic conductance of the nanotubes already at low degrees of coverage.


Menstrual-cycle characteristics and work conditions of workers in poultry slaughterhouses and canneries.
The food and agriculture industry employs 14.6% of the female industrial work force in France. Workers are exposed to a variety of environmental and organizational constraints (eg, irregular schedules, cold, uncomfortable postures, repetitive movements). In 1987-1988 a medical examination and questionnaire were administered to 726 workers with menstrual periods in 17 poultry slaughterhouses and six canning factories. Anomalies (irregular cycles, amenorrhea, long cycles) during the previous year were associated with work conditions. After adjustment for relevant nonoccupational variables, irregular cycles were significantly related to schedule variability and cold exposure, amenorrhea was associated with cold exposure, and long cycles with schedule variability. Other parameters such as repetitive work, standing posture, lifting weights, job satisfaction, and hours of domestic work were not associated with cycle anomalies. Cycle anomalies may be a useful indicator of occupational effects on female reproduction, analogous to the use of sperm parameters to warn of effects on male workers.


Towards a Belgian consensus for prevention of perinatal group B streptococcal disease.
In Belgium, as in many other countries, group B Streptococcus (GBS) is still the leading cause of sepsis and meningitis in neonates. In 2001, though no Belgian guidelines for their prevention were available, in some hospitals, obstetrical programmes included a GBS prevention policy. With an aim to reach a Belgian consensus for the prevention of perinatal group B streptococcal disease, a national consensum meeting was organized in 2001. We report here our experience and findings of this meeting. In November 2001, obstetricians, neonatologists, microbiologists and infectious diseases specialists were invited to participate in a GBS symposium. International and Belgian speakers presented epidemiological aspects, argued comparative cost-effectiveness of different approaches for prevention and debated technical and practical problems. Management of neonates with risk factors for GBS disease and progress in GBS vaccines were also included in the programme. Further results about Belgian obstetricians' practice and compliance to a policy for prevention of neonatal GBS diseases, as answered in two mail surveys, were commented and discussed. In an interactive session at the end, each participant was asked to vote on the key points related to the different steps of the ideal prevention strategy to recommend. For the main questions, 94 per cent of participants choose a screening-based approach and 94 per cent shifted from the current use of ampicillin to penicillin as first choice for antimicrobial prophylaxis. Further, 79 per cent voted for an approach with integrated neonatal prophylaxis for selected neonates at high risk for GBS disease and 47 per cent voted for a strategy based on an intrapartum rapid screening-based approach. The state of the question by different speakers, the data from Belgian epidemiology, and the debate about cost-effectiveness of different approaches led to a massive vote in favour of the universal screening-based approach. Based on these results, a working group has been appointed by the Ministry of Health to draft and edit Belgian recommendations for the prevention of perinatal GBS disease.


Testing the short-term effectiveness of primary care referral to online weight loss programmes: A randomised controlled trial.
Guidelines ask health professionals to offer brief advice to encourage weight loss for people living with obesity. We tested whether referral to one of three online programmes could lead to successful weight loss. A total of 528 participants aged ≥18 years with a body mass index of ≥30 kg/m2 were invited via a letter from their GP. Participants were randomised to one of three online weight loss programmes (NHS Weight Loss Plan, Rosemary Online or Slimming World Online) or to a control group receiving no intervention. Participants self-reported weight at baseline and 8 weeks. The primary outcome was weight change in each of the active intervention groups compared with control. We also compared the proportion of participants losing ≥5% or ≥10% of body weight. For Rosemary, Online mean weight loss was modestly greater than control (-1.5 kg [95% confidence interval (CI) -2.3 to -0.6]) and more than three times as many participants in this group lost ≥5% (relative risk [RR] = 3.64, 95% CI: 1.63-8.1). For Slimming World, mean weight loss was not significantly different from control (-0.8 kg [95%CI -1.7 to 0.1]), twice as many participants lost ≥5% (RR = 2.70, 1.17-6.23). There was no significant difference in weight loss for participants using the NHS Weight Loss Plan (-0.4 kg, [95% CI -1.3 to 0.5]), or the proportion losing ≥5% (RR = 2.09, 0.87-5.01). Only one of three online weight loss programmes was superior to no intervention and the effect size modest among participants living with obesity.


Diol-linked microporous networks of cubic siloxane cages.
A new class of inorganic-organic hybrid porous materials has been synthesized by a reaction between octa(hydridosilsesquioxane) (H(8)Si(8)O(12)), which has a double-four-ring (D4R) structure, and various diols, such as 1,3-propanediol (PD), 1,4-cyclohexanediol (CHD), and 1,3-adamantanediol (AD). Solid-state (29) Si magic-angle-spinning NMR spectroscopic analysis confirmed that most of the corner Si-H groups reacted with diols to form Si-O-C bonds with retention of the D4R cage. Nitrogen adsorption-desorption studies showed that the products are microporous solids with high BET surface areas (up to ≈580 m(2) g(-1) for CHD- and AD-linked products). If n-alkanediols are used as linkers, the surface area becomes smaller as the number of carbon atoms is increased. The thermal and hydrolytic stability of the products strongly depend on the type of diol linkers. The highest stabilities are found for the AD-linked products, which are thermally stable up to around 400 °C and remain intact even after being soaked in water for 1 day. In contrast, the PD-linked product is easily hydrolyzed in water to give microporous silica. These results offer a new route toward a series of silica-based porous materials with unique structures and properties.


Phylogenetic relationships between Sarcocystis species from reindeer and other Sarcocystidae deduced from ssu rRNA gene sequences.
Six Sarcocystis species from reindeer (S. grueneri, S. rangi, S. tarandivulpes, S. hardangeri, S. rangiferi and S. tarandi) have previously been genetically characterised. The aim of this study was to identify possible definitive hosts for S. hardangeri, S. rangiferi and S. tarandi by including the six species in phylogenetic analyses of the Sarcocystidae, and also to investigate the phylogenetic relationships between the species from reindeer and those from other hosts. The study also aimed at revealing whether the inclusion of six Sarcocystis species from the same intermediate host would have any effect on previously inferred phylogenetic relationships within the Sarcocystidae. The complete small subunit (ssu) rRNA gene sequences of all six Sarcocystis species from reindeer were used in the phylogenetic analyses along with ssu rRNA gene sequences of 85 other members of the Coccidea. Trees were constructed using Bayesian analysis and maximum likelihood estimations. All six Sarcocystis species from reindeer were placed together with other Sarcocystis species using an even-toed ungulate as their intermediate host. The three canine transmitted species, S. grueneri, S. rangi, S. tarandivulpes, formed a sister group to other Sarcocystis species with a canine definitive host. The position of S. hardangeri on the tree suggested that it uses another type of definitive host than the other Sarcocystis species in this clade. Considering the geographical distribution and infection intensity of S. hardangeri, corvid birds are perhaps its most likely definitive hosts. The phylogenetic position, geographical distribution, prevalence and morphological similarity to feline transmitted Sarcocystis species in closely related Cervidae suggest that the most likely definitive hosts of S. rangiferi and S. tarandi are felines, and in Norway notably the lynx. The overall phylogeny of the Sarcocystidae did not change by the inclusion of the six Sarcocystis species from reindeer. This study suggests that phylogentic analysis can be a useful tool in the search for possible definitive hosts for those Sarcocystis species for which they are unknown and difficult to find solely by other methods.


Interviewing witnesses: Eliciting coarse-grain information.
Eyewitnesses to crimes sometimes report inaccurate fine-grain details but fail to report accessible and potentially accurate coarse-grain details. We asked college students and community members (aged 17 to 62 years) who viewed a video of a simulated crime to answer interviewers' questions at coarse- and fine-grained levels of detail and measured the quantity and accuracy of their responses. Three experiments (overall N = 219) also (a) provided comparative data for participants who were interviewed using the open-ended Self-Administered Interview (Gabbert, Hope, & Fisher, 2009) or one of two "report everything" open-ended procedures, (b) tested the efficacy of the procedure using both written and verbal interviews, and (c) examined the generality of the findings across different encoding stimuli which required variations in the types of cued recall questions asked. Coarse-grain reporting seldom occurred under the free recall interview conditions. Witnesses provided abundant coarse-grain details when required to respond to probes about specific details (i.e., cued recall forced report conditions)-without obvious cost to overall accuracy relative to accuracy of similar detail reported under free recall conditions-regardless of whether they responded on a written questionnaire or in a face-to-face individual interview. These experiments suggest that a procedure that requires cued recall forced reporting of coarse-grain detail may offer potential in certain investigative situations as an adjunct to the widely recommended open-ended forensic interviewing techniques. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Post-translational tyrosine nitration of eosinophil granule toxins mediated by eosinophil peroxidase.
Nitration of tyrosine residues has been observed during various acute and chronic inflammatory diseases. However, the mechanism of tyrosine nitration and the nature of the proteins that become tyrosine nitrated during inflammation remain unclear. Here we show that eosinophils but not other cell types including neutrophils contain nitrotyrosine-positive proteins in specific granules. Furthermore, we demonstrate that the human eosinophil toxins, eosinophil peroxidase (EPO), major basic protein, eosinophil-derived neurotoxin (EDN) and eosinophil cationic protein (ECP), and the respective murine toxins, are post-translationally modified by nitration at tyrosine residues during cell maturation. High resolution affinity-mass spectrometry identified specific single nitration sites at Tyr349 in EPO and Tyr33 in both ECP and EDN. ECP and EDN crystal structures revealed and EPO structure modeling suggested that the nitrated tyrosine residues in the toxins are surface exposed. Studies in EPO(-/-), gp91phox(-/-), and NOS(-/-) mice revealed that tyrosine nitration of these toxins is mediated by EPO in the presence of hydrogen peroxide and minute amounts of NOx. Tyrosine nitration of eosinophil granule toxins occurs during maturation of eosinophils, independent of inflammation. These results provide evidence that post-translational tyrosine nitration is unique to eosinophils.


Libertarian paternalism and health care policy: a deliberative proposal.
Cass Sunstein and Richard Thaler have been arguing for what they named libertarian paternalism (henceforth LP). Their proposal generated extensive debate as to how and whether LP might lead down a full-blown paternalistic slippery slope. LP has the indubitable merit of having hardwired the best of the empirical psychological and sociological evidence into public and private policy making. It is unclear, though, to what extent the implementation of policies so constructed could enhance the capability for the exercise of an autonomous citizenship. Sunstein and Thaler submit it that in most of the cases in which one is confronted with a set of choices, some default option must be picked out. In those cases whoever devises the features of the set of options ought to rank them according to the moral principle of non-maleficence and possibly to that of beneficence. In this paper we argue that LP can be better implemented if there is a preliminary deliberative debate among the stakeholders that elicits their preferences, and makes it possible to rationally defend them.


Primary cilia and kidney injury: current research status and future perspectives.
Cilia, membrane-enclosed organelles protruding from the apical side of cells, can be divided into two classes: motile and primary cilia. During the past decades, motile cilia have been intensively studied. However, it was not until the 1990s that people began to realize the importance of primary cilia as cellular-specific sensors, particularly in kidney tubular epithelial cells. Furthermore, accumulating evidence indicates that primary cilia may be involved in the regulation of cell proliferation, differentiation, apoptosis, and planar cell polarity. Many signaling pathways, such as Wnt, Notch, Hedgehog, and mammalian target of rapamycin, have been located to the primary cilia. Thus primary cilia have been regarded as a hub that integrates signals from the extracellular environment. More importantly, dysfunction of this organelle may contribute to the pathogenesis of a large spectrum of human genetic diseases, named ciliopathies. The significance of primary cilia in acquired human diseases such as hypertension and diabetes has gradually drawn attention. Interestingly, recent reports disclosed that cilia length varies during kidney injury, and shortening of cilia enhances the sensitivity of epithelial cells to injury cues. This review briefly summarizes the current status of cilia research and explores the potential mechanisms of cilia-length changes during kidney injury as well as provides some thoughts to allure more insightful ideas and promotes the further study of primary cilia in the context of kidney injury.


Parental exposure to perfluorobutane sulfonate disturbs the transfer of maternal transcripts and offspring embryonic development in zebrafish.
Parental exposure to perfluorobutane sulfonate (PFBS), an aquatic pollutant of emerging concern, is previously found to impair the embryonic development of offspring. However, the impairing mechanisms remain to clarify. In the present study, adult zebrafish were exposed to 0, 10 and 100 μg/L PFBS for 28 d, after which disturbances in maternal transcript transfer and offspring embryogenesis were investigated. Prior to zygotic genome activation, high-throughput transcriptomic sequencing revealed that parental PFBS exposure significantly altered the transcript profile of maternal origin in offspring eggs, while toxic actions varied as a function of PFBS concentrations. In offspring eggs derived from 10 μg/L exposure group, differential transcripts were mainly associated with the histone-DNA interaction of nucleosome, which would modify the compacted chromatin configuration and accessibility of transcriptional factors to DNA sequences. In this regard, the timing of zygotic genome activation was presumably disrupted. Parental exposure to 100 μg/L PFBS primarily interrupted the maternal transfer of adherens junction transcripts, which was supposed to dysregulate the cell-cell adhesion during early embryo formation. Development and growth of offspring embryos were significantly compromised by parental PFBS exposure, as exemplified by higher mortality, delayed hatching, slower heart rate, reduced body weight and neurobehavioral disorders. Overall, the present study presented the first toxicological evidence about the disturbances of PFBS in maternal transcript transfer, although the inherent linkage between maternal transcript modifications and offspring development defects still needs future works to construct.


Temporal-spatial analysis of the immune response in a murine model of ovalbumin-induced airways inflammation.
The objective of this study was to define phenotypic changes of antigen-presenting cells (APCs) and T cells in a murine model of antigen-induced airways inflammation that involves intraperitoneal sensitization with ovalbumin (OVA)/adjuvant followed by antigen aerosolization. We investigated the APC and T-cell compartments both after sensitization (primary immune response) and after challenge (secondary immune response) at the thoracic lymph nodes (initiation site) and the lung (effector site). Our findings document a major cellular expansion in the lymph nodes after both sensitization and challenge. After sensitization, this expansion was comprised mainly of B cells, a considerable proportion of which expressed B7.2. At this time, T cells were markedly expanded and activated as assessed by CD69 expression; further, although GATA-3 and signal transducer and activator of transcription-6 were expressed at this time point, expression of interleukin (IL)-4, IL-5, and IL-13 messenger RNA (mRNA) levels were marginal. However, in vitro stimulation of lymph-node cells with OVA led to cytokine production. In contrast, 24 h after challenge, but not after sensitization, there was a major expansion of dendritic cells and macrophages in the lungs. This expansion was associated with enhanced expression of both B7.1 and B7.2. We also observed expansion of activated CD3(+)/CD4(+) T cells expressing the T helper-2-associated marker T1/ST2 in the lung, most notably 5 d after challenge. Further, IL-4, IL-5, and IL-13, but not interferon-gamma mRNA were expressed at high levels 3 h after challenge. This study helps to elucidate the "geography" of immune responses generated in a conventional murine model of allergic airways inflammation.


Midtrimester preterm prelabour rupture of membranes (PPROM): expectant management or amnioinfusion for improving perinatal outcomes (PPROMEXIL - III trial).
Babies born after midtrimester preterm prelabour rupture of membranes (PPROM) are at risk to develop neonatal pulmonary hypoplasia. Perinatal mortality and morbidity after this complication is high. Oligohydramnios in the midtrimester following PPROM is considered to cause a delay in lung development. Repeated transabdominal amnioinfusion with the objective to alleviate oligohydramnios might prevent this complication and might improve neonatal outcome. Women with PPROM and persisting oligohydramnios between 16 and 24 weeks gestational age will be asked to participate in a multi-centre randomised controlled trial. random allocation to (repeated) abdominal amnioinfusion (intervention) or expectant management (control). The primary outcome is perinatal mortality. Secondary outcomes are lethal pulmonary hypoplasia, non-lethal pulmonary hypoplasia, survival till discharge from NICU, neonatal mortality, chronic lung disease (CLD), number of days ventilatory support, necrotizing enterocolitis (NEC), periventricular leucomalacia (PVL) more than grade I, severe intraventricular hemorrhage (IVH) more than grade II, proven neonatal sepsis, gestational age at delivery, time to delivery, indication for delivery, successful amnioinfusion, placental abruption, cord prolapse, chorioamnionitis, fetal trauma due to puncture. The study will be evaluated according to intention to treat. To show a decrease in perinatal mortality from 70% to 35%, we need to randomise two groups of 28 women (two sided test, β-error 0.2 and α-error 0.05). This study will answer the question if (repeated) abdominal amnioinfusion after midtrimester PPROM with associated oligohydramnios improves perinatal survival and prevents pulmonary hypoplasia and other neonatal morbidities. Moreover, it will assess the risks associated with this procedure. NTR3492 Dutch Trial Register (http://www.trialregister.nl).


Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial.
The optimal duration of treatment of women with postmenopausal osteoporosis is uncertain. To compare the effects of discontinuing alendronate treatment after 5 years vs continuing for 10 years. Randomized, double-blind trial conducted at 10 US clinical centers that participated in the Fracture Intervention Trial (FIT). One thousand ninety-nine postmenopausal women who had been randomized to alendronate in FIT, with a mean of 5 years of prior alendronate treatment. Randomization to alendronate, 5 mg/d (n = 329) or 10 mg/d (n = 333), or placebo (n = 437) for 5 years (1998-2003). The primary outcome measure was total hip bone mineral density (BMD); secondary measures were BMD at other sites and biochemical markers of bone remodeling. An exploratory outcome measure was fracture incidence. Compared with continuing alendronate, switching to placebo for 5 years resulted in declines in BMD at the total hip (-2.4%; 95% confidence interval [CI], -2.9% to -1.8%; P<.001) and spine (-3.7%; 95% CI, -4.5% to -3.0%; P<.001), but mean levels remained at or above pretreatment levels 10 years earlier. Similarly, those discontinuing alendronate had increased serum markers of bone turnover compared with continuing alendronate: 55.6% (P<.001) for C-telopeptide of type 1 collagen, 59.5% (P < .001) for serum n = propeptide of type 1 collagen, and 28.1% (P<.001) for bone-specific alkaline phosphatase, but after 5 years without therapy, bone marker levels remained somewhat below pretreatment levels 10 years earlier. After 5 years, the cumulative risk of nonvertebral fractures (RR, 1.00; 95% CI, 0.76-1.32) was not significantly different between those continuing (19%) and discontinuing (18.9%) alendronate. Among those who continued, there was a significantly lower risk of clinically recognized vertebral fractures (5.3% for placebo and 2.4% for alendronate; RR, 0.45; 95% CI, 0.24-0.85) but no significant reduction in morphometric vertebral fractures (11.3% for placebo and 9.8% for alendronate; RR, 0.86; 95% CI, 0.60-1.22). A small sample of 18 transilial bone biopsies did not show any qualitative abnormalities, with bone turnover (double labeling) seen in all specimens. Women who discontinued alendronate after 5 years showed a moderate decline in BMD and a gradual rise in biochemical markers but no higher fracture risk other than for clinical vertebral fractures compared with those who continued alendronate. These results suggest that for many women, discontinuation of alendronate for up to 5 years does not appear to significantly increase fracture risk. However, women at very high risk of clinical vertebral fractures may benefit by continuing beyond 5 years. clinicaltrials.gov Identifier: NCT 00398931.


Theoretical and Experimental Study of the Crystal Structures, Lattice Vibrations, and Band Structures of Monazite-Type PbCrO4, PbSeO4, SrCrO4, and SrSeO4.
The crystal structures, lattice vibrations, and electronic band structures of PbCrO4, PbSeO4, SrCrO4, and SrSeO4 were studied by ab initio calculations, Raman spectroscopy, X-ray diffraction, and optical-absorption measurements. Calculations properly describe the crystal structures of the four compounds, which are isomorphic to the monazite structure and were confirmed by X-ray diffraction. Information is also obtained on the Raman- and IR-active phonons, with all of the vibrational modes assigned. In addition, the band structures and electronic densities of states of the four compounds were determined. All are indirect-gap semiconductors. In particular, chromates are found to have band gaps smaller than 2.5 eV and selenates higher than 4.3 eV. In the chromates (selenates), the upper part of the valence band is dominated by O 2p states and the lower part of the conduction band is composed primarily of electronic states associated with the Cr 3d and O 2p (Se 4s and O 2p) states. Calculations also show that the band gap of PbCrO4 (PbSeO4) is smaller than the band gap of SrCrO4 (SrSeO4). This phenomenon is caused by Pb states, which, to some extent, also contribute to the top of the valence band and the bottom of the conduction band. The agreement between experiments and calculations is quite good; however, the band gaps are underestimated by calculations, with the exception of the bang gap of SrCrO4, for which theory and calculations agree. Calculations also provide predictions of the bulk modulus of the studied compounds.