Endothelial progenitor cell mediates transport of hepatitis B.
Hepatitis B virus (HBV) replication has been reported to be involved in many extrahepatic viral disorders; however, the mechanism by which HBV is transinfected into extrahepatic tissues such as myocardium and causes HBV associated myocarditis remains largely unknown. In this study, endothelial progenitor cells (EPCs) were infected by HBV and then transfused into ischemic model of mice. HBV surface and core antigen as well as mutation of HBV particles were detected by immunohistochemistry, fluorescent activated cell sorter and transmission electron microscopy in vitro and in vivo. Human cord blood EPCs, but not human umbilical vein endothelial cells (HUVECs) could be effectively infected by taking up HBV in vitro. HBV envelope surface and core antigen expressions were first detectable in EPCs at day 3 after virus challenge, sustained for up to 11 days, and decreased thereafter. Similarly, the virus particles were the most abundant in EPCs in the first week observed by a transmission electron microscope, and declined in 3 weeks after HBV infection. HBV DNA but not HBV cccDNA in EPCs were detectable even 3 weeks after virus challenge, as shown by PCR analysis. Furthermore, intravenous transplantation of HBV-treated EPCs into myocardial infarction Sprague & Dawley rats model resulted in incorporation of both EPCs and HBV into injured endothelial tissues of capillaries in the ischemic border zone. These results strongly support that EPCs serve as virus carrier mediating HBV trans-infection into the injured myocardial tissues. The findings might suggest a novel mechanism for HBV-associated myocarditis.


Cutting edge: polyinosinic:polycytidylic acid boosts the generation of memory CD8 T cells through melanoma differentiation-associated protein 5 expressed in stromal cells.
Polyinosinic:polycytidylic acid (poly I:C), a synthetic analog of double-stranded viral RNA, serves as a potent adjuvant for vaccination against soluble proteins, pathogens, and tumors. Poly I:C is sensed by both TLR3 in the endosomes and melanoma differentiation-associated protein 5 (MDA5) in the cytoplasm. Although it is known that TLR3 is required for cross-priming of CD8 T cells specific for viral Ags, the role of MDA5 in inducing CD8 T cell responses is still unclear. In this study, we demonstrate that in mice lacking MDA5, the majority of CD8 T cells do not survive after primary immunization with poly I:C and Ag, impairing memory response to subsequent Ag challenge. Furthermore, bone marrow chimera experiments revealed that MDA5 expression in radiation-resistant stromal cells, but not in radiation-sensitive hematopoietic cells, is essential for establishing CD8 T cell memory. We conclude that MDA5 and TLR3 mediate substantially distinct yet complementary functions during poly I:C-mediated activation of Ag-specific CD8 T cell responses.


Schizophrenia Treatment with Second-Generation Antipsychotics: A Multi-Country Comparison of the Costs of Cardiovascular and Metabolic Adverse Events and Weight Gain.
Cardiovascular and metabolic adverse events are costly to treat, and their incidence is increased amongst people with schizophrenia, with different rates observed for second-generation antipsychotics. To inform treatment choice, this study sought to estimate the lifetime costs associated with antipsychotic choice, and how these costs varied across European countries. Systematic searches were conducted to identify evidence on effectiveness and costs. A Markov model was developed to assess the costs of ten antipsychotics: aripiprazole, brexpiprazole, cariprazine, lumateperone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone and ziprasidone. Costs were obtained for seven countries: Italy, Hungary, France, Slovenia, Spain, Sweden and the UK. The costs considered were adverse events (including diabetes, myocardial infarction, stroke and weight gain), drug costs, relapse, treatment discontinuation and schizophrenia management. Two adult populations were modelled; initiating either acute or maintenance treatment, with a lifetime horizon for both. Lurasidone was associated with the lowest lifetime costs amongst patients initiating acute treatment compared to all other atypical antipsychotics considered. The second lowest costs were for ziprasidone. These results were observed for all seven countries. The main drivers of cost differences were rates of diabetes and cardiovascular diseases, which were lowest for lurasidone, followed by ziprasidone then lumateperone. Costs for managing weight gain were lowest for lurasidone and ziprasidone. Similar results were observed for patients initiating maintenance treatment. Diabetes and cardiovascular events are large drivers of lifetime costs for people with schizophrenia. Lurasidone is predicted to have the lowest rates of these adverse events, and so the lowest costs amongst patients initiating acute treatment in seven European countries compared to nine other antipsychotics. Future research should investigate the individual costs of relapse management, including differences in the costs and proportions of hospitalizations.


Morphological and immunohistochemical studies on cleft palates induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in mice.
Morphological and immunohistological examinations were performed to reveal the mechanisms of cleft palate induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). ICR strain mice 8-10 weeks of age were used in the study. TCDD was administered in olive oil on gestation day (GD) 12.5 with gastric tubes at 40 microg/kg. From GD 13.5 to 16.5, palates were examined by scanning electron microscopy (SEM), hematoxyline-eosin (HE) staining, and immunohistochemical staining of FGFR1/2, TGF-beta3, MSX1 and LHX8. In the control group, both of the palatal shelves began elevating on GD 14.0 and finished within 6 h. After the elevation, all of the shelves had completely fused with each other on GD 14.5. In the TCDD-treated group, palatal shelves elevated 1 day later than in the control group. However, all palates had elevated by GD 15.0. After the elevation, the shelves contacted each other and fused; however, they were separated on GD16.0. HE staining showed that medial edge epithelium (MEE) was thinner in the TCDD group than in the control group. MEE observed under a high magnification (x2500) exhibited filopodia-like filaments and the cells were bulged in the control group. In contrast, in the TCDD group, no filaments were observed and the cells were flat with unclear boundaries. Immunohistologically, there were no characteristic findings except for FGFR1. FGFR1 was not expressed in the TCDD group after the fusion phase (GD 14.5). TCDD induces many morphological and molecular changes to MEE cells and causes cleft palates.


Escherichia coli tRNA (Gm18) methyltransferase, TrmH requires the correct localization of its methylation site (G18) in the D-loop for efficient methylation.
TrmH is a eubacterial tRNA methyltransferase responsible for formation of 2'-O-methylguaosine at position 18 (Gm18) in tRNA. In Escherichia coli cells, only 14 tRNA species possess the Gm18 modification. To investigate the substrate tRNA selection mechanism of E. coli TrmH, we performed biochemical and structural studies. E. coli TrmH requires a high concentration of substrate tRNA for efficient methylation. Experiments using native tRNASerCGA purified from a trmH gene disruptant strain showed that modified nucleosides do not affect the methylation. A gel mobility-shift assay reveals that TrmH captures tRNAs without distinguishing between relatively good and very poor substrates. Methylation assays using wild-type and mutant tRNA transcripts revealed that the location of G18 in the D-loop is very important for efficient methylation by E. coli TrmH. In the case of tRNASer, tRNATyr and tRNALeu, the D-loop structure formed by interaction with the long variable region is important. For tRNAGln, the short distance between G18 and A14 is important. Thus, our biochemical study explains all Gm18 modification patterns in E. coli tRNAs. The crystal structure of E. coli TrmH has also been solved, and the tRNA binding mode of E. coli TrmH is discussed based on the structure.


Mechanism of Hexane Displaced by Supercritical Carbon Dioxide: Insights from Molecular Simulations.
Supercritical carbon dioxide (sCO2) has great potential for displacing shale oil as a result of its high solubility and low surface tension and viscosity, but the underlying mechanisms have remained unclear up to now. By conducting equilibrium molecular dynamics (EMD) simulations, we found that the displacing process could be divided into three steps: the CO2 molecules were firstly injected in the central region of shale slit, then tended to adsorb on the SiO2-OH wall surface and mix with hexane, resulting in loose hexane layer on the shale surface, and finally displaced hexane from the wall due to strong interactions between CO2 and wall. In that process, the displacing velocity and efficiency of hexane exhibit parabolic and increased trends with pressure, respectively. To gain deep insights into this phenomenon, we further performed non-equilibrium molecular dynamics (NEMD) simulations and found that both the Onsager coefficients of CO2 and hexane were correlated to increase with pressure, until the diffusion rate of hexane being suppressed by the highly dense distribution of CO2 molecules at 12 MPa. The rapid transportation of CO2 molecules in the binary components (CO2 and hexane) actually promoted the hexane diffusion, which facilitated hexane flowing out of the nanochannel and subsequently enhanced oil recovery efficiency. The displacing process could occur effectively at pressures higher than 7.5 MPa, after which the interaction energies of the CO2-wall were stronger than that of the hexane-wall. Taking displacing velocity and efficiency and hexane diffusion rate into consideration, the optimal injection pressure was found at 10.5 MPa in this work. This study provides detailed insights into CO2 displacing shale oil and is in favor of deepening the understanding of shale oil exploitation and utilization.


Ixekizumab for treating ankylosing spondylitis.
Axial spondyloarthritis (axSpA) is an umbrella term that includes ankylosing spondylitis and nonradiographic axSpA. Presence or absence of definitive sacroiliitis on radiographs differentiates ankylosing spondylitis (also called radiographic axSpA) from nonradiographic axSpA. There is growing evidence that indicates IL-17 pathway is a key contributor to the pathogenesis of axSpA. Ixekizumab (IXE) is an IL-17A inhibitor (IL-17i) with data to support its use in patients with radiographic axSpA. The pharmacologic properties of IXE were reviewed. Data regarding the use and efficacy of IXE in patients with radiographic axSpA were evaluated. Quality life outcomes and safety profiles of IXE were examined as well. By comparison with other chronic inflammatory arthritides, the number of targeted treatment options for axSpA is currently limited to tumor necrosis factor inhibitor (TNFi) and IL-17i secukinumab. IXE has good evidence of improved outcomes in terms of clinical efficacy, patient reported outcomes and imaging outcomes, with an acceptable safety profile in patients with radiographic axSpA. The current results discussed in this article support use of IXE as a treatment option for TNFi naive as well as in subjects with prior inadequate response to or intolerance to TNFi agents.


Effects of methylcyclodextrin on lysosomes.
The cholesterol complexing agent methyl-cyclodextrin (MCD) provides an efficient mean for the removal of cholesterol from biological membranes. In order to study the effects of this agent on the lysosomal membrane in situ, we treated HepG2 cells with MCD and studied the effects of this treatment on lysosomes in isolated fractions. We found that lysosomes prepared from treated cells are more sensitive to various membrane perturbing treatments such as: incubation of lysosomes in isotonic glucose, in hypotonic sucrose or in the presence of the lytic agent glycyl-L-phenylalanine 2-naphthylamide. The lysosomal membrane is also less resistant to increased hydrostatic pressure. Centrifugation methods were used to analyse the effect of MCD on lysosomes. Isopycnic centrifugation in sucrose density gradients demonstrates that the drug induces a reversible density increase of the lysosomes. Our study indicates that extracellularly added MCD can modify the properties of the lysosomal membrane in living cells. It suggests that MCD could be an effective tool to modulate the physical properties of lysosomes within intact cells and to monitor the cellular responses to such modifications.


Wound healing, cellular regeneration and plasticity: the elegans way.
Regeneration and wound healing are complex processes that allow organs and tissues to regain their integrity and functionality after injury. Wound healing, a key property of epithelia, involves tissue closure that in some cases leads to scar formation. Regeneration, a process rather limited in mammals, is the capacity to regrow (parts of) an organ or a tissue, after damage or amputation. What are the properties of organs and the features of tissue permitting functional regrowth and repair? What are the cellular and molecular mechanisms underlying these processes? These questions are crucial both in fundamental and applied contexts, with important medical implications. The mechanisms and cells underlying tissue repair have thus been the focus of intense investigation. The last decades have seen rapid progress in the domain and new models emerging. Here, we review the fundamental advances and the perspectives that the use of C. elegans as a model have brought to the mechanisms of wound healing and cellular plasticity, axon regeneration and transdifferentiation in vivo.


Implementing a new governance model.
Purpose - The purpose of this paper is to discuss the lessons learnt from the process of implementing a new model of governance within Living Well, a New Zealand statutory mental health agency. Design/methodology/approach - It presents the findings from an organisational case study that involved qualitative interviews, meeting observations and document analysis. Archetype theory provided the analytical framework for the research enabling an analysis of both the formal structures and informal value systems that influenced the implementation of the governance model. Findings - The research found that the move to a new governance model did not proceed as planned. It highlighted the importance of staff commitment, the complexity of adopting a new philosophical approach and the undue influence of key personalities as key determining factors in the implementation process. The findings suggest that planners and managers within statutory mental health agencies need to consider the implications of any proposed governance change on existing roles and relationships, thinking strategically about how to secure professional commitment to change. Practical implications - There are ongoing pressures within statutory mental health agencies to improve the efficiency and effectiveness of organisational structures and systems. This paper has implications for how planners and managers think about the process of implementing new governance models within the statutory mental health environment in order to increase the likelihood of sustaining and embedding new approaches to service delivery. Originality/value - The paper presents insights into the process of implementing new governance models within a statutory mental health agency in New Zealand that has relevance for other jurisdictions.


Structural and functional investigation of flavin binding center of the NqrC subunit of sodium-translocating NADH:quinone oxidoreductase from Vibrio harveyi.
Na+-translocating NADH:quinone oxidoreductase (NQR) is a redox-driven sodium pump operating in the respiratory chain of various bacteria, including pathogenic species. The enzyme has a unique set of redox active prosthetic groups, which includes two covalently bound flavin mononucleotide (FMN) residues attached to threonine residues in subunits NqrB and NqrC. The reason of FMN covalent bonding in the subunits has not been established yet. In the current work, binding of free FMN to the apo-form of NqrC from Vibrio harveyi was studied showing very low affinity of NqrC to FMN in the absence of its covalent bonding. To study structural aspects of flavin binding in NqrC, its holo-form was crystallized and its 3D structure was solved at 1.56 Å resolution. It was found that the isoalloxazine moiety of the FMN residue is buried in a hydrophobic cavity and that its pyrimidine ring is squeezed between hydrophobic amino acid residues while its benzene ring is extended from the protein surroundings. This structure of the flavin-binding pocket appears to provide flexibility of the benzene ring, which can help the FMN residue to take the bended conformation and thus to stabilize the one-electron reduced form of the prosthetic group. These properties may also lead to relatively weak noncovalent binding of the flavin. This fact along with periplasmic location of the FMN-binding domains in the vast majority of NqrC-like proteins may explain the necessity of the covalent bonding of this prosthetic group to prevent its loss to the external medium.


Dementia care provision in rural Scotland: service users' and carers' experiences.
There has been global neglect of service users' and carers' experiences of dementia care provision in rural areas. The present paper draws on a qualitative study of service provision for people with dementia and their carers in remote and rural Scotland. It draws on interviews with 15 people with dementia and 16 carers to explore their views about health and social dementia care service provision in rural Scotland. A further 14 carers of people with dementia participated in one of three focus groups. The paper discusses perceived gaps in services as well as positive aspects of dementia service provision which service users attribute to living in a rural area. The important issues this raises for the development of dementia care provision in rural areas are briefly discussed.


Bis[μ-O-isopropyl (4-eth-oxy-phen-yl)dithio-phospho-nato-κ(2) S:S']bis-{[O-iso-propyl (4-eth-oxy-phen-yl)dithio-phos-phonato-κ(2) S,S']mercury(II)}.
The title compound, [Hg2(C11H16O2PS2)4], is a dinuclear complex with a distorted tetra-hedral geometry around each Hg(II) atom. Although the two Hg(II) atoms are surrounded by the same ligand, two different coordination modes are observed: one is chelating and the other bridging. The Hg-S bonds form two distinct pairs of long and short bonds. One pair includes both chelating and bridging Hg-S bonds with approximately equal bond lengths of 2.4042 (8) and 2.3997 (7) Å, respectively. The other pair is significantly longer at 2.9361 (9) and 2.8105 (8) Å, respectively. This pattern forms a center of inversion through the mol-ecule with an equal and opposite effect occurring at the other Hg(II) atom. The S-Hg-S angles vary widely from 76.26 (2) to 154.65 (3)°, indicative of a distorted tetra-hedral arrangement of the S atoms around the Hg(II) atom. The P-S bond lengths are 1.9681 (10) and 2.0519 (11)°, clearly indicating partial double-bond character in the former. The mol-ecule contains an inversion center situated between the two Hg(II) atoms.


[Agency and victimization in the trajectory of women involved in drug trafficking in Rio de Janeiro].
The goal of the present article is to discuss the traditional victimization of women who get involved in criminal activities, focusing on agency and personal initiative as the main motivators. Through the discursive analysis of qualitative interviews with five women with a history in drug trafficking in Rio de Janeiro we sought to capture the dilemmas that characterize the ways in which these women justify their participation in a traditional male activity. At a micro level, the analysis focuses on the rhetoric efficacy of the different positions assumed by the participants(1). At a macro level, the analysis investigates how the participants appropriate different discourses about womanhood in order to give sense to their personal histories(2). The results show that the participants oscillate between appealing to external causes for justifying their choice (such as the lack of options characterizing the trajectory of marginalized populations and the personal involvement with criminal partners) and assuming responsibility for having been involved in drug trafficking. In this case, they often mention the power and respect they used to experience as traffickers as the main motivator for their criminal trajectory.


Stent deformation, physical stress, and drug elution obtained with provisional stenting, conventional culotte and Tryton-based culotte to treat bifurcations: a virtual simulation study.
This study sought to investigate the possible influence of different bifurcation stenting techniques on stent deformation, physical stress, and drug elution using a virtual tool that includes structural, fluid dynamics and drug-eluting numerical models. A virtual bench test based on explicit dynamics modelling was used to simulate procedures on bifurcated coronary vessels performed according to three different stenting techniques: provisional side branch stenting, culotte, and Tryton-based culotte. Geometrical configurations obtained after virtual stenting simulations were used to perform fluid dynamics and drug elution analyses. The results showed that substantially different patterns of mechanical deformation, shear stress and theoretical drug elution were obtained using the different techniques. Compared with conventional culotte, the dedicated Tryton seems to facilitate the intervention in terms of improved access to the main branch and to lower its biomechanical influence on the coronary bifurcation in terms of mechanical and haemodynamic parameters. However, since the Tryton stent is a bare metal stent, the drug elution obtained is lower. Numerical models might successfully complement the information on stenting procedures obtained with traditional approaches such as in vitro bench testing or clinical trials. Devices dedicated to bifurcations may facilitate procedure completion and may result in specific patterns of mechanical stress, regional blood flow and drug elution.


Discrete Convolution-Based Energy Spectrum Configuring Method for the Analysis of the Intrinsic Radiation of 176Lu.
There has been considerable interest in inorganic scintillators based on lutetium due to their favorable physical properties. Despite their advantages, lutetium-based scintillators could face issues because of the natural occurring radioisotope of 176Lu that is contained in natural lutetium. In order to mitigate its potential shortcomings, previous works have studied to understand the energy spectrum of the intrinsic radiation of 176Lu (IRL). However, few studies have focused on the various principal types of photon interactions with matter; in other words, only the full-energy peak according to the photoelectric effect or internal conversion have been considered for understanding the energy spectrum of IRL. Thus, the approach we have used in this study considers other principal types of photon interactions by convoluting each energy spectrum with combinations for generating the spectrum of the intrinsic radiation of 176Lu. From the results, we confirm that the method provides good agreement with the experiment. A significant contribution of this study is the provision of a new approach to process energy spectra induced by mutually independent radiation interactions as a single spectrum.


Evaluation of Curcumin Gel as Adjunct to Scaling & Root Planing in Management of Periodontitis- Randomized Clinical & Biochemical Investigation.
Successful management of periodontitis requires treatment strategy that integrates therapies addressing both pathogen and host aspects of disease etiology. To evaluate sub gingivally applied curcumin gel in treatment of chronic periodontitis based on clinical and biochemical parameters. A randomized, double blind, parallel-group trial was carried out on 30 patients suffering from chronic generalized periodontitis with probing pocket depth≥5mm on at least 4 sites who were then randomly allocated to two groups. Control group was treated with Scaling and Root Planing (SRP) alone while experimental group was treated with SRP followed by subgingival application of curcumin gel. Saliva collection was done and the clinical parameters were recorded at baseline and follow up periods. Saliva analysis for IL-1β was done by ELISA. The statistical differences for the intra-group and intergroup measurements were analyzed by using Mann Whitney test. Spearman's rank correlation coefficient was used to examine the relationship between Interleukin - 1β and clinical parameters. Study elucidated mild adjunctive benefit of curcumin gel in reduction of gingival inflammation for a limited period of time. Though improvement in other clinical parameters was also greater in subjects treated with curcumin gel, results were not statistically different from those treated with SRP alone. None of the subjects who received curcumin gel experienced any adverse effect. Within limitations, it can be concluded that single application of curcumin (turmeric) gel has limited added benefit over scaling and root planing in treatment of chronic periodontitis.


Biobased carbon content of resin extracted from polyethylene composite by carbon-14 concentration measurements using accelerator mass spectrometry.
An estimation procedure for biobased carbon content of polyethylene composite was studied using carbon-14 ((14)C) concentration ratios as measured by accelerated mass spectrometry (AMS). Prior to the measurement, additives and fillers in composites should be removed because they often contain a large amount of biobased carbon and may shift the estimation. Samples of resin with purity suitable for measurement were isolated from composites with a Soxhlet extractor using heated cyclohexanone. After cooling of extraction solutions, the resin was recovered as a fine semi-crystalline precipitate, which was easily filtered. Recovery rates were almost identical (99%), even for low-density polyethylene and linear low-density polyethylene, which may have lower crystallinity. This procedure could provide a suitable approach for estimation of biobased carbon content by AMS on the basis of the standard ASTM D 6866. The biobased carbon content for resin extracted from polyethylene composites allow for the calculation of biosynthetic polymer content, which is an indicator of mass percentage of the biobased plastic resin in the composite.


A Review of Services and Interventions for Runaway and Homeless Youth: Moving Forward.
Research focused on the impact of community-based services and treatment interventions designed to intervene in the lives of runaway and homeless youth has increased in the last two decades in the U.S. and internationally. In light of the tremendous need for identifying effective strategies to end homelessness and its associated problems among youth, this paper summarizes and critiques the findings of the extant literature including U.S., international, and qualitative studies. Thirty-two papers met criteria for inclusion in the review. Among the conclusions are that comprehensive interventions which target the varied and interconnected needs of these youth and families may be worthy of more study than studies that isolate the intervention focus on one problem. Also, more research incorporating design strategies that increase the reliability and validity of study findings is needed. Other preliminary conclusions and future directions are offered.


Host effects on the optically active 4f and 5d levels of Ce3+ in garnets.
When Ce(3+) is doped in a garnet, it substitutes for some cations. The effect of the substitution on the optically active 4f and 5d levels of Ce(3+) can be analyzed in terms of an undistorted substitution followed by a structural relaxation, but, whereas the contribution of the undistorted substitution can be predicted/calculated using the crystallographic structure of the pure garnet, which is at hand, that of the structural relaxation demands the detailed local structure around the Ce(3+) impurity, which is hard to know. Hence the importance of knowing the role of the undistorted substitution. What we study in this paper is the role of the unrelaxed host effects on the 4f and 5d levels of Ce(3+)-doped garnets (i.e. the interactions between Ce and the second and more distant neighbors). When they are added to the (previously studied) unrelaxed first-neighbor effects, they give the contributions of the undistorted substitutions. We performed spin-orbit coupling, relativistic, embedded cluster, wave function based ab initio calculations on the (CeO8)(13-) cluster under the effects of the embedding potentials of 21 selected garnets of Si, Al, and Ga, which have been obtained in this work, using experimental unrelaxed structures of the pure garnets. The calculations reveal that the unrelaxed host effect: (1) produces a red shift of the first 4f → 5d transition and (2) is an important contribution to this transition which plays a very important role in differentiating the values it has in different garnet families. The unrelaxed host effect is found to be responsible for the low value of the first 4f → 5d transition in Ce(3+)-doped Lu2CaMg2Si3O12. It is analyzed in terms of 5d and 4f centroid energy contributions and crystal field splitting contributions in the 21 doped garnets. The effect on the splittings of the 4f and 5d levels is also discussed. The undistorted host approximation is found to give reasonable comparison with experiments, so that it represents a relatively fast way to provide reliable ab initio information on the 4f and 5d levels of Ce(3+) in garnets.


Bariatric surgery, safety and type 2 diabetes.
Obesity and type 2 diabetes (T2D) represent major health concerns in the USA. Weight loss is the most important aspect in T2D management, as it reduces both morbidity and mortality. Available lifestyle, behavioral, and pharmacological strategies provide just mild to moderate weight loss. The greatest degree of T2D prevention or T2D amelioration in obese subjects has been reported in subjects who underwent bariatric surgery. In the current review, we will describe various types of bariatric surgery, related safety profiles, and their effect on T2D, as well as the potential mechanisms involved in the remission of T2D. Finally, we hereby examine whether bariatric surgery may be considered a treatment for T2D in pregnant women, children, adolescents and subjects at least 65 years old.


Human papillomavirus-related diseases of the female lower genital tract: oncogenic aspects and molecular interaction.
The causal role of human papillomavirus (HPV) in all cancers of the uterine cervix has been firmly established biologically and epidemiologically. Most cancers of both the vulva and the vagina are also induced by HPV. Papillomaviruses are perfectly adapted to their natural host tissue, the differentiating epithelial cell of skin or mucosae, and exploit the cellular machinery for their own purposes. The infectious cycle is initiated once the infectious particles reach the basal layer of the epithelium, where they bind to and enter the cells. The critical molecules in the process of virus replication are the viral proteins E6 and E7, which interact with a number of cellular proteins. In experimental system these interactions have been shown to induce proliferation and eventually immortalization and malignant transformation of cells. Binding of E7 to pRb activates the E2F transcription factor, which then triggers the expression of proteins necessary for DNA replication. Unscheduled S-phase would normally lead to apoptosis by the action of p53. However, in HPV-infected cells, this process is counteracted by the viral E6 protein, which targets p53 for proteolytic degradation. Besides blocking p53 function in regulation of apoptosis, high-risk HPV proteins interact with both extrinsic and intrinsic apoptotic pathways. As an aberration of virus infection, constant activity of the viral proteins E6 and E7 leads to increasing genomic instability, accumulation of oncogene mutations, further loss of cell-growth control and ultimately cancer. The immune system uses innate and adaptive immunity to recognize and combat foreign agents that invade the body, but these methods are sometimes ineffective against human papillomavirus. HPV has several mechanisms for avoiding the immune system. Furthermore, HPV infections disrupt cytokine expression with the E6 and E7 oncoproteins, particularly targeting the expression of interferon genes. Approximately 10% of individuals develop a persistent infection, and it is this cohort who is at risk of cancer progression, with the development of high-grade precursor lesions and eventually invasive carcinoma.


Monocular deprivation in humans: a study of identical twins.
Ultrasonic axial length measurements and psychophysical vernier acuity thresholds were determined for a pair of identical human twins, one of whom had been monocularly deprived since birth with a congenital lens opacity. Axial lengths of both eyes in the normal twin and the nondeprived eye in the other twin differed by less than 0.2 mm, whereas the axial measurement of the deprived eye was approximately 2.0 mm longer. Monocular vernier acuity thresholds in the nondeprived eye of the one twin were not significantly different from those obtained in the normal twin. Our findings are consistent with previous reports of increased axial length after monocular deprivation deprivation but do not support the concept of enhanced vernier acuity in the nondeprived eye of monocularly deprived humans.


Granulocyte Colony-Stimulating Factor Mediated Regulation of Early Myeloid Cells in Zebrafish.
Colony-stimulating factor 3 (CSF3), more commonly known as granulocyte colony-stimulating factor (G-CSF), acts via a specific cell surface receptor CSF3R (or G-CSFR) to regulate hematopoiesis, with a particularly key role in the myeloid cell lineage where it impacts the development and function of neutrophilic granulocytes. Zebrafish possess a conserved CSF3R homologue, Csf3r, which is involved in both steady-state and emergency myelopoiesis, as well as regulating early myeloid cell migration. Two CSF3 proteins have been identified in zebrafish, Csf3a and Csf3b. This study investigated the roles of the Csf3a and Csf3b ligands as well as the downstream Janus kinase (JAK) and phosphatidylinositol 3-kinase (PI3K) pathways in mediating the effects of Csf3r in early myeloid cell development and function using gene knockdown and pharmacologic approaches. This study revealed that both Csf3a and Csf3b contribute to the developmental and emergency production of early myeloid cells, but Csf3a is responsible for the developmental migration of early neutrophils whereas Csf3b plays the major role in their wounding-induced migration, differentially participated in these responses, as did several downstream signaling pathways. Both JAK and PI3K signaling were required for developmental production and migration of early myeloid cells, but PI3K signaling was required for emergency production and initial migration in response to wounding, while JAK signaling mediated retention at the site of wounding. This study has revealed both distinct and overlapping functions for Csf3a and Csf3b and the downstream JAK and PI3K signaling pathways in early myeloid cell production and function.


Multiple interactions among the competence proteins of Bacillus subtilis.
Proteins required for transformation of Bacillus subtilis and other competent bacteria are associated with the membrane or reside in the cytosol. Previous work has shown that RecA, ComGA, ComFA and SsbB are directed to the cell poles in competent cells, and that the uptake of transforming DNA occurs preferentially at the poles. We show that ComGA, ComFA, DprA (Smf), SsbB (YwpH), RecA and YjbF (CoiA) are located at the cell poles, where they appear to colocalize. Using fluorescence resonance energy transfer, we have shown that these six competent (Com) proteins reside in close proximity to one another. This conclusion was supported by the effects of com gene knockouts on the stabilities of Com proteins. Data obtained from the com gene knockout studies, as well as information from other sources, extend the list of proteins in the transformation complex to include ComEC and ComEA. Because ComGA and ComFA are membrane-associated, while DprA, SsbB, RecA and YjbF are soluble, a picture emerges of a large multiprotein polar complex, involving both cytosolic and membrane proteins. This complex mediates the binding and uptake of single-stranded DNA, the protection of this DNA from cellular nucleases and its recombination with the recipient chromosome.


Understanding caregivers' decision to vaccinate childhood cancer survivors against COVID-19.
Vaccination against COVID-19 is recommended for childhood cancer survivors (CCS). This study aimed to identify antecedents contributing to caregivers' decisions to vaccinate CCS aged 5-17 years against COVID-19 by applying the Theory of Planned Behavior. Participants in this cross-sectional study completed an online survey assessing caregiver attitudes, subjective norms, perceived behavioral control, intention to vaccinate CCS, CCS vaccination status, COVID-19 health literacy, and frequency of COVID-19 information-seeking. Surveys were completed between May and June 2022 following approval for the emergency use of COVID-19 vaccines among children aged ≥5 years in the U.S. Data were analyzed using unadjusted linear regressions and structural equation modeling. Participants were caregivers (n = 160, 87.5% biological mothers, 75.6% white/non-Hispanic) of CCS (n = 160, 44.4% female, mean (M) = 12.5 years old, M = 8.0 years off treatment). 70.0% (n = 112) of caregivers and 53.8% (n = 86) of CCS received a COVID-19 vaccine. Over one-third (37.5%) of caregivers reported disagreement or indecision about future COVID-19 vaccination for the CCS. Caregivers' intention (β = 0.962; standard error [S.E.] = 0.028; p < 0.001) was highly related to CCS vaccination status. Attitudes (β = 0.568; S.E. = 0.078; p < 0.001) and subjective norms (β = 0.322; S.E. = 0.062; p < 0.001) were associated with intention. Higher frequency of COVID-19 information-seeking (β = 0.313; S.E. = 0.063; p < 0.001) and COVID-19 health literacy (β = 0.234; S.E. = 0.059; p < 0.001) had a positive indirect effect on intention through attitudes and subjective norms. Caregivers' vaccination intentions for minor CCS are highly related to vaccination behavior and shaped by attitudes, subjective norms, COVID-19 health literacy, and frequency of COVID-19 information-seeking. Promoting tailored communication with caregivers of CCS and encouraging them to review reputable sources of information can address their vaccine hesitancy.


Allograft rejection by T cell receptor transgenic mice.
We have used a line of T cell receptor (TcR) transgenic mice, in which a significant portion of CD8+ T cells expresses a TcR that is specific for the minor histocompatibility antigen H-Y presented by the H-2Db Class I molecule, to examine the immune response to H-Y-incompatible skin or pancreatic islet allografts. Our results indicate that, in contrast to the conclusions of previous reports, pancreatic islet endocrine cells are invulnerable or only weakly vulnerable to an H-Y-directed immune response. An even more unexpected finding was that unlike normal female mice of the C57BL/6 background which consistently reject male skin within a few weeks, TcR transgene+ littermates reject male skin only infrequently. Our results are consistent with the conclusion that the inability of H-Y TcR females to reject male skin is due to a deficiency of cells with male-specific helper activity. Long-term acceptance of male grafts by H-Y TcR females leads to a state of T cell hyporesponsiveness to male skin grafts. In addition, T cells harvested from long-term skin acceptors were hyporesponsive to in vitro stimulation by a clonotype-specific monoclonal antibody. Transgenic mice with TcRs having antigenic specificity for defined transplantation antigens provide a unique model for study of the allograft response.


Investigation of the Unusual Ability of the [FeFe] Hydrogenase from Clostridium beijerinckii to Access an O2-Protected State.
[FeFe] hydrogenases are enzymes capable of producing and oxidizing H2 at staggering submillisecond time scales. A major limitation in applying these enzymes for industrial hydrogen production is their irreversible inactivation by oxygen. Recently, an [FeFe] hydrogenase from Clostridium beijerinckii (CbHydA1) was reported to regain its catalytic activity after exposure to oxygen. In this report, we have determined that artificially matured CbHydA1 is indeed oxygen tolerant in the absence of reducing agents and sulfides by means of reaching an O2-protected state (Hinact). We were also able to generate the Hinact state anaerobically via both chemical and electrochemical oxidation. We use a combination of spectroscopy, electrochemistry, and density functional theory (DFT) to uncover intrinsic properties of the active center of CbHydA1, leading to its unprecedented oxygen tolerance. We have observed that reversible, low-potential oxidation of the active center leads to the protection against O2-induced degradation. The transition between the active oxidized state (Hox) and the Hinact state appears to proceed without any detectable intermediates. We found that the Hinact state is stable for more than 40 h in air, highlighting the remarkable resilience of CbHydA1 to oxygen. Using a combination of DFT and FTIR, we also provide a hypothesis for the chemical identity of the Hinact state. These results demonstrate that CbHydA1 has remarkable stability in the presence of oxygen, which will drive future efforts to engineer more robust catalysts for biofuel production.


Pharmacological evaluation of N-allynormetazocine (SKF 10,047) on the basis of its discriminative stimulus properties in the rat.
The purpose of the present experiments was to evaluate the pharmacological properties of the discriminative stimulus effects of the prototypic sigma receptor agonist N-allylnormetazocine (NANM, SKF 10,047). Rats were trained to discriminate between saline and 3.0 or 5.6 mg/kg of NANM in a two-choice, shock-avoidance procedure. NANM-like stimulus control of behavior was produced by the opiates, in order of relative molar potency, cyclazocine greater than NANM greater than N-propylnormetazocine HCI greater than levallorphan greater than dextrorphan greater than pentazocine. Metazocine produced NANM-like discriminative effects but only when tested concomitantly with naloxone. Seven other opiate derivatives, including levorphanol, ethylketazocine and nalorphine, failed to produce NANM-like discriminative stimuli. Among enantiomeric pairs tested in the lower training dose group, d-NANM and l-NANM as well as levallorphan and dextrallorphan were equipotent, but the levo isomers of cyclazocine and pentazocine were more potent than their dextro counterparts, whereas dextrorphan but not levorphanol produced NANM-like discriminative stimuli. In the lower training dose group, the opioid antagonist naloxone failed to antagonize the NANM-like discriminative effects of NANM, l-cyclazocine and levallorphan, although naloxone did produce a parallel shift to the right of the dose-effect curve for pentazocine, and "unmasked" NANM-like effects of higher doses of metazocine. The nonopiate psychoactive drugs phencyclidine and dexoxadrol, but not its enantiomer levoxadrol produced NANM-like discriminative stimuli. Propranolol also occasioned an appreciable percentage of NANM-appropriate responding in the lower training dose group but not the higher dose group. Diazepam, d-amphetamine, d-lysergic acid diethylamide tartrate, imipramine, clonidine and haloperidol also failed to produce NANM-like discriminative stimuli in the lower training dose group. The present results demonstrate that the discriminative stimulus properties of NANM are distinguishable from those of morphine and ethylketazocine but similar to those of dissociative anesthetics such as phencyclidine and lend additional support to the hypothesis that sigma receptors mediate the common actions of NANM and phencyclidine.


A review of neuroendocrine neoplasms of the larynx: update on diagnosis and treatment.
Neuroendocrine neoplasms of the larynx have been divided into those of epithelial or neural origin. The latter consist of paragangliomas while the epithelial origin group can be divided into the typical and atypical carcinoids and small cell neuroendocrine carcinomata, the latter consisting of the oat cell type, the intermediate cell type and the combined cell type. There are now over 500 cases of neuroendocrine neoplasms of the larynx in the literature. The diagnosis is primarily based on light microscopy, and, in some instances, it may be supported by special histochemical studies. It should be confirmed by immunocytochemical and/or ultrastructural investigation. The different biological behaviour of neuroendocrine neoplasms of the larynx makes a specific diagnosis of paramount importance, since treatment depends on diagnostic accuracy. Typical carcinoid is an extremely rare lesion. It is treated preferably by conservative surgery; elective neck dissection is not necessary because of the lack of lymph node metastases at diagnosis. Chemotherapy and/or radiotherapy have not been effective in the limited number of patients treated thus far. Prognosis is excellent with cure following surgery. Atypical carcinoid is the most frequent non-squamous carcinoma of the larynx. The mainstay of treatment is surgery. Elective neck dissection should be performed because of the high likelihood of cervical lymph node metastases. Primary radiation therapy with adjuvant chemotherapy is not indicated. The survival rate is 48 per cent at five years and 30 per cent at 10 years. Although the larynx is one of its most common extrapulmonary sites, small cell neuroendocrine carcinoma is still a rare tumour. Surgical results for this tumour have been disappointing and is reserved for cases of local relapse with no evidence of metastasis. Chemotherapy and radiotherapy currently appear to offer the least disabling and most effective forms of therapy. The two- and five-year survival rates are 16 per cent and five per cent, respectively. Paraneoplastic syndromes have occasionally been reported in association with carcinoid tumours (typical and atypical) and small cell neuroendocrine carcinoma. There have been also rare reports of an elevated neuropeptide serum level. Paraganglioma is the only laryngeal neuroendocrine neoplasm with a female preponderance (3:1). Confusion with atypical carcinoid has led to incorrect diagnosis and inappropriate classification schemes, erroneously suggesting that laryngeal paraganglioma has the potential for aggressive behaviour. Conservative surgery represents the treatment of choice; elective neck dissection is not necessary, and the prognosis is excellent.


The development of a multitarget, multicolor fluorescence in situ hybridization assay for the detection of urothelial carcinoma in urine.
The purpose of this study was to develop a multitarget, multicolor fluorescence in situ hybridization (FISH) assay for the detection of urothelial carcinoma (UC) in urine specimens. Urinary cells obtained from voided urine specimens of 21 patients with UC and 9 normal donors were analyzed with nine different centromere enumeration probes and a single locus-specific indicator probe to determine an optimal set of FISH probes for UC detection. The four probes with the greatest sensitivity for UC detection were then labeled with a unique fluorophore and combined into a single probe set. The probes with the greatest combined sensitivity for UC detection were CEP3, CEP7, CEP17, and the 9p21 (P16) LSI. This probe set was used to evaluate urine specimens acquired from 179 patients for prospective testing (46 with biopsy-proven UC). FISH slides were evaluated by scanning the slide for cells with nuclear features suggestive of malignancy and assessing the FISH signal pattern of these cells for polysomy (ie, gains of two or more different chromosomes). A receiver operator characteristic curve revealed that a cutoff of 5 cells with polysomy as the positive criterion for cancer resulted in an overall sensitivity of 84.2% for patients with biopsy-proven UC and a specificity of 91.8% among patients with genitourinary disorders but no evidence of UC. This study demonstrates that a multitarget, multicolor FISH assay containing centromeric probes to chromosomes 3, 7, and 17 and a locus-specific probe to band 9p21 has high sensitivity and specificity for the detection of UC in voided urine specimens.


Enhancing public health programs with performance-based memorandum of understanding.
This Viewpoint presents a case study that explored the effects of using a performance-based Memorandum of Understanding (MoU) in public health donor programs to enhance health metrics, program efficiency, and accountability. The MoU between Kebbi State Government in Nigeria and the United States Agency for International Development (USAID) focused on strengthening primary healthcare. It covered Health Systems Strengthening (HSS) indicators, overseen by an Operations Committee (OC) and a high-level Steering Committee (SC). Quarterly and biannual reviews tracked indicators through a dashboard developed by the Integrated Health Program (IHP). Results suggest that the MoU led to better monitoring of primary healthcare (PHC) revitalization, health sector work plan harmonization, and data quality. Dashboard tracking showed improved health facility financing, immunization, antenatal care, and skilled attendants at births. The use of the MoU demonstrated potential for boosting program efficiency, cost-effectiveness, and political commitment for resource mobilization in public health initiatives. Results support recommending MoUs as valuable tools for effective outcome-driven public health funding.


The relationship between improved prognosis in gastric cancer patients in the last 25 years and changing methods of surgical and combined treatment.
Poland is among the countries with the high morbidity and mortality rates for gastric carcinoma (GC). The differences of GC biology depending on the geographical regions were suggested. In the literature, there are no reports from detailed clinicopathologic studies carried out in large series of GC patients in Poland. Based on the prospectively collected data of 3696 GC patient treated surgically between 1977-1999, potentially significant prognostic factors were analyzed to assess their prognostic value, and their time related distribution during the over 20-year period of the study. The mean age of the patients was 59.0 (SD 11.6) years and ranged from 20 to 93 years. The male-to-female ratio was 2.3. Overall cumulative 5-year survival was 0.28 (for early GC 0.85) and significantly increased over the period of study. Among factors analyzed the depth of invasion, lymph nodes status, tumor size, age, UICC-R classification and rate of involved to removed lymph nodes are of statistically significant and most important prognostic value. In the over 20-year period of study the rate of diffuse type carcinoma acc. to Lauren increased but the tumor locations did not changed significantly. The rate of early GC did not change throughout the period of study but number of most advanced cases decreased. Chemo- and chemotherapy improved outcomes in some groups of patients. The basic clinicopathologic profile of Polish patients is similar to the reported in Western Europe and Japan, except for significantly higher early GC occurrence in Japan. According to the obtained results the prognosis of GC depends clearly upon the stage of the disease at the time of surgery. The improvement of outcomes during over 20 years of GC study in Poland was due to introducing better diagnosis and routine multimodal treatment.


The Relationship between Disordered Eating Pathology, Sense of Coherence and Body Image among Adolescent Boys in Israel.
Disordered eating pathology (DEP) and body dissatisfaction are well-documented risk factors for eating disorders and have become more prevalent among adolescent males. The sample consisted of 256 Israeli boys, in grades 8-12. Participants completed questionnaires measuring, Sense of Coherence (SOC), Body Shape (BSQ), Eating attitudes (EAT-26), and the Eating Disorder Inventory (EDI-2). Findings revealed low levels of DEP among adolescent boys. Younger adolescents (grade 8-9) had higher levels of clinically relevant DEP than older adolescents (grade 10-12). SOC was negatively associated with DEP and a significant interaction for age and SOC emerged with younger age being associated with both lower levels of SOC and higher DEP. These results demonstrate a low overall prevalence rate of DEP among adolescent boys and is consistent with the developmental literature relating to SOC and mental health and in contrast with a similar population of girls documented in Israel and the US.


Uncovering the Anticancer Potential of Murine Cytomegalovirus against Human Colon Cancer Cells.
Human cytomegalovirus (HCMV) components are often found in tumors, but the precise relationship between HCMV and cancer remains a matter of debate. Pro-tumor functions of HCMV were described in several studies, but an association between HCMV seropositivity and reduced cancer risk was also evidenced, presumably relying on recognition and killing of cancer cells by HCMV-induced lymphocytes. This study aimed at deciphering whether CMV influences cancer development in an immune-independent manner. Using immunodeficient mice, we showed that systemic infection with murine CMV (MCMV) inhibited the growth of murine carcinomas. Surprisingly, MCMV, but not HCMV, also reduced human colon carcinoma development in vivo. In vitro, both viruses infected human cancer cells. Expression of human interferon-β (IFN-β) and nuclear domain (ND10) were induced in MCMV-infected, but not in HCMV-infected human colon cancer cells. These results suggest a decreased capacity of MCMV to counteract intrinsic defenses in the human cellular host. Finally, immunodeficient mice receiving peri-tumoral MCMV therapy showed a reduction of human colon cancer cell growth, albeit no clinical sign of systemic virus dissemination was evidenced. Our study, which describes a selective advantage of MCMV over HCMV to control human colon cancer, could pave the way for the development of CMV-based therapies against cancer.


Lactoferrin interacts with deoxyribonucleic acid: a preferential reactivity with double-stranded DNA and dissociation of DNA-anti-DNA complexes.
LF was found to bind to deoxyribonucleic acid as assessed by immunofluorescence studies on cell nuclei, affinity chromatography of DNA on immobilized LF, and gel chromatography of an LF-DNA reaction mixture. LF immobilized on Sepharose 4-B was reacted with 125I-labeled DNA in both its double-stranded and single-stranded configurations; dsDNA eluted with a 0.69M NaCl buffer, whereas ssDNA eluted with a 0.25M NaCl buffer. Additional evidence for a preferential reactivity with dsDNA was provided by the enzymatic treatment of preformed dsDNA-LF and ssDNA-LF complexes with S1 endonuclease, and DNAse 1--DNase digestion alone liberated free LF. The interaction of LF with DNA partially inhibited the binding of anti-DNA antibodies from patients with SLE, as assayed in a standard Farr assay. Furthermore, DNA-anti-DNA (labeled with 125I-IgG) complexes could be dispersed in vitro by the addition of LF. It is hypothesized that the release of LF by neutrophils chemotactically attracted to DNA-anti-DNA complexes may act as a feedback loop to modulate the inflammatory response in SLE.


Chapter 16: Asthma in pregnancy.
The course of asthma during pregnancy may be affected by maternal physiological changes and triggers of asthma such as viral infections, exposure to allergens, and nonadherence with therapy. If asthma is uncontrolled, there are recognized harmful effects not only to the mother but also to the fetus. However, with effective asthma control, most women have outcomes, at or near that of the general population. Many medications are considered appropriate for use in pregnancy including inhaled corticosteroids (ICSs) such as budesonide, beclomethasone dipropionate, and fluticasone and the leukotriene receptor antagonists montelukast and zafirlukast. When ICSs or ICS/long-acting beta(2)-adrenergic agonist combinations are not effective during exacerbations of asthma, short courses of oral corticosteroids should be administered earlier rather than later. Spirometry and flow volume loop tracings are useful measures of pulmonary function for gravidas. Results may be compared with nonpregnant reference values. Vocal cord dysfunction may be suspected when the inspiratory loop is truncated. The gravida does not reject the fetus because of lack of vascular continuity, a trophoblast layer causing separation, and suppressive mechanisms at the placental interface. The secretion of IL-10 increases in pregnancy and is lower in women with recurrent spontaneous abortions. Only immunoglobulin G (IgG) subclasses are transported across the placenta, especially IgG1, IgG3, and IgG4. Fetal B cells can produce endogenous IgE by 20 weeks of gestation.


International randomized clinical trial, stroke inpatient rehabilitation with reinforcement of walking speed (SIRROWS), improves outcomes.
Feedback about performance may optimize motor relearning after stroke. Develop an international collaboration to rapidly test the potential efficacy of daily verbal feedback about walking speed during inpatient rehabilitation after stroke, using a protocol that requires no research funds. This phase 2, single-blinded, multicenter trial randomized inpatients to either feedback about self-selected fast walking speed (daily reinforcement of speed, DRS) immediately after a single, daily 10-m walk or to no reinforcement of speed (NRS) after the walk, performed within the context of routine physical therapy. The primary outcome was velocity for a 15.2-m (50-foot) timed walk at discharge. Secondary outcomes were walking distance in 3 minutes, length of stay (LOS), and level of independence (Functional Ambulation Classification, FAC). Within 18 months, 179 participants were randomized. The groups were balanced for age, gender, time from onset of stroke to entry, initial velocity, and level of walking-related disability. The walking speed at discharge for DRS (0.91 m/s) was greater (P = .01) than that for NRS (0.72 m/s). No difference was found for LOS. LOS for both DRS and NRS was significantly shorter, however, for those who had mean walking speeds >0.4 m/s at entry. The DRS group did not have a higher proportion of FAC independent walkers (P = .1) and did not walk longer distances ( P = .09). An Internet-based collaboration of 18 centers found that feedback about performance once a day produced gains in walking speed large enough to permit unlimited, slow community ambulation at discharge from inpatient rehabilitation.


The mouse mutant "motheaten." II. Functional studies of the immune system.
Motheaten mice have normal levels of T lymphocytes but reduced levels of B lymphocytes. Those B cells that are present show an impaired proliferative response to B cell mitogens and no plaque-forming cell response to thymus-independent antigens. T lymphocyte function is also defective in motheaten mice, as assayed by the proliferative responses to T cell mitogens, and by the capacity to develop cytotoxic killer cells against allogeneic cells. Motheaten mice possess spleen cells capable of suppressing normal B cell responses to thymus-independent antigens. This suppressor cell is not sensitive to anti-Thy-1 antibody plus complement treatment but is partially removed by adherence on plastic. Overall, the motheaten mouse suffers a functional severe combined immunodeficiency of both B and T cells, even though these cells are present. We postulate that the inescapable lethality of the motheaten defect is due to the lack of immunocompetence during the critical developmental period before adulthood and perhaps to an autoaggressive component as well.


Hydrogen sulfide modulates the release of nitric oxide and VEGF in human keratinocytes.
Hydrogen sulfide (H(2)S) is a novel signaling molecule with both pro- or anti-inflammatory effect. The present study aimed to: (i) characterize the in vitro effects of H(2)S on human keratinocyte's proliferation and death; (ii) investigate the ability of H(2)S to modulate VEGF and NO production; (iii) examine the intracellular signaling pathways involved in VEGF and NO modulatory effect. We found that exogenous application of H(2)S (NaHS and GYY4137 as H(2)S donors) significantly enhances NO through increase of iNOS, in a manner Akt-dependent. The increment in NO down-regulates ERK1/2 activation thereby resulting in the decrease of VEGF release. We suggest that H(2)S-releasing agents may be promising therapeutics for chronic inflammatory disorders of the skin, i.e. psoriasis, in which NO increases as well as anti-VEGF treatments have been suggested to be novel effective approaches.


Management of dengue in Australian travellers: a retrospective multicentre analysis.
To describe the epidemiology, clinical and laboratory features and outcomes of dengue in returned Australian travellers, applying the revised WHO dengue classification (2009) to this population. Retrospective case series analysis of confirmed dengue cases hospitalised at one of four Australian tertiary hospitals, January 2012 - May 2015. Clinical features, laboratory findings and outcomes of patients with dengue; dengue classification according to 2009 WHO guidelines. 208 hospitalised patients (median age, 32 years; range, 4-76 years) were included in the study. Dengue was most frequently acquired in Indonesia (94 patients, 45%) and Thailand (40, 19%). The most common clinical features were fever (98% of patients) and headache (76%). 84 patients (40%) met the WHO criteria for dengue with warning signs, and one the criteria for severe dengue; the most common warning signs were mucosal bleeding (44 patients, 21%) and abdominal pain (43, 21%). Leukopenia (176 patients, 85%), thrombocytopenia (133, 64%), and elevated liver enzyme levels (154, 76%) were the most common laboratory findings. 46 patients (22%) had serological evidence of previous exposure to dengue virus. WHO guidelines were documented as a management benchmark in ten cases (5%); 46 patients (22%) received non-steroidal anti-inflammatory drugs (NSAIDs). A significant proportion of returning Australian travellers hospitalised for dengue have unrecognised warning signs of severe disease. Many received NSAIDs, which can increase the risk of haemorrhage in dengue. As travel to Asia from Australia continues to increase, it is vital for averting serious outcomes that clinicians can recognise and manage dengue.


Water-borne testosterone levels predict exploratory tendency in male poison frogs.
Hormones play a fundamental role in mediating social behaviors of animals. However, it is less well understood to what extent behavioral variation between individuals can be attributed to variation in underlying hormonal profiles. The goal of the present study was to infer if individual androgen levels, and/or the modulation thereof, can explain among-individual variation in aggressiveness, boldness and exploration. We used as a model the dart-poison frog Allobates femoralis and took repeated non-invasive water-borne hormonal samples of individual males before (baseline) and after (experimental) a series of behavioral tests for assessing aggression, boldness, and exploratory tendency. Our results show that androgen levels in A. femoralis are quite stable across the reproductive season. Repeatability in wbT baseline levels was high, while time of day, age of the frog, and trial order did not show any significant impact on measured wbT levels. In general, experimental wbT levels after behavioral tests were lower compared to the respective baseline levels. However, we identified two different patterns with regard to androgen modulation in response to behavioral testing: individuals with low baseline wbT tended to have increased wbT levels after the behavioral testing, while individuals with comparatively high baseline wbT levels rather showed a decrease in hormonal levels after testing. Our results also suggest that baseline wbT levels are linked to the personality trait exploration, and that androgen modulation is linked to boldness in A. femoralis males. These results show that differences in hormonal profiles and/or hormonal modulation in response to social challenges can indeed explain among-individual differences in behavioral traits.


Regression of ocular adnexal lymphoma after Chlamydia psittaci-eradicating antibiotic therapy.
Some infectious agents contributing to lymphomagenesis have been considered targets for new therapeutic strategies. Chlamydia psittaci DNA has been detected in 80% of ocular adnexal lymphomas. The present pilot study was carried out to assess whether C psittaci-eradicating antibiotic therapy is associated with tumor regression in ocular adnexal lymphomas. Nine patients with C psittaci-positive marginal-zone B-cell lymphoma of the ocular adnexa at diagnosis or relapse were treated with doxycycline 100 mg, bid orally, for 3 weeks. The presence of C psittaci DNA in peripheral-blood mononuclear cells (PBMCs) was also assessed before and after treatment in seven patients. Objective lymphoma regression was assessed 1, 3, and 6 months after therapy conclusion and every 6 months during follow-up. All patients completed antibiotic therapy with excellent tolerability. At 1 month from doxycycline assumption, chlamydial DNA was no longer detectable in PBMCs of all four positive patients. Objective response was complete in two patients, partial response (> 50%) was observed in two patients, and minimal response (< 50%) was observed in three patients. Duration of response in the seven responders was 12+, 29+, 31+, 8+, 7+, 2+, and 1+ months, respectively. C psittaci-eradicating antibiotic therapy with doxycycline is followed by objective response in patients with ocular adnexal lymphoma, even after multiple relapses of the disease. A confirmatory, large, phase II trial is warranted to confirm whether this fast, cheap, and well-tolerated therapy could replace other more aggressive strategies as first-line treatment against ocular adnexal lymphomas.


Structure of the apoptosome: mechanistic insights into activation of an initiator caspase from Drosophila.
Apoptosis is executed by a cascade of caspase activation. The autocatalytic activation of an initiator caspase, exemplified by caspase-9 in mammals or its ortholog, Dronc, in fruit flies, is facilitated by a multimeric adaptor complex known as the apoptosome. The underlying mechanism by which caspase-9 or Dronc is activated by the apoptosome remains unknown. Here we report the electron cryomicroscopic (cryo-EM) structure of the intact apoptosome from Drosophila melanogaster at 4.0 Å resolution. Analysis of the Drosophila apoptosome, which comprises 16 molecules of the Dark protein (Apaf-1 ortholog), reveals molecular determinants that support the assembly of the 2.5-MDa complex. In the absence of dATP or ATP, Dronc zymogen potently induces formation of the Dark apoptosome, within which Dronc is efficiently activated. At 4.1 Å resolution, the cryo-EM structure of the Dark apoptosome bound to the caspase recruitment domain (CARD) of Dronc (Dronc-CARD) reveals two stacked rings of Dronc-CARD that are sandwiched between two octameric rings of the Dark protein. The specific interactions between Dronc-CARD and both the CARD and the WD40 repeats of a nearby Dark protomer are indispensable for Dronc activation. These findings reveal important mechanistic insights into the activation of initiator caspase by the apoptosome.


Dihydrotestosterone Induces Proliferation, Migration, and Invasion of Human Glioblastoma Cell Lines.
Glioblastomas (GBM) are the most frequent and aggressive human brain tumors due to their high capacity to migrate, invade healthy brain tissue, and resist anticancer therapies. It has been reported that testosterone (T) levels are higher in patients with GBM than in healthy controls. It has also been dem{}onstrated that T induces proliferation, migration, and invasion of human GBM cell lines. T is mainly metabolized to 5α-dihydrotestosterone (DHT) by the enzyme 5α-reductase (5αR), but the role of this metabolite in GBM cells is unknown. The expression of 5αR isoenzymes and AR in biopsies of GBMs was determined by the analysis of TCGA. U87 and U251 GBM cell lines were grown in supplemented DMEM. For evaluating the expression of AR in U251 and U87 cells, a RT-qPCR was performed. The cells were treated with T, DHT, finasteride (FIN), dutasteride (D), and the combined treatments, FIN+T and D+T or vehicle. After treatments, the viability was quantified by the trypan blue exclusion assay, the proliferation was evaluated by BrdU incorporation, and migration and invasion were analyzed by the scratch-wound and the transwell assays, respectively. In a set of glioma biopsies from TCGA, we observed that SRD5A2 (5αR2) expression was higher in GBM and in low-grade gliomas than in normal brain tissue. We observed that DHT and T increased proliferation, migration, and invasion of human GBM cell lines: U87 and U251. F and D, drugs that inhibit 5αR activity, blocked the effects of T on GBM cells. These data suggest that T induces human GBM progression through its conversion into DHT. These results can be related to the chemical structure of DHT, which increases its affinity for AR and decreases five times the rate of dissociation compared to T. Also, it is possible that DHT mediates the effects of T on cell human GBM cells motility by changing the expression of genes involved in tumor infiltration.


[Detection of RS viral sequences in otitis media effusion from children].
The role of respiratory syncytial virus (RS virus) in otitis media with effusion was studied. Reverse transcriptase-polymerase chain reaction (RT-PCR) and nested polymerase chain reaction (Nested PCR) were used to provide accurate methods for detection of RS viral sequences in the otitis media effusion from children. We could find RS viral sequences in 10/12 samples tested which had been collected during and even after natural outbreak of RSV in the community. These observations suggest RS virus as an important factor in the pathogenesis of otitis media with effusion. The disturbance of the local humoral and cell-mediated immune response in the middle ear accompanied with RS virus infection may lead to the development of infection-induced inflammation and ventilatory compromise, development of suppurative and effusion, multiplication of low virulence pathogens and subsequent development of mucosal damage.


Enzymatic release of dipeptidyl peptidase-4 inhibitors (gliptins) from pigeon pea (Cajanus cajan) nutrient reservoir proteins: In silico and in vitro assessments.
In silico and in vitro parameters were used to assess the potential of pigeon pea (Cajanus cajan) nutrient reservoir proteins as sources of dipeptidyl peptidase (DPP)-4 inhibitors. In silico, 40 pigeon pea proteins evaluated had 46% of amino acids associated with DPP-4 inhibition. After virtual hydrolysis, pepsin had the highest frequency of release and bioactivity of released DPP-4 inhibiting peptides, compared to papain and thermolysin. In vitro, thermolysin released the most active DPP-4 inhibitors. The protein hydrolysates contained similar amino acids but different particle sizes. Thus, the bioactivity patterns are attributable to the different nature and behavior of proteins/peptides under actual and virtual conditions. Using eight physicochemical variables, a random forest model with moderate prediction accuracy was developed for predicting DPP-4 inhibitory activity of papain hydrolysates. The findings demonstrate that proteins from pigeon pea are precursors of DPP-4 inhibitors, with potential use in formulating functional food for managing type 2 diabetes. PRACTICAL APPLICATIONS: The emerging use of in silico simulations to predict bioactivity of peptides can provide a framework to direct further wet lab assessments. This pattern can enhance focusing on factors relevant to the bioactive properties of interest. However, there is still limited evidence to confirm the reliability and accuracy of this tool. This study therefore provides insight into the practical use of in silico simulations to predict bioactivity of food peptides by assessing the factors relevant to the enzymatic release of dipeptidyl peptidase-4 inhibitors from pigeon pea seed storage proteins and validating the findings with wet lab assessment. This work also provides important information that can enhance the utilization of pigeon pea, which is an orphan crop, in developing functional food products for managing type 2 diabetes mellitus in developing countries.


Evanescent field waveguide sensing with subwavelength grating structures in silicon-on-insulator.
We explore, to the best of our knowledge, the potential of diffractionless subwavelength grating waveguides for sensing applications. We show that by subwavelength patterning of silicon-wire waveguides the field delocalization can be engineered to increase the sensitivity. Fully vectorial 3D-FDTD simulations confirm the sensitivity enhancement, achieving sensitivities of 0.83 RIU/RIU and 1.5·10(-3) RIU/nm for bulk and surface sensing, respectively, which compare favorably to state-of-the-art sensing waveguides.


Unilateral chronic subdural hematoma due to spontaneous intracranial hypotension: a report of four cases.
Background: Chronic subdural hematoma (CSDH) is a common neurosurgical disease. A subset of patients with CSDH may exhibit underlying spontaneous intracranial hypotension (SIH). Bilateral CSDH has a causal relationship with SIH, but there is no known causal relationship between unilateral CSDH and SIH.Case description: We encountered four cases of unilateral CSDH due to SIH. The patients' age ranged between 44 and 64 years; there were three males and one female. All patients presented with headache as their initial symptom, and then became comatose. Computed tomography demonstrated unilateral CSDH and transtentorial herniation in all patients. Treatments were emergency epidural blood patch (EBP) and evacuation of CSDH. The site of cerebrospinal fluid leak could not be identified in three patients; therefore, EBP was performed at upper and lower spine. All patients recovered from SIH; however, one patient experienced poor outcome due to Duret hemorrhage and ischemic complications of transtentorial herniation. Cranial asymmetry was present in all four patients, and unilateral CSDH was located on the side of the most curved cranial convexity.Conclusions: Unilateral CSDH, asymmetric cranial morphology, and transtentorial herniation in relatively young patients may indicate underlying SIH.


Stereotactic radiotherapy for neovascular age-related macular degeneration: 52-week safety and efficacy results of the INTREPID study.
To determine the safety and efficacy of low-voltage, external-beam, stereotactic radiotherapy (SRT) for patients with neovascular age-related macular degeneration (nvAMD). Randomized, double-masked, sham-controlled, multicenter, clinical trial. Two hundred thirty patients with onset of nvAMD within 3 years who received 3 or more injections of ranibizumab or bevacizumab within the preceding year and who needed continuing ranibizumab or bevacizumab treatment. Participants were randomized 2:1:2:1 to 16 Gy plus pro re nata (PRN) ranibizumab, sham 16 Gy plus PRN ranibizumab, 24 Gy plus PRN ranibizumab, or sham 24 Gy plus PRN ranibizumab, respectively. The primary efficacy end point was the mean number of ranibizumab injections at 52 weeks. Secondary end points were change in mean best-corrected visual acuity (VA), loss of fewer than 15 Early Treatment Diabetic Retinopathy Study letters, gain of 0 or more and 15 or more letters, and change in angiographic total lesion size and choroidal neovascularization (CNV) lesion size. Both the 16-Gy and 24-Gy SRT arms received significantly fewer ranibizumab treatments compared with the sham arms: mean number of treatments, 2.64 (median, 2), 2.43 (median, 2), and 3.74 (median, 3.5), respectively (P = 0.013 and P = 0.004, respectively, vs. sham). Change in mean VA was -0.28, +0.40, and -1.57 letters for the 16-Gy, 24-Gy, and sham arms, respectively. The 16-Gy, 24-Gy, and sham arms lost fewer than 15 letters in 93%, 89%, and 91% of eyes, respectively, with 53%, 57%, and 56% gaining 0 or more letters, respectively, and 4% gaining 15 letters or more in all arms. Mean total angiographic lesion area changed by -1.15 mm(2), +0.49 mm(2), and +0.75 mm(2), respectively; mean CNV lesion area decreased by 0.16 mm(2), 0.18 mm(2), and 0.10 mm(2), respectively. Optical coherence tomography central subfield thickness decreased by 85.90 μm, 70.39 μm, and 33.51 μm, respectively. The number of adverse events (AEs) and number of serious AEs (SAEs) were similar across arms. No AEs were attributed to radiation. No SAEs occurred in the study eye. A single dose of SRT significantly reduces ranibizumab retreatment for patients with nvAMD, with a favorable safety profile at 1 year. Whereas chronic nvAMD typically results in loss of VA over time, SRT is associated with relatively well-preserved VA over 1 year. Proprietary or commercial disclosure may be found after the references.


Interlocking intramedullary nailing in femoral shaft fractures. A report of forty-eight cases.
We treated forty-eight femoral-shaft fractures in forty-seven patients with the Grosse-Kempf interlocking intramedullary nail. Fifteen fractures were transverse or short oblique, ten were long oblique or spiral, and twenty-three were comminuted. Only twenty-four (50 per cent) of the fractures were located in the middle one-third of the shaft. The median time until full weight-bearing was thirty days (range, seven to 150 days). Radiographic consolidation was seen in all fractures at a median of sixteen weeks (range, nine to fifty-six weeks). The patients were followed for one to four years, and no infections developed. The results in thirty fractures were classified as excellent; in eight, as good; in seven, as fair; and in two, as poor. We have found the Grosse-Kempf method to be useful in treating patients with high-energy fractures, multiple injuries, open fractures, and osteoporosis. Since there is a risk of rotational and longitudinal instability with the dynamic method of interlocking nailing, we recommend that the static method be used whenever there is doubt about the stability of the fracture. We did not observe any delay in bone-healing when the static method was used.


Effectiveness of disease-management programs for improving diabetes care: a meta-analysis.
We conducted a meta-analysis of randomized controlled trials to assess the effectiveness of disease-management programs for improving glycemic control in adults with diabetes mellitus and to study which components of programs are associated with their effectiveness. We searched several databases for studies published up to December 2009. We included randomized controlled trials involving adults with type 1 or 2 diabetes that evaluated the effect of disease-management programs on glycated hemoglobin (hemoglobin A₁(C)) concentrations. We performed a meta-regression analysis to determine the effective components of the programs. We included 41 randomized controlled trials in our review. Across these trials, disease-management programs resulted in a significant reduction in hemoglobin A₁(C) levels (pooled standardized mean difference between intervention and control groups -0.38 [95% confidence interval -0.47 to -0.29], which corresponds to an absolute mean difference of 0.51%). The finding was robust in the sensitivity analyses based on quality assessment. Programs in which the disease manager was able to start or modify treatment with or without prior approval from the primary care physician resulted in a greater improvement in hemoglobin A₁(C) levels (standardized mean difference -0.60 v. -0.28 in trials with no approval to do so; p < 0.001). Programs with a moderate or high frequency of contact reported a significant reduction in hemoglobin A₁(C) levels compared with usual care; nevertheless, only programs with a high frequency of contact led to a significantly greater reduction compared with low-frequency contact programs (standardized mean difference -0.56 v. -0.30, p = 0.03). Disease-management programs had a clinically moderate but significant impact on hemoglobin A₁(C) levels among adults with diabetes. Effective components of programs were a high frequency of patient contact and the ability for disease managers to adjust treatment with or without prior physician approval.


Ischemia detection with a self-organizing map supplemented by supervised learning.
The problem of maximizing the performance of the detection of ischemia episodes is a difficult pattern classification problem. The motivation for developing the supervising network self-organizing map (sNet-SOM) model is to exploit this fact for designing computationally effective solutions both for the particular ischemic detection problem and for other applications that share similar characteristics. Specifically, the sNet-SOM utilizes unsupervised learning for the "simple" regions and supervised for the "difficult" ones in a two stage learning process. The unsupervised learning approach extends and adapts the self-organizing map (SOM) algorithm of Kohonen. The basic SOM is modified with a dynamic expansion process controlled with an entropy based criterion that allows the adaptive formation of the proper SOM structure. This extension proceeds until the total number of training patterns that are mapped to neurons with high entropy reduces to a size manageable numerically with a capable supervised model. The second learning phase has the objective of constructing better decision boundaries at the ambiguous regions. At this phase, a special supervised network is trained for the computationally reduced task of performing the classification at the ambiguous regions only. The utilization of sNet-SOM with supervised learning based on the radial basis functions and support vector machines has resulted in an improved accuracy of ischemia detection especially in the last case. The highly disciplined design of the generalization performance of the support vector machine allows designing the proper model for the number of patterns transferred to the supervised expert.


Oleuropein aglycone stabilizes the monomeric α-synuclein and favours the growth of non-toxic aggregates.
α-synuclein plays a key role in the pathogenesis of Parkinson's disease (PD); its deposits are found as amyloid fibrils in Lewy bodies and Lewy neurites, the histopathological hallmarks of PD. Amyloid fibrillation is a progressive polymerization path starting from peptide/protein misfolding and proceeding through the transient growth of oligomeric intermediates widely considered as the most toxic species. Consequently, a promising approach of intervention against PD might be preventing α-synuclein build-up, misfolding and aggregation. A possible strategy involves the use of small molecules able to slow down the aggregation process or to alter oligomer conformation favouring the growth of non-pathogenic species. Here, we show that oleuropein aglycone (OleA), the main olive oil polyphenol, exhibits anti-amyloidogenic power in vitro by interacting with, and stabilizing, α-synuclein monomers thus hampering the growth of on-pathway oligomers and favouring the growth of stable and harmless aggregates with no tendency to evolve into other cytotoxic amyloids. We investigated the molecular basis of such interference by both biophysical techniques and limited proteolysis; aggregate morphology was monitored by electron microscopy. We also found that OleA reduces the cytotoxicity of α-synuclein aggregates by hindering their binding to cell membrane components and preventing the resulting oxidative damage to cells.


Multiple systems for motor skill learning.
Motor learning is a ubiquitous feature of human competence. This review focuses on two particular classes of model tasks for studying skill acquisition. The serial reaction time (SRT) task is used to probe how people learn sequences of actions, while adaptation in the context of visuomotor or force field perturbations serves to illustrate how preexisting movements are recalibrated in novel environments. These tasks highlight important issues regarding the representational changes that occur during the course of motor learning. One important theme is that distinct mechanisms vary in their information processing costs during learning and performance. Fast learning processes may require few trials to produce large changes in performance but impose demands on cognitive resources. Slower processes are limited in their ability to integrate complex information but minimally demanding in terms of attention or processing resources. The representations derived from fast systems may be accessible to conscious processing and provide a relatively greater measure of flexibility, while the representations derived from slower systems are more inflexible and automatic in their behavior. In exploring these issues, we focus on how multiple neural systems may interact and compete during the acquisition and consolidation of new behaviors. Copyright © 2010 John Wiley & Sons, Ltd. This article is categorized under: Psychology > Motor Skill and Performance.


Pharmacokinetics and pharmacodynamics of antibacterials, antifungals, and antivirals used most frequently in neonates and infants.
Antimicrobials and antivirals are widely used in young infants and neonates. These patients have historically been largely excluded from clinical trials and, as a consequence, the pharmacokinetics and pharmacodynamics of commonly used antibacterials, antifungals, and antivirals are incompletely understood in this population. This review summarizes the current literature specific to neonates and infants regarding pharmacokinetic parameters and changes in neonatal development that affect antimicrobial and antiviral pharmacodynamics. Specific drug classes addressed include aminoglycosides, aminopenicillins, cephalosporins, glycopeptides, azole antifungals, echinocandins, polyenes, and guanosine analogs. Within each drug class, the pharmacodynamics, pharmacokinetics, and clinical implications and future directions for prototypical agents are discussed. β-Lactam antibacterial activity is maximized when the plasma concentration exceeds the minimum inhibitory concentration for a prolonged period, suggesting that more frequent dosing may optimize β-lactam therapy. Aminoglycosides are typically administered at longer intervals with larger doses in order to maximize exposure (i.e., area under the plasma concentration-time curve) with gestational age and weight strongly influencing the pharmacokinetic profile. Nonetheless, safety concerns necessitate therapeutic drug monitoring across the entire neonatal and young infant spectrum. Vancomycin, representing the glycopeptide class of antibacterials, has a long history of clinical utility, yet there is still uncertainty about the optimal pharmacodynamic index in neonates and young infants. The high degree of pharmacokinetic variability in this population makes therapeutic drug monitoring essential to ensure adequate therapeutic exposure. Among neonates treated with the triazole agent fluconazole, it has been speculated that loading doses may improve pharmacodynamic target attainment rates. The use of voriconazole necessitates therapeutic drug monitoring and dose adjustments for patients with hepatic dysfunction. Neonates treated with lipid-based formulations of the polyene amphotericin B may be at an increased risk of death, such that alternative antifungal agents should be considered for neonates with invasive fungal infections. Alternative antifungal agents such as micafungin and caspofungin also exhibit unique pharmacokinetic considerations in this population. Neonates rapidly eliminate micafungin and require nearly three times the normal adult dose to achieve comparable levels of systemic exposure. Conversely, peak caspofungin concentrations have been reported to be similar among neonates and adults. However, both of these drugs feature favorable safety profiles. Recent studies with acyclovir have suggested that current dosing regimens may not result in therapeutic central nervous system concentrations and more frequent dosing may be required for neonates at later postmenstrual ages. Though ganciclovir and valganciclovir demonstrate excellent activity against cytomegalovirus, they are associated with significant neutropenia. In summary, many pharmacokinetic and pharmacodynamic studies have been conducted in this vulnerable population; however, there are also substantial gaps in our knowledge that require further investigation. These studies will be invaluable in determining optimal neonatal dosing regimens that have the potential to improve clinical outcomes and decrease adverse effects associated with antimicrobial and antiviral treatments.


Association of serum 25-hydroxyvitamin D (25-OHD) concentrations with maternal sex steroids and IGF-1 hormones during pregnancy.
Vitamin D may influence circulating levels of sex steroid hormones in women during reproductive life, but associations in pregnant women have not been explored. Correlation and linear regression models were used to assess the association between sex steroids, (estradiol, progesterone, 17-hydroxyprogesterone, testosterone, and androstenedione), IGF-1, and serum 25-hydroxyvitamin D (25-OHD) concentrations during the first trimester of pregnancy in 106 cancer-free women from the Finnish Maternity Cohort. There was no significant association of serum 25-OHD with any of the hormones measured. One-unit increase in serum 25-OHD concentration was associated with a non-significant 6% increase in estradiol concentrations. Multiparous women had higher levels of vitamin D (40.4 vs. 32.9 nmol/L, p-value = 0.01) than primiparous women. Our study does not support an association between maternal serum 25-OHD levels and sex steroids or IGF-I concentrations during the first trimester of pregnancy.


Social Isolation and Loneliness in a Population Study of Cognitive Impairment: The MYHAT Study.
In this study, we examined associations of social isolation and loneliness with cognitive impairment among older adults from a Rust Belt region in Southwest Pennsylvania. We used data from the population-based Monongahela-Youghiogheny Healthy Aging Team (MYHAT) study. We found that (a) 11 items combined into two reliable composites of social isolation and loneliness; (b) unique to this study, providing unpaid help to others was an indicator of reduced social isolation; (c) social isolation and loneliness were positively associated with cognitive impairment; and (d) these associations were appreciably attenuated by general health and physical functional status and depressive symptoms, respectively. We concluded that social isolation and loneliness are differentially associated with older adults' cognitive health, and that their effects might operate through separate pathways. Approaches to address social isolation and loneliness should consider the community context and its implications for older adults' cognitive health.


Molecular characterization of silver-stearate nanoparticles (AgStNPs): A hydrophobic and antimicrobial material against foodborne pathogens.
In this study, silver-stearate nanoparticles (AgStNPs) have been produced from silver nitrate solutions by replacing the nitrate by stearate ions and then reducing by thermal treatment. AgStNPs were characterized by particle size, zeta-potential, ATR-FTIR, contact angle and SEM (scanning electron microscopy) analyses. The mean particle size and zeta potential of AgStNPs were determined to be 69.22±7.30nm and +8.02±0.88mV. ATR-FTIR analysis showed characteristic IR bands of stearate, revealing the two strong peaks at 2848 and 2915cm-1 associated to symmetric (νs(CH2)) and asymmetric (νas(CH2)) stretching vibrations of methylene groups, respectively. On the other hand, the scissoring and rocking modes of methylene group were observed at 1470 and 718cm-1, respectively. Nanomorphological characterization by SEM revealed a layered morphology of AgStNPs. Contact angle measurements demonstrated that a contact angle of water drop on glass coated with AgStNPs was found to be 108.76°, which proved the strong hydrophobic properties of AgStNPs. AgStNPs seemed to be very effective in inhibiting foodborne pathogens (Salmonella Typhimurium, Escherichia coli O157:H7, Staphylococcus aureus, Listeria monocytogenes and Candida albicans). The results suggest the use of AgStNPs as a coating material to reduce biofilm or biofouling formation in terms of achieving appropriate food contact surfaces and higher hygiene/easier sanitation due to their strong hydrophobic and antimicrobial properties.


Oxcarbazepine in the maintenance treatment of bipolar disorder.
Some studies have suggested that oxcarbazepine has a role in preventing episode recurrence in bipolar affective disorder. This review attempted to investigate the existing evidence from randomised controlled trials for its use in the maintenance treatment of this illness. To review the efficacy of oxcarbazepine, relative to placebo and other agents, in the prevention of affective episodes of bipolar affective disorder. The efficacy of oxcarbazepine was considered in terms of episode recurrence, general and social functioning. Adverse effects, overall acceptability to participants and mortality were also considered. CCDANCTR-Studies and CCDANCTR-References were searched on 7/11/2007. Medline, CENTRAL, EMBASE and PsycINFO were searched in March 2007. Specialist journals and conference proceedings were handsearched. Reference lists of relevant papers and major textbooks of affective disorder were checked. Authors, experts in the field and pharmaceutical companies were contacted requesting information on published or unpublished trials. Randomised controlled trials comparing oxcarbazepine with placebo or alternative agents, where the stated intent of intervention was the maintenance treatment of bipolar affective disorder were sought. Participants with bipolar disorder, male and female, of all ages, were included. Data were extracted from the original reports individually by two review authors. The methodological quality of included studies was assessed individually by two review authors. The main outcomes were the efficacy of oxcarbazepine maintenance treatment in preventing or attenuating further episodes of bipolar affective disorder (including its efficacy in rapid cycling disorder), the acceptability of oxcarbazepine treatment to participants, the prevalence of side-effects, and mortality, if any, on oxcarbazepine treatment. Where appropriate, data concerning outcome measures and adverse effects were to be extracted from the studies and analysed using Review Manager software. Two randomised controlled trials were found that met the methodological criteria for inclusion in the review. However, they did not report data with sufficient clarity to allow their confident extraction for inclusion in the meta-analysis. Findings from the two studies were presented descriptively. There is an insufficient methodologically rigorous evidence base to provide guidance on the use of oxcarbazepine in the maintenance treatment of bipolar disorder. Given the need for more efficacious therapeutic agents, there is a need for good quality randomised controlled trials examining the therapeutic potential of this and related agents in bipolar disorder.


Outcomes after Multiligament Knee Injury Reconstruction using Novel Graft Constructs and Techniques.
Clinical outcomes after reconstruction for multiligamentous knee injury (MLKI) can be consistently favorable. However, recent implants and technique advances may allow for improvement in outcomes. Our institution has developed novel graft constructs and techniques for reconstructions with preclinical data supporting clinical use. Our study purpose was to assess clinical outcomes after reconstruction for MKLI using our constructs and techniques. Overall success rate, failure/revision rates, return to work (RTW)/return to sports (RTS) rates, and complications were evaluated testing the hypothesis that novel methods would be associated with clinical benefits with respect to applications and outcomes compared with historical results. We reviewed a single-surgeon, longitudinal database of 42 patients who underwent multiligament reconstruction at our institution using these techniques for at least two-ligament injuries. Visual analogue scale (VAS) pain score and PROMIS (patient-reported outcomes measurement information system) were collected preoperatively and postoperatively at a minimum 1-year follow-up. Among these patients, 33 patients (mean age of 28.9 years, mean body mass index (BMI) of 33.2 kg/m2, mean follow-up of 14.2 months) were included for outcomes analyses. With the definition of success as having a VAS score of less than or equal to 2 without revision/salvage surgery due to recurrent/residual instability or arthritis, overall success rate was 88% (29/33). The mean VAS scores improved from 5 ± 2 to 2 ± 2. The mean preoperative PROMIS mental health score was 36.2 ± 7, general health was 33.5 ± 6, pain was 62.7 ± 8, and physical function score was 29.4 ± 3. At the final follow-up, PROMIS MH was 50.2 ± 10, GH was 44.4 ± 9, pain was 54.3 ± 9, and PF was 42.6 ± 8.4. Return to work rate was 94% (31/33), and 52% (17/33) of patients were able to RTS at any level. Our results demonstrated excellent clinical outcomes associated with a primary success rate of 88% and RTW rate of 94%. Intraoperative complications occurred in 9.5% of cases and revision and failure rates were 9% and 3%, respectively. Our initial results suggest that multiligament reconstructions using novel graft constructs and techniques are safe and effective and can be considered an appropriate option for reconstruction of the full clinical spectrum of MLKIs.