Distinct effects of Hedgehog signaling on neuronal fate specification and cell cycle progression in the embryonic mouse retina.
Cell-extrinsic signals can profoundly influence the production of various neurons from common progenitors. Yet mechanisms by which extrinsic signals coordinate progenitor cell proliferation, cell cycle exit, and cell fate choices are not well understood. Here, we address whether Hedgehog (Hh) signals independently regulate progenitor proliferation and neuronal fate decisions in the embryonic mouse retina. Conditional ablation of the essential Hh signaling component Smoothened (Smo) in proliferating progenitors, rather than in nascent postmitotic neurons, leads to a dramatic increase of retinal ganglion cells (RGCs) and a mild increase of cone photoreceptor precursors without significantly affecting other early-born neuronal cell types. In addition, Smo-deficient progenitors exhibit aberrant expression of cell cycle regulators and delayed G(1)/S transition, especially during the late embryonic stages, resulting in a reduced progenitor pool by birth. Deficiency in Smo function also causes reduced expression of the basic helix-loop-helix transcription repressor Hes1 and preferential elevation of the proneural gene Math5. In Smo and Math5 double knock-out mutants, the enhanced RGC production observed in Smo-deficient retinas is abolished, whereas defects in the G(1)/S transition persist, suggesting that Math5 mediates the Hh effect on neuronal fate specification but not on cell proliferation. These findings demonstrate that Hh signals regulate progenitor pool expansion primarily by promoting cell cycle progression and influence cell cycle exit and neuronal fates by controlling specific proneural genes. Together, these distinct cellular effects of Hh signaling in neural progenitor cells coordinate a balanced production of diverse neuronal cell types.


Hemorrhagic lumbar synovial cyst.
Synovial cysts of the lumbar spine are an uncommon cause of back and radicular pain. These cysts most frequently present as back pain, followed by chronic progressive radiculopathy or gradual onset of symptoms secondary to spinal canal compromise. Although less common, they can also present with acute spinal cord or root compression symptoms. We report of a case in which hemorrhaging into a right L2-3 facet synovial cyst caused an acute onset of back pain and radiculopathy, requiring surgical excision.


Within-plant signalling via volatiles overcomes vascular constraints on systemic signalling and primes responses against herbivores.
Plant volatiles play important roles in signalling between plants and insects, but their role in communication among plants remains controversial. Previous research on plant-plant communication has focused on interactions between neighbouring plants, largely overlooking the possibility that volatiles function as signals within plants. Here, we show that volatiles released by herbivore-wounded leaves of hybrid poplar (Populus deltoides x nigra) prime defences in adjacent leaves with little or no vascular connection to the wounded leaves. Undamaged leaves exposed to volatiles from wounded leaves on the same stem had elevated defensive responses to feeding by gypsy moth larvae (Lymantria dispar L.) compared with leaves that did not receive volatiles. Volatile signals may facilitate systemic responses to localized herbivory even when the transmission of internal signals is constrained by vascular connectivity. Self-signalling via volatiles is consistent with the short distances over which plant response to airborne cues has been observed to occur and has apparent benefits for emitting plants, suggesting that within-plant signalling may have equal or greater ecological significance than signalling between plants.


Cloning of human anti-IgE autoantibodies and their role in the regulation of IgE synthesis.
In vivo experiments using anti-IgE antibodies have clearly documented that they inhibit IgE production. In vitro experiments showed that not only IgE synthesis but also the effector phase of the allergic response may be influenced, because anti-IgE antibodies can prevent basophil sensitization with IgE or even remove IgE-receptor-bound IgE molecules. However, the question remains whether naturally occurring anti-IgE autoantibodies possess similar biological activity. To generate such antibodies for the necessary in vitro studies, we have cloned human Ig variable genes and selected anti-IgE antibodies using phage display libraries. Most of the human anti-IgE antibodies were anti-idiotypes, but anti-isotypes were also isolated.


Associations between peripheral artery disease and ischemic stroke: implications for primary and secondary prevention.
Although peripheral artery disease (PAD) has a particularly poor prognosis compared with vascular disease in other territories, little attention is paid to its epidemiology, treatment, and prevention. Despite the high prevalence of PAD in patients with stroke, and of stroke in patients with PAD, PAD is omitted from all guidelines for treatment, prevention, and rehabilitation of stroke, although coronary artery disease risk is considered. Therefore, routine PAD screening is seldom undertaken and so disease is probably often missed. Summary of Review- This review evaluates epidemiology of PAD in patients with stroke and of stroke in patients with PAD. The role of the ankle-brachial pressure index; imaging and novel markers in risk prediction of PAD in patients with stroke; and treatment and prevention of PAD are reviewed. In both primary and secondary prevention settings, PAD indicates a high risk of future events. Data on which additional preventive measures are beneficial in this patient group are lacking, but the presence of PAD does have implications for current management in both primary and secondary prevention of stroke.


Qualitative differences in the spatiotemporal brain states supporting configural face processing emerge in adolescence in autism.
Studying the neural processing of faces can illuminate the mechanisms of compromised social expertise in autism. To resolve a longstanding debate, we examined whether differences in configural face processing in autism are underpinned by quantitative differences in the activation of typical face processing pathways, or the recruitment of non-typical neural systems. We investigated spatial and temporal characteristics of event-related EEG responses to upright and inverted faces in a large sample of children, adolescents, and adults with and without autism. We examined topographic analyses of variance and global field power to identify group differences in the spatial and temporal response to face inversion. We then examined how quasi-stable spatiotemporal profiles - microstates - are modulated by face orientation and diagnostic group. Upright and inverted faces produced distinct profiles of topography and strength in the topographical analyses. These topographical profiles differed between diagnostic groups in adolescents, but not in children or adults. In the microstate analysis, the autistic group showed differences in the activation strength of normative microstates during early-stage processing at all ages, suggesting consistent quantitative differences in the operation of typical processing pathways; qualitative differences in microstate topographies during late-stage processing became prominent in adults, suggesting the increasing involvement of non-typical neural systems with processing time and over development. These findings suggest that early difficulties with configural face processing may trigger later compensatory processes in autism that emerge in later development.


Follicular dendritic cell sarcoma: a report of six cases and a review of the Chinese literature.
The main purpose of this study is to broaden the clinicopathological spectrum and increase recognition of follicular dendritic cell sarcoma (FDCS) through analysis of the clinical and pathological features of 50 cases. The clinicopathological features of total 50 cases of FDCS were analyzed including a review of 44 cases reported in Chinese literature before October 2009 and six original cases from the pathology files conducted by the authors. The youngest patient came under observation in this study is only seven years old. Including the cases contributed by the authors, our literary review indicated that male dominated the tumor cases (M: F = 3: 2). 28 cases (56%) present with this disease in extranodal sites. Tumor cells demonstrated positive staining for the follicular dendritic cell markers CD21 (47/49), CD35 (43/45), CD23 (20/23) and CD68 (23/25). In situ hybridization for Epstein-Barr virus-encoded RNA was performed in 10 cases. Nevertheless, EBV expression was absent in all these cases. The follow-up analysis of all cases shows that 26 (81.2%) patients were alive and disease free; 6 (18.8%) patients were alive with recurrent disease or metastasis; and nobody had died of this disease at the time of last follow-up. The diagnosis of the FDCS is based on the findings of morphology and immunohistochemistry. The FDCS occurred in China should be viewed and treated as a low-grade sarcoma, and the role of the EBV in the pathogenesis of this tumor is still uncertain. There is a possibility that the tumor might be racial or geographic correlated, because most cases were reported from Eastern Asia area; it's particular the case of the liver or spleen tumor.


Assessing National Biodiversity Trends for Rocky and Coral Reefs through the Integration of Citizen Science and Scientific Monitoring Programs.
Reporting progress against targets for international biodiversity agreements is hindered by a shortage of suitable biodiversity data. We describe a cost-effective system involving Reef Life Survey citizen scientists in the systematic collection of quantitative data covering multiple phyla that can underpin numerous marine biodiversity indicators at high spatial and temporal resolution. We then summarize the findings of a continental- and decadal-scale State of the Environment assessment for rocky and coral reefs based on indicators of ecosystem state relating to fishing, ocean warming, and invasive species and describing the distribution of threatened species. Fishing impacts are widespread, whereas substantial warming-related change affected some regions between 2005 and 2015. Invasive species are concentrated near harbors in southeastern Australia, and the threatened-species index is highest for the Great Australian Bight and Tasman Sea. Our approach can be applied globally to improve reporting against biodiversity targets and enhance public and policymakers' understanding of marine biodiversity trends.


[Contemporary therapy of chronic obstructive pulmonary disease and its new directions].
Chronic obstructive pulmonary disease (COPD) gives rise to substantial structural changes in the respiratory tract and lungs with the development of chronic inflammation and bronchiolitis, as well as pulmonary parenchymatous destruction and the formation of emphysema. The listed changes substantiate the development of new treatment techniques, which will help correct structural changes in the respiratory tract and will slow down or even reverse progressive worsening of the respiratory function. In the future, the development of blood and/or saliva infection of inflammation biomarkers (e.g. endogenic protease inhibitors, antioxidants, cytokines etc.) will make it possible to find valuable diagnostic signs of forthcoming exacerbation, as well as to evaluate the effectiveness of new therapeutic techniques in clinical studies. COPD, or chronic bronchitis, airway obstruction, and emphysema, should be considered among pathological processes which result in smoking-induced chronic system inflammatory syndrome including cardiovascular diseases, metabolic disorder, and cancer. Possibly, treatment with new preparations, directed towards treating the patient as a whole rather than separate COPD symptoms, will be developed in the future.


A TCRα framework-centered codon shapes a biased T cell repertoire through direct MHC and CDR3β interactions.
Selection of biased T cell receptor (TCR) repertoires across individuals is seen in both infectious diseases and autoimmunity, but the underlying molecular basis leading to these shared repertoires remains unclear. Celiac disease (CD) occurs primarily in HLA-DQ2.5+ individuals and is characterized by a CD4+ T cell response against gluten epitopes dominated by DQ2.5-glia-α1a and DQ2.5-glia-α2. The DQ2.5-glia-α2 response recruits a highly biased TCR repertoire composed of TRAV26-1 paired with TRBV7-2 harboring a semipublic CDR3β loop. We aimed to unravel the molecular basis for this signature. By variable gene segment exchange, directed mutagenesis, and cellular T cell activation studies, we found that TRBV7-3 can substitute for TRBV7-2, as both can contain the canonical CDR3β loop. Furthermore, we identified a pivotal germline-encoded MHC recognition motif centered on framework residue Y40 in TRAV26-1 engaging both DQB1*02 and the canonical CDR3β. This allowed prediction of expanded DQ2.5-glia-α2-reactive TCR repertoires, which were confirmed by single-cell sorting and TCR sequencing from CD patient samples. Our data refine our understanding of how HLA-dependent biased TCR repertoires are selected in the periphery due to germline-encoded residues.


Upregulation of miR-23a-27a-24-2 cluster induces caspase-dependent and -independent apoptosis in human embryonic kidney cells.
miRNAs have emerged as important players in the regulation of gene expression and their deregulation is a common feature in a variety of diseases, especially cancer. Currently, many efforts are focused on studying miRNA expression patterns, as well as miRNA target validation. Here, we show that the over expression of miR-23a approximately 27a approximately 24-2 cluster in HEK293T cells induces apoptosis by caspase-dependent as well as caspase-independent pathway as proved by the annexin assay, caspase activation, release of cytochrome-c and AIF (apoptosis inducing factor) from mitochondria. Furthermore, the over expressed cluster modulates the expression of a number of genes involved in apoptosis including FADD (Fas Associated protein with Death Domain). Bioinformatically, FADD is predicted to be the target of hsa-miR-27a and interestingly, FADD protein was found to be up regulated consistent with very less expression of hsa-miR-27a in HEK293T cells. This effect was direct, as hsa-miR-27a negatively regulated the expression of FADD 3'UTR based reporter construct. Moreover, we also showed that over expression of miR-23a approximately 27a approximately 24-2 sensitized HEK293T cells to TNF-alpha cytotoxicity. Taken together, our study demonstrates that enhanced TNF-alpha induced apoptosis in HEK293T cells by over expression of miR-23a approximately 27a approximately 24-2 cluster provides new insights in the development of novel therapeutics for cancer.


Five-year review of corticosteroid duration and complications in the management of immune checkpoint inhibitor-related diarrhoea and colitis in advanced melanoma.
Immune-related diarrhoea/colitis (ir-D/C) is a common adverse event of immune checkpoint inhibitor (ICI) therapy. Guidelines recommend corticosteroid (CS) treatment; however, the average treatment duration for ir-D/C remains poorly defined. All advanced melanoma patients treated with ICI therapy at the Royal Marsden Hospital between 2011 and 2016 were reviewed to identify ir-D/C cases alongside clinical variables. 117 any-grade ir-D/C episodes occurred in 109 (21%) patients out of a total of 519 patients treated (ipilimumab=77 episodes, anti-PD1=17 (nivolumab or pembrolizumab), ipilimumab and nivolumab=23 (ipi+nivo)) (seven patients had ir-D/C more than once on different lines of treatment) and >/=grade 3 ir-D/C occurred most frequently (63/519 patients (12%) vs 29/519 (5%) grade 1, and 25/519 (5%) grade 2). Median onset (days) of all-grade ir-D/C after starting ICI therapy was 41 for ipilimumab (IQR 24 to 59, n=77), 91 for anti-PD1 (IQR 46 to 355, n=17) and 45 for ipi+nivo (IQR 24 to 67, n=23). In 71/117 (61%) patients, ir-D/C episodes were treated with CS (17% grade 2; 79% grade 3/4): 54 being steroid-responsive; 17 being steroid-refractory and received additional anti-tumor necrosis factor (TNF) treatment. Median grade 3 ir-D/C CS duration was similar across treatments, averaging 58 days. Median overall CS duration (days) was longer in the grade 3/4 D/C steroid-refractory group (94 vs 45 days). Infection developed in 11/71 (15%) CS recipients and in 6/17 (35%) anti-TNF recipients. In 65/117 (55%) patients, ir-D/C episodes were investigated with flexible sigmoidoscopy. Of these patients, 38/65 (58%) had macroscopic colitis and 12/65 (18%) had microscopic colitis. The steroid-refractory group had more macroscopic changes, 13/17 (76%), than the steroid-responsive group, 22/41 (54%). Rates of grade 3 ir-D/C were higher than reported in clinical trials. The 58-day median duration of CS therapy for grade 3 ir-D/C places a significant number of patients at risk of complications. We demonstrate that microscopic colitis is an important subgroup, advocating biopsies in ir-D/C even with macroscopically normal bowel.


Glutamatergic hypofunction in medication-free major depression: Secondary effects of affective diagnosis and relationship to peripheral glutaminase.
There is uncertainty as to whether alterations in glutamatergic function in affective disorders differ between unipolar and bipolar disorders and between depressive and euthymic states. Additionally, there are currently no available blood-based markers of central glutamatergic function to support clinical diagnosis and aid brain based investigations. In this study, we measured levels of glutamate in the dorsal anterior cingulate cortex in-vivo using 1H-Magnetic Resonance Spectroscopy in medication free unipolar and bipolar patients (n = 29, 20 unipolar and 9 bipolar) experiencing a major depressive episode, in comparison with a group of matched healthy controls (n = 20). We also analysed peripheral glutaminase measured in serum to examine the relationship between central and peripheral measures. Anterior cingulate glutamate levels were reduced in both unipolar and bipolar depression groups relative to healthy controls, although this only reached significance in the unipolar group. Peripheral glutaminase levels did not differentiate bipolar from unipolar depression and a positive correlation with central glutamate levels did not reach statistical significance. The sample of bipolar disorder patients was relatively small due to the difficulties involved in finding medication-free patients experiencing a depressive episode. These results suggest that glutamatergic hypofunction might represent a state marker for a depressive episode irrespective of diagnosis. Peripheral glutaminase did not index central glutamate levels in this study, which could potentially reflect a small magnitude of the effect requiring larger samples for detection.


Complementary active sites cause size-selective reactivity of aluminum cluster anions with water.
The reactions of metal clusters with small molecules often depend on cluster size. The selectivity of oxygen reactions with aluminum cluster anions can be well described within an electronic shell model; however, not all reactions are subject to the same fundamental constraints. We observed the size selectivity of aluminum cluster anion reactions with water, which can be attributed to the dissociative chemisorption of water at specific surface sites. The reactivity depends on geometric rather than electronic shell structure. Identical arrangements of multiple active sites in Al16-, Al17-, and Al18- result in the production of H2 from water.


Structural Analysis of the Menangle Virus P Protein Reveals a Soft Boundary between Ordered and Disordered Regions.
The paramyxoviral phosphoprotein (P protein) is the non-catalytic subunit of the viral RNA polymerase, and coordinates many of the molecular interactions required for RNA synthesis. All paramyxoviral P proteins oligomerize via a centrally located coiled-coil that is connected to a downstream binding domain by a dynamic linker. The C-terminal region of the P protein coordinates interactions between the catalytic subunit of the polymerase, and the viral nucleocapsid housing the genomic RNA. The inherent flexibility of the linker is believed to facilitate polymerase translocation. Here we report biophysical and structural characterization of the C-terminal region of the P protein from Menangle virus (MenV), a bat-borne paramyxovirus with zoonotic potential. The MenV P protein is tetrameric but can dissociate into dimers at sub-micromolar protein concentrations. The linker is globally disordered and can be modeled effectively as a worm-like chain. However, NMR analysis suggests very weak local preferences for alpha-helical and extended beta conformation exist within the linker. At the interface between the disordered linker and the structured C-terminal binding domain, a gradual disorder-to-order transition occurs, with X-ray crystallographic analysis revealing a dynamic interfacial structure that wraps the surface of the binding domain.


Low expression of transforming growth factor beta-1 in cancer tissue predicts a poor prognosis for patients with stage III rectal cancers.
Transforming growth factor beta (TGF-β) plays an important role in tumorigenesis and metastasis. It works as a tumor suppressor in the normal colon, but acts as a cancer promoter during the late stages of colorectal carcinogenesis. High expression of TGF-β is known to be associated with advanced stages, tumor recurrence and decreased survival of patients. We investigated the expression of TGF-β and its signaling axis molecules and evaluated their prognostic significance in patients with stage III rectal cancers. Tissues from 201 cases of stage III rectal cancer were subjected to immunohistochemistry for TGF-β1, type II TGF-β receptor, Smad3, Smad4 and Smad7 proteins. The immunoactivities of these molecules were evaluated and the results were compared with clinicopathological variables including patient survival. Low expression of TGF-β1 protein was correlated with a decreased disease-free survival in univariate Kaplan-Meier (p = 0.003) and multivariate Cox regression (HR 9.188 and 95% CI 1.256-67.198, p = 0.029) analyses. The loss of Smad4 protein expression was associated with a reduction in disease-free survival in the univariate analysis, but this finding was not significant after the multivariate analysis. Low expression of TGF-β1 protein is associated with a poor prognosis for patients with stage III rectal cancers.


Sphagnum moss disperses spores with vortex rings.
Sphagnum spores, which have low terminal velocities, are carried by turbulent wind currents to establish colonies many kilometers away. However, spores that are easily kept aloft are also rapidly decelerated in still air; thus, dispersal range depends strongly on release height. Vascular plants grow tall to lift spores into sufficient wind currents for dispersal, but nonvascular plants such as Sphagnum cannot grow sufficiently high. High-speed videos show that exploding capsules of Sphagnum generate vortex rings to efficiently carry spores high enough to be dispersed by turbulent air currents. Spores launched ballistically at similar speeds through still air would travel a few millimeters and not easily reach turbulent air. Vortex rings are used by animals; here, we report vortex rings generated by plants.


The comparison of frequency of the upper limb musculoskeletal disorders among patients with diabetes type II with normal cases.
Musculoskeletal disease, that is recognized in diabetes and diabetes mellitus (DM) has shown a higher prevalence of chronic musculoskeletal complications. This study aimed at assessing the frequency of upper limb musculoskeletal disorders among patients with diabetes type II with normal cases in Mashhad, Iran. A cross-section of 100 patients with upper limb musculoskeletal disorders were enrolled in this study. The patients were examined by a unique physician considering carpal tunnel syndrome disorder, trigger finger, adhesive capsulitis, and Dupuytren's contracture at Ghaem hospital, Mashhad, Iran in 2015. All collected data were recorded by using SPSS version 21 and were analyzed through independent-samples t-test for comparing changes, and Chi-square. In this study, the mean age was 51.7±8.7 years old. Gender frequency was 114 (57%) male, and 86 (43%) female. There was no significant difference between groups in cases of gender frequency and mean of age (p>0.05). In evaluation of association between the two groups, there was significant difference for adhesive capsulitis, (p=0.04). Chi-square test showed significant association for age and adhesive capsulitis between the two groups, (p=0.040); but no other diabetes-related disorders, (p<0.05). The results of this study showed that in patients with diabetes mellitus and musculoskeletal complications such as upper limb musculoskeletal abnormalities, it will lead to an increase in skeletal muscle effects in DM patients. It is recommended that musculoskeletal examination is done periodically in DM patients for identification of these disorders and necessary actions are carried out for prevention of the disorders as soon as possible.


The acute wheezy adult with airways disease in the emergency department: a retrospective case-note review of exacerbations of COPD.
Introduction: There has been an increase in interest in the peripheral blood eosinophil count as a biomarker in COPD. Few studies have examined the eosinophil count in patients attending the emergency department (ED) with acute exacerbations of COPD (AECOPD). We investigated the relationship between the blood eosinophil and other variables collected routinely at ED presentation and outcomes. Methods: Retrospective case note review of patients attending the ED with an AECOPD over 18 months. Demographic, clinical and pharmacological data were analyzed at the time of presentation, and clinical outcomes relating to hospital admission, length of hospital stay and mortality were investigated. Results: There were 743 AECOPD index events in 537 patients. Over half (57%) of all attendees were admitted to hospital. They were older, reported an increased number of exacerbations and higher levels of total leukocytes and neutrophils. Length of stay was shorter in patients with a blood eosinophil count ≥2% compared to <2% (median (IQR) 3 days (1-7) vs 4 days (2-8) respectively, p<0.05). Length of stay correlated with peripheral blood neutrophils (r=0.12, p=0.021), peripheral blood absolute and relative eosinophils (r=-0.12, p=0.024 and r=-0.11, p=0.035, respectively) and CRP (r=0.16, p=0.027). Non-eosinophilic AECOPD were associated with an increased risk of mortality during an exacerbation (χ2 5.9, OR 3.08, 95% CI 1.19-7.96, p=0.015). Conclusion: In exacerbations of COPD presenting to ED, a higher blood eosinophil count is associated with a shorter length of stay and reduced mortality.


Membrane Permeabilization by Oligomeric α-Synuclein: In Search of the Mechanism.
The question of how the aggregation of the neuronal protein α-synuclein contributes to neuronal toxicity in Parkinson's disease has been the subject of intensive research over the past decade. Recently, attention has shifted from the amyloid fibrils to soluble oligomeric intermediates in the α-synuclein aggregation process. These oligomers are hypothesized to be cytotoxic and to permeabilize cellular membranes, possibly by forming pore-like complexes in the bilayer. Although the subject of α-synuclein oligomer-membrane interactions has attracted much attention, there is only limited evidence that supports the pore formation by α-synuclein oligomers. In addition the existing data are contradictory. Here we have studied the mechanism of lipid bilayer disruption by a well-characterized α-synuclein oligomer species in detail using a number of in vitro bilayer systems and assays. Dye efflux from vesicles induced by oligomeric α-synuclein was found to be a fast all-or-none process. Individual vesicles swiftly lose their contents but overall vesicle morphology remains unaltered. A newly developed assay based on a dextran-coupled dye showed that non-equilibrium processes dominate the disruption of the vesicles. The membrane is highly permeable to solute influx directly after oligomer addition, after which membrane integrity is partly restored. The permeabilization of the membrane is possibly related to the intrinsic instability of the bilayer. Vesicles composed of negatively charged lipids, which are generally used for measuring α-synuclein-lipid interactions, were unstable to protein adsorption in general. The dye efflux from negatively charged vesicles upon addition of α-synuclein has been hypothesized to occur through the formation of oligomeric membrane pores. However, our results show that the dye efflux characteristics are consistent with bilayer defects caused by membrane instability. These data shed new insights into potential mechanisms of toxicity of oligomeric α-synuclein species.


Adjuvant treatment improves overall survival in women with high-intermediate risk early-stage endometrial cancer with lymphovascular space invasion.
Adjuvant therapy in early-stage endometrial cancer has not shown a clear overall survival benefit, and hence, patient selection remains crucial. To determine whether women with high-intermediate risk, early-stage endometrial cancer with lymphovascular space invasion particularly benefit from adjuvant treatment in improving oncologic outcomes. A multi-center retrospective study was conducted in women with stage IA, IB, and II endometrial cancer with lymphovascular space invasion who met criteria for high-intermediate risk by Gynecologic Oncology Group (GOG) 99. Patients were stratified by the type of adjuvant treatment received. Clinical and pathologic features were abstracted. Progression-free and overall survival were evaluated using multivariable analysis. 405 patients were included with the median age of 67 years (range 27-92, IQR 59-73). 75.0% of the patients had full staging with lymphadenectomy, and 8.6% had sentinel lymph node biopsy (total 83.6%). After surgery, 24.9% of the patients underwent observation and 75.1% received adjuvant therapy, which included external beam radiation therapy (15.1%), vaginal brachytherapy (45.4%), and combined brachytherapy + chemotherapy (19.1%). Overall, adjuvant treatment resulted in improved oncologic outcomes for both 5-year progression-free survival (77.2% vs 69.6%, HR 0.55, p=0.01) and overall survival (81.5% vs 60.2%, HR 0.42, p<0.001). After adjusting for stage, grade 2/3, and age, improved progression-free survival and overall survival were observed for the following adjuvant subgroups compared with observation: external beam radiation (overall survival HR 0.47, p=0.047, progression-free survival not significant), vaginal brachytherapy (overall survival HR 0.35, p<0.001; progression-free survival HR 0.42, p=0.003), and brachytherapy + chemotherapy (overall survival HR 0.30 p=0.002; progression-free survival HR 0.35, p=0.006). Compared with vaginal brachytherapy alone, external beam radiation or the addition of chemotherapy did not further improve progression-free survival (p=0.80, p=0.65, respectively) or overall survival (p=0.47, p=0.74, respectively). Adjuvant therapy improves both progression-free survival and overall survival in women with early-stage endometrial cancer meeting high-intermediate risk criteria with lymphovascular space invasion. External beam radiation or adding chemotherapy did not confer additional survival advantage compared with vaginal brachytherapy alone.


EJPRM systematic continuous update on Cochrane reviews in rehabilitation: news from February 2011 to April 2011.
Since 2007 we focused our attention as EJPRM to the best available clinical evidence as offered by the Cochrane Collaboration. Due to the absence of a specific Rehabilitation Group.only a Field exists), reviews of PRM interest are in different groups and not easy to find. Consequently, the EJPRM offer the service of listing and presenting all these reviews systematically. The aim of the present paper is to systematically review all the new rehabilitation papers published from February 2011 up to April 2011 from the Cochrane Library in order to provide to physicians involved in the field a summary of the best evidence nowadays available. The authors systematically searched all the new papers of rehabilitative interest in the 2nd of February 2011 to the 22nd of April 2011 in the Cochrane Library. The retrieved papers have been then divided in subgroups on the base of the topic and the Cochrane Groups. The number of included papers was 5, 3 new reviews and 2 updates reviews. Three reviews deals with neurological rehabilitation, 2 with musculoskeletal disorders and one with orthoses. The Cochrane Collaboration and his product, the Cochrane Library, are really relevant instruments to improve EBM in medical practice and thus also in the Rehabilitation Field. The present paper can help Rehabilitation Specialists to easily retrieve the conclusions of the most relevant and updated reviews in order to change their clinical practice in a more rapid and effective way.


Self-Assembled Thin-Layer Glycomaterials With a Proper Shell Thickness for Targeted and Activatable Cell Imaging.
The construction of targeted and activatable materials can largely improve the precision of disease diagnosis and therapy. However, the currently developed systems either target a transmembrane antigen or are activatable to release imaging and/or therapeutic reagents intracellularly. Here, we develop a simple thin-layer glycomaterial through the self-assembly between fluorescent glycoprobes, in which the carbohydrate-targeting reagent and the fluorophore are linked to each other by polyethylene glycol with a suitable chain length, and thin-layer manganese dioxide. The fluorogenic material developed is both capable of targeting a transmembrane glycoprotein receptor and fluorescently activatable by intracellular biothiols. The shell thickness of the material was determined to be important for achieving the biothiol-induced activation of fluorescence. This research might provide insight into the development of precision-enhanced self-assembled materials for disease theranostics.


Potential-functional embedding theory for molecules and materials.
We introduce a potential-functional embedding theory by reformulating a recently proposed density-based embedding theory in terms of functionals of the embedding potential. This potential-functional based theory completes the dual problem in the context of embedding theory for which density-functional embedding theory has existed for two decades. With this potential-functional formalism, it is straightforward to solve for the unique embedding potential shared by all subsystems. We consider charge transfer between subsystems and discuss how to treat fractional numbers of electrons in subsystems. We show that one is able to employ different energy functionals for different subsystems in order to treat different regions with theories of different levels of accuracy, if desired. The embedding potential is solved for by directly minimizing the total energy functional, and we discuss how to efficiently calculate the gradient of the total energy functional with respect to the embedding potential. Forces are also derived, thereby making it possible to optimize structures and account for nuclear dynamics. We also extend the theory to spin-polarized cases. Numerical examples of the theory are given for some homo- and hetero-nuclear diatomic molecules and a more complicated test of a six-hydrogen-atom chain. We also test our theory in a periodic bulk environment with calculations of basic properties of bulk NaCl, by treating each atom as a subsystem. Finally, we demonstrate the theory for water adsorption on the MgO(001)surface.


Noise-cancellation-based nonuniformity correction algorithm for infrared focal-plane arrays.
The spatial fixed-pattern noise (FPN) inherently generated in infrared (IR) imaging systems compromises severely the quality of the acquired imagery, even making such images inappropriate for some applications. The FPN refers to the inability of the photodetectors in the focal-plane array to render a uniform output image when a uniform-intensity scene is being imaged. We present a noise-cancellation-based algorithm that compensates for the additive component of the FPN. The proposed method relies on the assumption that a source of noise correlated to the additive FPN is available to the IR camera. An important feature of the algorithm is that all the calculations are reduced to a simple equation, which allows for the bias compensation of the raw imagery. The algorithm performance is tested using real IR image sequences and is compared to some classical methodologies.


The development of an arm activity survey for breast cancer survivors using the Protection Motivation Theory.
Current research evidence indicates that women should return to normal use of their arm after breast cancer surgery. However, it appears some women continue to hold the view that they are supposed to protect their arm from strenuous activities because of the risk of lymphoedema. Many factors contribute to women's perceptions about lymphoedema and their ability to use their affected arm, and it is the aim of this study to explore and understand these perceptions. A survey, based on the Protection Motivation Theory, has been developed and tested. The survey assesses whether subjective norms, fear and/or coping attributes predict women's intention to use their affected arm. In addition, the survey includes questions regarding cancer treatment and demographic characteristics, arm and chest symptoms, and arm function. Recruitment of 170 breast cancer survivors has begun at 3 cancer treatment sites in Sydney, Australia. This study will identify perceptions that help predict the extent women use their affected arm. The results will also determine whether upper limb impairments arise secondary to over-protection of the affected arm. Identification of factors that limit arm use will enable appropriate prevention and better provision of treatment to improve upper limb outcomes.


The relation between promotional spending on drugs and their therapeutic gain: a cohort analysis.
Whether drug promotion helps or hinders appropriate prescribing by physicians is debated. This study examines the most heavily promoted drugs and the therapeutic value of those drugs to help determine whether doctors should be using promotional material to inform themselves about drugs. Lists were constructed of the 50 most heavily promoted drugs (amount of money spent on journal advertisements and visits by sales representatives) and the 50 top-selling drugs (by dollar value) for 2013, 2014 and 2015. Therapeutic gain was determined by examining ratings from the Patented Medicine Prices Review Board and the French drug bulletin Prescrire International and was categorized as major, moderate or little to none. For each of the 3 years, the number of drugs in the 3 therapeutic categories for drugs in both groups was compared. The amount and proportion of money spent on promotion for drugs in each of the 3 therapeutic categories for the 3 years was also determined. Therapeutic ratings were available for 42 of 79 of the most heavily promoted drugs over the 3 years and for 40 of 61 of the top-selling drugs. Nearly all the money spent on promotion in each of the 3 years went to drugs with little to no therapeutic gain. The distribution of therapeutic gain for drugs in both groups was statistically significantly different only in 2013 (p = 0.04). Most of the money spent on promotion went to drugs that offer little to no therapeutic gain. This result calls into question whether doctors should read journal advertisements or see sales representatives to acquire information about important medical therapies.


Personalisation of warfarin therapy using thermal ink-jet printing.
Warfarin is a widely used anticoagulant that is critical in reducing patient morbidity and mortality associated with thromboembolic disorders. However, its narrow therapeutic index and large inter-individual variability can lead to complex dosage regimes. Formulating warfarin as an orodispersible film (ODF) using thermal ink-jet (TIJ) printing could enable personalisation of therapy to simplify administration. Commercial TIJ printers are currently unsuitable for printing the milligram dosages, typically required for warfarin therapy. As such, this study aimed to modify a commercial TIJ printing system to formulate personalised warfarin ODFs containing therapeutic dosages. A TIJ printer was modified successfully with the printer functionality intact; the substrate (paper) rolling mechanism of the printer was replaced by printing onto a stationary stage. Free film substrates were composed of hydroxypropyl methylcellulose (20%w/w) and glycerol (3%w/w). The resulting ODFs were characterised for morphology, disintegration, solid-state properties and drug content. Printed film stability was assessed at 40 °C/75% relative humidity for 30 days. Therapeutic warfarin doses (1.25 and 2.5 mg) were successfully printed onto the film substrates. Excellent linearity was observed between the theoretical and measured dose by changing the warfarin feed concentration (R2 = 0.9999) and length of the print objective, i.e. the Y-value, (R2 = 0.9998). Rapid disintegration of the ODFs was achieved. As such, this study successfully formulated personalised warfarin ODFs using a modified TIJ printer, widening the range of applications for TIJ printing to formulate narrow therapeutic index drugs.


Selective estrogen receptor modulators: A possible new treatment of osteoporosis in males.
More recently, osteoporosis in men has been recognized as an important public health problem. Bone loss begins in mid life and is associated with the decline of the sex steroids production. Although there is no equivalent of the menopause, gonadal function in men is affected in a slow progressive way leading to hypogonadism. Testosterone, the major androgen in men, exerts its effect on bone by local conversion to 5alpha-dihydrotestosterone or by aromatization to estrogens. Several studies have found that estrogen, rather than testosterone, levels are more closely correlated with BMD in elderly men. Selective estrogen receptor modulator (SERM) raloxifene binds to estrogen receptors and exhibit estrogenic effect in bone, but, contrary to estrogen, without feminizing effect. There are limited numbers of studies investigating the effects of SERMs in males. Animal studies demonstrated that SERMs inhibit bone turnover and prevent bone loss in orchidectomised adult male rats. Raloxifene has been shown to increase bone mineral density of the hip in men receiving androgen deprivation therapy for prostate cancer. Moreover, experimental data demonstrated dramatic increase in cell death in human prostate cancer cell lines after the treatment with raloxifene. All these observations suggest that SERMs may be useful for the prevention and treatment of osteoporosis not only in postmenopausal women but also in elderly men. However, our hypothesis should be tested in a proper designed clinical trial. Several important issues have to be addressed. Does the same drug dose that has been shown to be effective in postmenopausal women should be used in men, too? Does treatment with SERMs reduce the fracture risk in men and is it comparable to that observed in women? Does treatment with SERMs have any beneficial effect on cardiovascular system and prostate cancer? And finally, do men experience adverse events other than women treated with SERMs? Answering to these questions will have great impact in getting the decision of possible SERMs usage in the treatment of osteoporosis in elderly males.


AINTEGUMENTA utilizes a mode of DNA recognition distinct from that used by proteins containing a single AP2 domain.
The Arabidopsis protein AINTEGUMENTA (ANT) is an important regulator of organ growth during flower development. ANT is a member of the AP2 subclass of the AP2/ERF family of plant-specific transcription factors. These proteins contain either one or two copies of a DNA-binding domain called the AP2 domain. Here, it is shown that ANT can act as a transcriptional activator in yeast through binding to a consensus ANT-binding site. This activity was used as the basis for a genetic screen to identify amino acids that are critical for the DNA binding ability of ANT. Mutants that showed reduced or no activation of a reporter gene under the control of ANT-binding sites were identified. The mutations identified in the screen as well as additional site-directed mutations suggest that the mode of DNA recognition by members of the AP2 subfamily is distinct from that of ERF proteins. Surprisingly, it appears that each AP2 domain of ANT uses different amino acids to contact DNA. Identification of several linker mutations argues that this sequence acts in the positioning of each AP2 domain on the DNA or makes direct DNA contacts.


Many physicians are willing to use patients' electronic personal health records, but doctors differ by location, gender, and practice.
Electronic personal health records could become important tools for patients to use in managing and monitoring their health information and communicating with clinicians. With the emergence of new products and federal incentives that might indirectly encourage greater use of personal health records, policy makers should understand the views of physicians on using these records. In a national survey of physicians in 2008-09, we found that although 64 percent have never used a patient's electronic personal health record, 42 percent would be willing to try. Strikingly, rural physicians expressed much more willingness to use such records compared to urban or suburban physicians. Female physicians were significantly less willing to use these tools than their male peers (34 percent versus 46 percent). Physicians broadly have concerns about the impact on patients' privacy, the accuracy of underlying data, their potential liability for tracking all of the information that might be entered into a personal health record, and the lack of payment to clinicians for using or reviewing these patient records.


Targeting of KRAS mutant tumors by HSP90 inhibitors involves degradation of STK33.
Previous efforts to develop drugs that directly inhibit the activity of mutant KRAS, the most commonly mutated human oncogene, have not been successful. Cancer cells driven by mutant KRAS require expression of the serine/threonine kinase STK33 for their viability and proliferation, identifying STK33 as a context-dependent therapeutic target. However, specific strategies for interfering with the critical functions of STK33 are not yet available. Here, using a mass spectrometry-based screen for STK33 protein interaction partners, we report that the HSP90/CDC37 chaperone complex binds to and stabilizes STK33 in human cancer cells. Pharmacologic inhibition of HSP90, using structurally divergent small molecules currently in clinical development, induced proteasome-mediated degradation of STK33 in human cancer cells of various tissue origin in vitro and in vivo, and triggered apoptosis preferentially in KRAS mutant cells in an STK33-dependent manner. Furthermore, HSP90 inhibitor treatment impaired sphere formation and viability of primary human colon tumor-initiating cells harboring mutant KRAS. These findings provide mechanistic insight into the activity of HSP90 inhibitors in KRAS mutant cancer cells, indicate that the enhanced requirement for STK33 can be exploited to target mutant KRAS-driven tumors, and identify STK33 depletion through HSP90 inhibition as a biomarker-guided therapeutic strategy with immediate translational potential.


Medium Moderates the Message. How Users Adjust Their Communication Trajectories to Different Media in Collaborative Task Solving.
Rapid development of information and communications technologies (ICT) has triggered profound changes in how people manage their social contacts in both informal and professional contexts. ICT mediated communication may seem limited in possibilities compared to face-to-face encounters, but research shows that puzzlingly often it can be just as effective and satisfactory. We posit that ICT users employ specific communication strategies adapted to particular communication channels, which results in a comparable effectiveness of communication. In order to maintain a satisfactory level of conversational intelligibility they calibrate the content of their messages to a given medium's richness and adjust the whole conversation trajectory so that every stage of the communication process runs fluently. In the current study, we compared complex task solving trajectories in chat, mobile phone and face-to-face dyadic conversations. Media conditions did not influence the quality of decision outcomes or users' perceptions of the interaction, but they had impact on the amount of time devoted to each of the identified phases of decision development. In face-to-face contacts the evaluation stage of the discussion dominated the conversation; in the texting condition the orientation-evaluation-control phases were evenly distributed; and the phone condition provided a midpoint between these two extremes. The results show that contemporary ICT users adjust their communication behavior to the limitations and opportunities of various media through the regulation of attention directed to each stage of the discussion so that as a whole the communication process remains effective.


Enhancing dental and dental hygiene student awareness of the lesbian, gay, bisexual and transgender population.
Although cultural competence education is being incorporated into most health care curricula, content addressing sexual minorities is lacking or, if present, inadequate. This void can result in compromised health care and can contribute to the social stigma surrounding the lesbian, gay, bisexual and transgender (LGBT) community. Increasing the knowledge and demystifying sexual minority issues can enhance the confidence and attitudes of health care workers when treating LGBT individuals. Suggestions for creating a more welcoming health care environment for LGBT individuals in different health care settings such as private clinics, public health settings and school based programs are offered. The purpose of this literature review was to systematically review available literature on health care providers' delivery of culturally competent care to the LGBT community. The investigators searched electronic databases that included Medline (Ovid), Eric and PubMed with consultation from information specialists at the Health Sciences and Human Services Library at the University of Maryland. The information was categorized into content areas. Discussion of the findings and future directions regarding health care delivery for the LGBT community are provided.


Quantifying short-term dynamics of Parkinson's disease using self-reported symptom data from an Internet social network.
Parkinson's disease (PD) is an incurable neurological disease with approximately 0.3% prevalence. The hallmark symptom is gradual movement deterioration. Current scientific consensus about disease progression holds that symptoms will worsen smoothly over time unless treated. Accurate information about symptom dynamics is of critical importance to patients, caregivers, and the scientific community for the design of new treatments, clinical decision making, and individual disease management. Long-term studies characterize the typical time course of the disease as an early linear progression gradually reaching a plateau in later stages. However, symptom dynamics over durations of days to weeks remains unquantified. Currently, there is a scarcity of objective clinical information about symptom dynamics at intervals shorter than 3 months stretching over several years, but Internet-based patient self-report platforms may change this. To assess the clinical value of online self-reported PD symptom data recorded by users of the health-focused Internet social research platform PatientsLikeMe (PLM), in which patients quantify their symptoms on a regular basis on a subset of the Unified Parkinson's Disease Ratings Scale (UPDRS). By analyzing this data, we aim for a scientific window on the nature of symptom dynamics for assessment intervals shorter than 3 months over durations of several years. Online self-reported data was validated against the gold standard Parkinson's Disease Data and Organizing Center (PD-DOC) database, containing clinical symptom data at intervals greater than 3 months. The data were compared visually using quantile-quantile plots, and numerically using the Kolmogorov-Smirnov test. By using a simple piecewise linear trend estimation algorithm, the PLM data was smoothed to separate random fluctuations from continuous symptom dynamics. Subtracting the trends from the original data revealed random fluctuations in symptom severity. The average magnitude of fluctuations versus time since diagnosis was modeled by using a gamma generalized linear model. Distributions of ages at diagnosis and UPDRS in the PLM and PD-DOC databases were broadly consistent. The PLM patients were systematically younger than the PD-DOC patients and showed increased symptom severity in the PD off state. The average fluctuation in symptoms (UPDRS Parts I and II) was 2.6 points at the time of diagnosis, rising to 5.9 points 16 years after diagnosis. This fluctuation exceeds the estimated minimal and moderate clinically important differences, respectively. Not all patients conformed to the current clinical picture of gradual, smooth changes: many patients had regimes where symptom severity varied in an unpredictable manner, or underwent large rapid changes in an otherwise more stable progression. This information about short-term PD symptom dynamics contributes new scientific understanding about the disease progression, currently very costly to obtain without self-administered Internet-based reporting. This understanding should have implications for the optimization of clinical trials into new treatments and for the choice of treatment decision timescales.


Chemical discrimination and aggressiveness via cuticular hydrocarbons in a supercolony-forming ant, Formica yessensis.
Territorial boundaries between conspecific social insect colonies are maintained through nestmate recognition systems. However, in supercolony-forming ants, which have developed an extraordinary social organization style known as unicoloniality, a single supercolony extends across large geographic distance. The underlying mechanism is considered to involve less frequent occurrence of intraspecific aggressive behaviors, while maintaining interspecific competition. Thus, we examined whether the supercolony-forming species, Formica yessensis has a nestmate recognition system similar to that of the multicolonial species, Camponotus japonicus with respect to the cuticular hydrocarbon-sensitive sensillum (CHC sensillum), which responds only to non-nestmate CHCs. We further investigated whether the sensory system reflects on the apparent reduced aggression between non-nestmates typical to unicolonial species. F. yessensis constructs supercolonies comprising numerous nests and constitutes the largest supercolonies in Japan. We compared the within-colony or between-colonies' (1) similarity in CHC profiles, the nestmate recognition cues, (2) levels of the CHC sensillar response, (3) levels of aggression between workers, as correlated with geographic distances between nests, and (4) their genetic relatedness. Workers from nests within the supercolony revealed a greater similarity of CHC profiles compared to workers from colonies outside it. Total response of the active CHC sensilla stimulated with conspecific alien CHCs did not increase as much as in case of C. japonicus, suggesting that discrimination of conspecific workers at the peripheral system is limited. It was particularly limited among workers within a supercolony, but was fully expressed for allospecific workers. We demonstrate that chemical discrimination between nestmates and non-nestmates in F. yessensis was not clear cut, probably because this species has only subtle intraspecific differences in the CHC pattern that typify within a supercolony. Such an incomplete chemical discrimination via the CHC sensilla is thus an important factor contributing to decreased occurrence of intraspecific aggressive behavior especially within a supercolony.


Surface Chemical Gradient Affects the Differentiation of Human Adipose-Derived Stem Cells via ERK1/2 Signaling Pathway.
To understand the role of surface chemistry on cell behavior and the associated molecular mechanisms, we developed and utilized a surface chemical gradient of amine functional groups by carefully adjusting the gas composition of 1,7-octadiene (OD) and allylamine (AA) of the plasma phase above a moving substrate. The chemical gradient surface used in the present work shows an increasing N/C ratio and wettability from the OD side toward the AA side with no change in surface topography. Under standard culture conditions (with serum), human adipose-derived stem cells (hASCs) adhesion and spreading area increased toward the AA side of the gradient. However, there were no differences in cell behavior in the absence of serum. These results, supported by the trends in proteins adsorption on the gradient surface, demonstrated that surface chemistry affects the response of hASCs through cell-adhesive serum proteins, rather than interacting directly with the cells. The expression of p-ERK and the osteogenic differentiation increased toward the AA side of the gradient, while adipogenic differentiation decreased in the same direction; however, when the activation of ERK1/2 was blocked by PD98059, the levels of osteogenic or adipogenic differentiation on different regions of the chemical gradient were the same. This indicates that ERK1/2 may be an important downstream signaling pathway of surface chemistry directed stem cell fate.


Endoplasmic Reticulum stress in chronic kidney disease. New molecular targets from bench to the bedside.
The identification of new biomarkers/pharmacological targets for chronic kidney disease (CKD) is required for the development of more effective therapies. Several studies in vitro and in vivo have shown the importance of the endoplasmic reticulum (ER) (cellular organelle devolved to protein biosynthesis and maturation, and cellular detoxification processes) in the pathophysiology of CKD. Hence, the synthesis and development of novel drugs against the different ER intracellular pathways is crucial in order to slow down the development and progression of renal diseases. This review aims to dissect the role of the different ER branches (PERK, IRE1α, ATF6) and their function in CKD, providing potential insights for the development of new treatments.


Prospective Assessment of an innovative test for prostate cancer screening using the VITA process model framework.
Healthcare innovations are crucial for enhancing patient treatment and a high-quality healthcare system. However, bringing new technologies, methods and procedures into the healthcare market is challenging. Enormous amounts of financial, personnel and organizational resources are required with no upfront certainty for the medical and economic benefit. A new and innovative approach uses interdisciplinary medical, technical and economic expertise to forecast effects of healthcare innovations already at the early research and concept phase of an idea and before major investments are made. A process model framework was developed to operationalize this structured assessment of healthcare innovations. The Visionary Iterative Tailored Approach (VITA) is based on conceptual modeling, simulation and health economics evaluation. Its application for the prospective assessment of an innovative prostate cancer screening is presented.


Treatment access is only the first step to hepatitis C elimination: experience of universal anti-viral treatment access in Australia.
Global targets to eliminate hepatitis C (HCV) might be met by sustained treatment uptake. To describe factors facilitating HCV treatment uptake and potential challenges to sustaining treatment levels after universal access to direct-acting anti-virals (DAA) across Australia. We analysed national Pharmaceutical Benefits Scheme data to determine the number of DAA prescriptions commenced before and after universal access from March 2016 to June 2017. We inferred facilitators and barriers to treatment uptake, and challenges that will prevent local and global jurisdictions reaching elimination targets. In 2016, 32 877 individuals (14% of people living with HCV in Australia) commenced HCV DAA treatment, and 34 952 (15%) individuals commenced treatment in the first year of universal access. Treatment uptake peaked at 13 109 DAA commencements per quarter immediately after universal access, but more than halved (to 5320 in 2017 Q2) within 12 months. General practitioners have written 24% of all prescriptions but with a significantly increased proportion over time (9% in 2016 Q1 to 37% in 2017 Q2). In contrast, hepatology or infectious diseases specialists have written a declining share from 74% to 38% during the same period. General practitioners provided a greater proportion (47%) of care in regional/remote areas than major cities. Broad treatment access led to rapid initial increases in treatment uptake, but this uptake has not been sustained. Our results suggest achieving global elimination targets requires more than treatment availability: people with HCV need easy access to testing and linkage to care in community settings employing a diverse prescriber base.


Patients with Cerebellar Ataxia Do Not Benefit from Limb Weights.
Patients with cerebellar ataxia are sometimes treated by the addition of mass to the limbs, though this practice has received limited study. Recent work suggests that adding mass to the limbs might have predictable effects on the pattern of cerebellar dysmetria (i.e., over or undershooting) that depends on a hypothesized mismatch between the actual limb inertia and the brain's estimate of limb inertia. Based on this model, we predicted that addition of mass would only be effective in reducing dysmetria in hypometric patients. Cerebellar patients were challenged with making a single-joint, single degree of freedom reaching movement while various limb masses were tested. In this task, some single-jointed reaches were improved by adding masses that were optimized in a patient-specific manner. However, this improvement did not translate to multi-joint movements. In multi-joint movements, the "best" patient-specific masses (as determined in a single-joint task) generally exacerbated subjects' reaching errors. This finding raises questions as to the merits of adding limb weights as a therapy to mitigate the effects of dysmetria.


Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis.
Spontaneous errors in DNA replication have been suggested to play a significant role in neoplastic transformation and to explain the chromosomal alterations seen in cancer cells. A defective replication factor could increase the mutation rate in clonal variants arising during tumour progression, but despite intensive efforts, increases in tumour cell mutation rates have not been unambiguously shown. Here we use an unbiased genomic fingerprinting technique to show that 12 per cent of colorectal carcinomas carry somatic deletions in poly(dA.dT) sequences and other simple repeats. We estimate that cells from these tumours can carry more than 100,000 such mutations. Only tumours with affected poly(dA.dT) sequences carry mutations in the other simple repeats examined, and such mutations can be found in all neoplastic regions of multiple tumours from the same patient, including adenomas. Tumours with these mutations show distinctive genotypic and phenotypic features. We conclude that these mutations reflect a previously undescribed form of carcinogenesis in the colon (predisposition to which may be inherited) mediated by a mutation in a DNA replication factor resulting in reduced fidelity for replication or repair (a 'mutator mutation').


Adjustment of the munsell-value and w*-scales to uniform lightness steps for various background reflectances.
For background reflectances taken equal to, or slightly lower than, the specimen reflectances, the Munsell-value, V, and the CIE 1964, W*, scales are found to be essentially linear with a power formulation for lightness previously shown to accord with lightness-spacing data for a wide variety of specimen and background reflectances. Adjustments required to make the Munsell-value function accord precisely with the power formulation for this background condition are all less than 0.2 of a Munsell-value step between 1/ and 9/. The power formulation is used to construct a table to show in Munsell terms the influence of background reflectance on perceived lightness for all combinations of specimen and background reflectance including Takasaki crispening for specimen reflectance approaching that of the background.


Increased expression of the NG2 chondroitin-sulfate proteoglycan after brain injury.
Injury to the adult mammalian CNS results in reactive changes among the glial cells surrounding the site of damage. Recently, an unusual class of glial cells has been identified within the intact adult rat cerebellum on the basis of the expression of the NG2 chondroitin-sulfate proteoglycan (Levine and Card, 1987). To determine whether the cells that express the NG2 proteoglycan show reactive changes after injury, small puncture lesions were made into the cerebelli of adult rats, and changes among astrocytes, microglia and NG2-positive cells were examined using immunohistochemical staining with cell type-specific marker antibodies. Beginning at 24 hr after lesion, NG2-positive cells immediately adjacent to the lesion site bound the anti-NG2 antibodies more heavily than cells within the undamaged areas of the cerebellum. This increase in anti-NG2 immunoreactivity was transient, reaching a maximum at 7 d postlesion and declining slowly thereafter. The increase in anti-NG2 immunoreactivity was accompanied by an increase in the levels of mRNA encoding the NG2 core protein as demonstrated by in situ hybridization. NG2-positive cells adjacent to the lesion site incorporated 3H-thymidine into their nuclei beginning at 24 hr postlesion and increased in number. Concurrent with these changes, microglia became activated and increased in number, monocytes invaded the damaged tissue, and an astrocytic scar formed. These observations demonstrate that the cells that express the NG2 proteoglycan are a reactive cell type that responds to brain injury. The increased expression of the NG2 chondroitin-sulfate proteoglycan may contribute to the failure of damaged CNS axons to regenerate successfully.


BMP signaling is essential for development of skeletogenic and neurogenic cranial neural crest.
BMP signaling is essential for a wide variety of developmental processes. To evaluate the role of Bmp2/4 in cranial neural crest (CNC) formation or differentiation after its migration into the branchial arches, we used Xnoggin to block their activities in specific areas of the CNC in transgenic mice. This resulted in depletion of CNC cells from the targeted areas. As a consequence, the branchial arches normally populated by the affected neural crest cells were hypomorphic and their skeletal and neural derivatives failed to develop. In further analyses, we have identified Bmp2 as the factor required for production of migratory cranial neural crest. Its spatial and temporal expression patterns mirror CNC emergence and Bmp2 mutant embryos lack both branchial arches and detectable migratory CNC cells. Our results provide functional evidence for an essential role of BMP signaling in CNC development.


Nicotine facilitates nicotinic acetylcholine receptor targeting to mitochondria but makes them less susceptible to selective ligands.
Several nicotinic acetylcholine receptor (nAChR) subtypes are expressed in mitochondria to regulate the internal pathway of apoptosis in ion channel-independent manner. However, the mechanisms of nAChR activation in mitochondria and targeting to mitochondria are still unknown. Nicotine has been shown to favor nAChR pentamer assembly, folding, and maturation on the way of biosynthesis. The idea of the present work was to determine whether nicotine affects the content, glycosylation, and function of mitochondrial nAChRs. Experiments were performed in isolated liver mitochondria from mice, that either consumed or not nicotine with the drinking water (200μL/L) for 7days. Mitochondria detergent lysates were studied by sandwich or lectin ELISA for the presence and carbohydrate composition of different nAChR subunits. Intact mitochondria were examined by flow cytometry for the binding of fluorescently labeled α-cobratoxin and were tested in functional assay of cytochrome c release under the effect of either Ca2+ or wortmannin in the presence or absence of nAChR-selective ligands, including PNU-282987 (1nM), dihydro-β-erythroidine (DhβE, 1μM), PNU-120596 (0.3, 3, or 10μM) and desformylflustrabromine hydrochloride (dFBr, 0.001, 0.3, or 1μM). It was found that nicotine consumption increased the ratio of mitochondrial vs non-mitochondrial nAChRs in the liver, enhanced fucosylation of mitochondrial nAChRs, but prevented the binding of α-cobratoxin and the cytochrome c release-attenuating effects of nAChR-specific agonists, antagonists, or positive allosteric modulators. It is concluded that nicotine consumption in vivo favors nAChR glycosylation and trafficking to mitochondria but makes them less susceptible to the effects of specific ligands.


A mouse with an N-Ethyl-N-nitrosourea (ENU) Induced Trp589Arg Galnt3 mutation represents a model for hyperphosphataemic familial tumoural calcinosis.
Mutations of UDP-N-acetyl-alpha-D-galactosamine polypeptide N-acetyl galactosaminyl transferase 3 (GALNT3) result in familial tumoural calcinosis (FTC) and the hyperostosis-hyperphosphataemia syndrome (HHS), which are autosomal recessive disorders characterised by soft-tissue calcification and hyperphosphataemia. To facilitate in vivo studies of these heritable disorders of phosphate homeostasis, we embarked on establishing a mouse model by assessing progeny of mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU), and identified a mutant mouse, TCAL, with autosomal recessive inheritance of ectopic calcification, which involved multiple tissues, and hyperphosphataemia; the phenotype was designated TCAL and the locus, Tcal. TCAL males were infertile with loss of Sertoli cells and spermatozoa, and increased testicular apoptosis. Genetic mapping localized Tcal to chromosome 2 (62.64-71.11 Mb) which contained the Galnt3. DNA sequence analysis identified a Galnt3 missense mutation (Trp589Arg) in TCAL mice. Transient transfection of wild-type and mutant Galnt3-enhanced green fluorescent protein (EGFP) constructs in COS-7 cells revealed endoplasmic reticulum retention of the Trp589Arg mutant and Western blot analysis of kidney homogenates demonstrated defective glycosylation of Galnt3 in Tcal/Tcal mice. Tcal/Tcal mice had normal plasma calcium and parathyroid hormone concentrations; decreased alkaline phosphatase activity and intact Fgf23 concentrations; and elevation of circulating 1,25-dihydroxyvitamin D. Quantitative reverse transcriptase-PCR (qRT-PCR) revealed that Tcal/Tcal mice had increased expression of Galnt3 and Fgf23 in bone, but that renal expression of Klotho, 25-hydroxyvitamin D-1α-hydroxylase (Cyp27b1), and the sodium-phosphate co-transporters type-IIa and -IIc was similar to that in wild-type mice. Thus, TCAL mice have the phenotypic features of FTC and HHS, and provide a model for these disorders of phosphate metabolism.


Trap and Replace: Defending Backdoor Attacks by Trapping Them into an Easy-to-Replace Subnetwork.
Deep neural networks (DNNs) are vulnerable to backdoor attacks. Previous works have shown it extremely challenging to unlearn the undesired backdoor behavior from the network, since the entire network can be affected by the backdoor samples. In this paper, we propose a brand-new backdoor defense strategy, which makes it much easier to remove the harmful influence of backdoor samples from the model. Our defense strategy, Trap and Replace, consists of two stages. In the first stage, we bait and trap the backdoors in a small and easy-to-replace subnetwork. Specifically, we add an auxiliary image reconstruction head on top of the stem network shared with a light-weighted classification head. The intuition is that the auxiliary image reconstruction task encourages the stem network to keep sufficient low-level visual features that are hard to learn but semantically correct, instead of overfitting to the easy-to-learn but semantically incorrect backdoor correlations. As a result, when trained on backdoored datasets, the backdoors are easily baited towards the unprotected classification head, since it is much more vulnerable than the shared stem, leaving the stem network hardly poisoned. In the second stage, we replace the poisoned light-weighted classification head with an untainted one, by re-training it from scratch only on a small holdout dataset with clean samples, while fixing the stem network. As a result, both the stem and the classification head in the final network are hardly affected by backdoor training samples. We evaluate our method against ten different backdoor attacks. Our method outperforms previous state-of-the-art methods by up to 20.57%, 9.80%, and 13.72% attack success rate and on-average 3.14%, 1.80%, and 1.21% clean classification accuracy on CIFAR10, GTSRB, and ImageNet-12, respectively. Code is available at https://github.com/VITA-Group/Trap-and-Replace-Backdoor-Defense.


Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt.
Proapoptotic nuclear receptor family member Nur77 translocates from the nucleus to the mitochondria, where it interacts with Bcl-2 to trigger apoptosis. Nur77 translocation is induced by certain apoptotic stimuli, including the synthetic retinoid-related 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN)/CD437 class. In this study, we investigated the molecular mechanism by which AHPN/CD437 analog (E)-4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) induces Nur77 nuclear export. Our results demonstrate that 3-Cl-AHPC effectively activated Jun N-terminal kinase (JNK), which phosphorylates Nur77. Inhibition of JNK activation by a JNK inhibitor suppressed 3-Cl-AHPC-induced Nur77 nuclear export and apoptosis. In addition, several JNK upstream activators, including the phorbol ester TPA, anisomycin and MAPK kinase kinase-1 (MEKK1), phosphorylated Nur77 and induced its nuclear export. However, Nur77 phosphorylation by JNK, although essential, was not sufficient for inducing Nur77 nuclear export. Induction of Nur77 nuclear export by MEKK1 required a prolonged MEKK1 activation and was attenuated by Akt activation. Expression of constitutively active Akt prevented MEKK1-induced Nur77 nuclear export. Conversely, transfection of dominant-negative Akt or treatment with a phosphatidylinositol 3-kinase (PI3-K) inhibitor accelerated MEKK1-induced Nur77 nuclear export. Furthermore, mutation of an Akt phosphorylation residue Ser351 in Nur77 abolished the effect of Akt or the PI3-K inhibitor. Together, our results demonstrate that both activation of JNK and inhibition of Akt play a role in translocation of Nur77 from the nucleus to the cytoplasm.


Temporal ordering of interstitial cystitis/bladder pain syndrome and non-bladder conditions.
To examine the prevalence and timing of nonbladder conditions in a community cohort of women with symptoms of interstitial cystitis/bladder pain syndrome (IC/BPS). As part of the Rand Interstitial Cystitis Epidemiology (RICE) study, we identified 3397 community women who met a validated case definition for IC/BPS symptoms. Each completed a survey asking if they had a physician diagnose them as having irritable bowel syndrome, fibromyalgia, chronic fatigue syndrome, migraines, panic attacks, or depression. If a positive response was received, subjects were asked to provide the age of symptom onset. All subjects were also asked to provide the date of IC/BPS symptom onset. A total of 2185 women reported a diagnosis of at least one of the nonbladder conditions. Onset of bladder symptoms was not consistently earlier or later than the onset of nonbladder symptoms. Depression tended to occur earlier (P < .05), whereas fibromyalgia generally occurred later (P < .05). Mean age of onset was lowest for migraine symptoms, depression symptoms, and panic attacks symptoms, and greatest for fibromyalgia and chronic fatigue syndrome symptoms. Mean age of irritable bowel syndrome and IC/BPS symptom onset was between these other conditions. These findings confirm the common co-occurrence of IC/BPS with chronic nonbladder conditions. In women with IC/BPS symptoms and coexistent nonbladder conditions, bladder symptoms do not uniformly predate the nonbladder symptoms. These observations suggest that phenotypic progression from isolated bladder symptoms to regional/systemic symptoms is not a predominant pattern in IC/BPS, although such a pattern may occur in a subset of individuals.


Birth interval and the sex of children in a traditional African population: an evolutionary analysis.
Birth interval is a major determinant of rates of fertility, and is also a measure of parental investment in a child. In this paper the length of the birth interval in a traditional African population is analysed by sex of children. Birth intervals after the birth of a boy were significantly longer than after the birth of a girl, indicating higher parental investment in boys. However, in women of high parity, this differential disappeared. Birth intervals for women with no son were shorter than for those with at least one son. All these results are compatible with an evolutionary analysis of reproductive decision-making. First born sons have particularly high reproductive success, daughters have average reproductive success and late born sons have low reproductive success. The birth interval follows a similar trend, suggesting that longer birth intervals represent higher maternal investment in children of high reproductive potential.


Curcumin inhibited the arylamines N-acetyltransferase activity, gene expression and DNA adduct formation in human lung cancer cells (A549).
It is well known that N-acetyltransferase (NAT) plays an important role in the arylamine metabolism. We analysed the response of A549 human lung cancer cells for N-acetylation of 2-aminofluorene (AF) to curcumin. After curcumin treatment, the NAT activity was examined by HPLC, AF-DNA adduct formation was examined by HPLC, and NAT gene expression by polymerase chain reaction were detected. The NAT activity in the human A549 cells and cytosols was suppressed by curcumin in a dose-dependent manner. The results also demonstrated that gene expression (NAT1 mRNA) in human lung A549 tumor cells was inhibited and decreased by curcumin. After the incubation of human lung A549 tumor cells with AF with or without curcumin co-treatment, the cells were recovered and DNA was prepared and hydrolyzed to nucleotides. The adducted nucleotides were extracted into butanol and analyzation of AF-DNA adducts was done by HPLC. The results also demonstrated that curcumin decreases AF-DNA adduct formation in the human lung A549 tumor cells.


Influencing Adolescent Leisure Motivation: Intervention Effects of HealthWise South Africa.
This study investigates changes in self-reported motivation for leisure due to participation in HealthWise, a high school curriculum aimed at decreasing risk behavior and promoting health behavior. Participants were 2,193 mixed race adolescents (M = 14 years old) from 9 schools (4 intervention, 5 control) near Cape Town, South Africa. Students in the HealthWise school with the greatest involvement in teacher training and implementation fidelity reported increased intrinsic and identified motivation and decreased introjected motivation and amotivation compared to students in control schools. These results point to the potential for intervention programming to influence leisure motivation among adolescents in South Africa and represent a first step toward identifying leisure motivation as a mediator of program effects.


Induction of premature termination of transcription of the mouse beta-globin gene by 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB).
Hybridization of pulse-labeled RNA from DRB-treated Friend cells to mouse beta-globin cDNA revealed that the appearance of beta-globin mRNA in the cytoplasm was inhibited by greater than 87%. To examine the effect of DRB (125 microM) on HnRNA synthesis, nuclear RNA was electrophoresed in methyl mercuric hydroxide gels, transferred to nitrocellulose, and hybridized with beta-globin specific probes. Full-length nuclear transcripts, while present in untreated cells, were not detected in DRB-treated cells. Using restriction enzymes, the cloned beta-globin gene was divided into fragments proceeding from the 5' gene region to the 3' gene region. RNA labeled in vitro by transcription in nuclei isolated from DRB-treated cells hybridized only to the promoter proximal DNA fragment. Transcripts hybridizing to fragments from both the 5' and 3' regions of the gene were produced in nuclei from untreated cells. Together these results indicate that DRB causes premature termination of transcription within the beta-globin gene.


Peripherin is a biomarker of axonal damage in peripheral nervous system disease.
Valid, responsive blood biomarkers specific to peripheral nerve damage would improve management of peripheral nervous system (PNS) diseases. Neurofilament light chain (NfL) is sensitive for detecting axonal pathology but is not specific to PNS damage, as it is expressed throughout the PNS and CNS. Peripherin, another intermediate filament protein, is almost exclusively expressed in peripheral nerve axons. We postulated that peripherin would be a promising blood biomarker of PNS axonal damage. We demonstrated that peripherin is distributed in sciatic nerve, and to a lesser extent spinal cord tissue lysates, but not in brain or extra-neural tissues. In the spinal cord, anti-peripherin antibody bound only to the primary cells of the periphery (anterior horn cells, motor axons and primary afferent sensory axons). In vitro models of antibody-mediated axonal and demyelinating nerve injury showed marked elevation of peripherin levels only in axonal damage and only a minimal rise in demyelination. We developed an immunoassay using single molecule array technology for the detection of serum peripherin as a biomarker for PNS axonal damage. We examined longitudinal serum peripherin and NfL concentrations in individuals with Guillain-Barré syndrome (GBS, n = 45, 179 time points), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP, n = 35, 70 time points), multiple sclerosis (n = 30), dementia (as non-inflammatory CNS controls, n = 30) and healthy individuals (n = 24). Peak peripherin levels were higher in GBS than all other groups (median 18.75 pg/ml versus < 6.98 pg/ml, P < 0.0001). Peak NfL was highest in GBS (median 220.8 pg/ml) and lowest in healthy controls (median 5.6 pg/ml), but NfL did not distinguish between CIDP (17.3 pg/ml), multiple sclerosis (21.5 pg/ml) and dementia (29.9 pg/ml). While peak NfL levels were higher with older age (rho = +0.39, P < 0.0001), peak peripherin levels did not vary with age. In GBS, local regression analysis of serial peripherin in the majority of individuals with three or more time points of data (16/25) displayed a rise-and-fall pattern with the highest value within the first week of initial assessment. Similar analysis of serial NfL concentrations showed a later peak at 16 days. Group analysis of serum peripherin and NfL levels in GBS and CIDP patients were not significantly associated with clinical data, but in some individuals with GBS, peripherin levels appeared to better reflect clinical outcome measure improvement. Serum peripherin is a promising new, dynamic and specific biomarker of acute PNS axonal damage.


Simulations of skin barrier function: free energies of hydrophobic and hydrophilic transmembrane pores in ceramide bilayers.
Transmembrane pore formation is central to many biological processes such as ion transport, cell fusion, and viral infection. Furthermore, pore formation in the ceramide bilayers of the stratum corneum may be an important mechanism by which penetration enhancers such as dimethylsulfoxide (DMSO) weaken the barrier function of the skin. We have used the potential of mean constraint force (PMCF) method to calculate the free energy of pore formation in ceramide bilayers in both the innate gel phase and in the DMSO-induced fluidized state. Our simulations show that the fluid phase bilayers form archetypal water-filled hydrophilic pores similar to those observed in phospholipid bilayers. In contrast, the rigid gel-phase bilayers develop hydrophobic pores. At the relatively small pore diameters studied here, the hydrophobic pores are empty rather than filled with bulk water, suggesting that they do not compromise the barrier function of ceramide membranes. A phenomenological analysis suggests that these vapor pores are stable, below a critical radius, because the penalty of creating water-vapor and tail-vapor interfaces is lower than that of directly exposing the strongly hydrophobic tails to water. The PMCF free energy profile of the vapor pore supports this analysis. The simulations indicate that high DMSO concentrations drastically impair the barrier function of the skin by strongly reducing the free energy required for pore opening.


Short-term complications of the Latarjet procedure.
Although the results of the Latarjet procedure have been reported previously, there is little literature regarding the early complications of this procedure. The purpose of this study was to report our experience with the Latarjet procedure for glenohumeral instability and to highlight the initial complications that may occur following this procedure. Forty-seven patients (forty-eight shoulders) underwent the Latarjet procedure for anterior glenohumeral instability between January 2005 and January 2010. All shoulders had some osseous deficiency of the anterior glenoid rim or had undergone an unsuccessful prior soft-tissue Bankart repair. The minimum duration of patient follow-up was six months. Forty-five shoulders were available for follow-up. The overall complication rate was 25% (twelve of the original forty-eight shoulders). Complications were divided into three groups: infection, recurrent glenohumeral instability, and neurologic injury. A superficial infection developed in three shoulders (6%); in all cases, the infection resolved following irrigation and debridement and administration of antibiotics for up to four weeks. Four shoulders (8%) developed recurrent glenohumeral instability; this occurred within eight months in two shoulders and at nineteen and forty-two months postoperatively in the other two. Five procedures (10%) resulted in a neurologic injury. Two of these involved the musculocutaneous nerve, one involved the radial nerve, and two involved the axillary nerve. The three musculocutaneous and radial nerve injuries involved sensory neurapraxia that resolved fully within two months. Both of the patients with axillary nerve dysfunction continued to have persistent sensory disturbances and one continued to have residual weakness that had not yet resolved fully at the time of the final follow-up. The overall complication rate of 25% is higher than that reported in the literature. Although most of these complications resolved completely, two patients continued to have residual neurologic symptoms. Patients should be informed of the risk of complications associated with the Latarjet procedure, although most of the potential complications will resolve.


A Systematic Review of Black American Same-Sex Couples Research: Laying the Groundwork for Culturally-Specific Research and Interventions.
ABSTRACTThis article presents the findings of a systematic review of the empirical literature related to Black American same-sex couples (BASCs). We found 16 articles that met inclusion criteria. Most articles were published in journals that focused on interdisciplinary studies, HIV/AIDS, and couples and families' studies. Approximately 63% of the articles reported external funding support. However, only one of these grants was awarded to a Black investigator. Articles predominately focused on BASCs composed of Black sexual minority men residing in major U.S. cities. Only 25% of the articles focused on couples where both partners were Black. Most studies were cross-sectional, used convenience samples, and were reported without mention of a theoretical framework that explicated the philosophical assumptions that guided the research. The articles focused on a range of topics such as resilience, relationship dynamics, couple-level social support, rituals with extended families, and partner-health associations. The implications of these findings for advancing culturally-specific behavioral and social science health research and interventions with BASCs are presented.


Clinical characteristics associated with Mycoplasma genitalium among female sex workers in Nairobi, Kenya.
The prevalence of Mycoplasma genitalium is high in vulnerable populations of women in low-resource settings. However, the epidemiology of infection in these populations is not well established. To determine the prevalence of Mycoplasma genitalium and its association with cervical cytology and other correlates, we recruited 350 female sex workers (FSW) who were 18 to 50 years old in Nairobi, Kenya, for a cross-sectional study. A questionnaire was administered at baseline to obtain information on sociodemographics and sexual behaviors. Women underwent a pelvic exam, during which a physician collected cervical-exfoliation samples for conventional cytology and sexually transmitted infection (STI) testing. Samples were tested for M. genitalium and other STI organisms (Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis) and the E6/E7 mRNA of human papillomavirus (HPV) by Aptima nucleic amplification assays. The prevalence of M. genitalium was 12.9%. FSW who engaged in sexual intercourse during menses were less likely to have M. genitalium infection than those who did not (odds ratio [OR], 0.3; 95% confidence interval [95% CI], 0.1, 0.9). M. genitalium was also less prevalent among FSW who had worked in prostitution for >5 years (6.2%) than among those who had worked for <3 years (17.6%) (OR, 0.3; 95% CI, 0.1, 0.8). FSW who reported more frequent condom use were more likely to be infected with M. genitalium than those who reported less frequent use (OR, 3.8; 95% CI, 1.2, 11.6). These correlates differ from those found in M. genitalium studies conducted with FSW from West Africa and China. Further longitudinal analyses assessing associations with persistent M. genitalium infection are needed.


Phase II enzymes induction blocks the enhanced IgE production in B cells by diesel exhaust particles.
Oxidant pollutants such as diesel exhaust particles (DEPs) can initiate and exacerbate airway allergic responses through enhanced IgE production. These effects are especially pronounced in individuals in whom phase II antioxidant enzyme responses are impaired. We confirmed that DEPs and DEP extracts (DEPX) can act directly on B lymphocytes and showed that DEPX could enhance IgH epsilon germline transcription in a B cell line and in PBMCs. We therefore studied the regulation in B cells of NAD(P)H: quinone oxidoreductase (NQO1) as a typical model phase II enzyme and its role in modulating DEPX-enhanced IgE responses. DEPX increased NQO1 mRNA expression in a dose-dependent manner. NQO1 protein induction by DEPX was confirmed by Western blot. DEPs induced activity of the antioxidant response element located in the NQO1 gene promoter. Induction of both NQO1 mRNA and protein expression could be blocked by coculture with an antioxidant and partly repressed by inhibitors of PI3K and p38 MAPK, but not by inhibitors of MAPK/ERK kinase (MEK/ERK) or protein kinase C. The ability of DEPX to enhance IgE production was blocked by the induction of phase II enzymes, including NQO1 in B cells by the chemical sulforaphane. These findings suggest that a natural protective mechanism in B cells from oxidant pollutants such as diesel particles is the expression of phase II enzymes through induction of antioxidant response elements and support the approach of overexpression of these enzymes as a potential future chemopreventative strategy.


Proximal junctional failure in primary thoracolumbar fusion/fixation to the sacrum/pelvis for adult symptomatic lumbar scoliosis: long-term follow-up of a prospective multicenter cohort of 160 patients.
Proximal junctional failure (PJF) is a severe form of proximal junctional kyphosis. Previous reports on PJF have been limited by heterogeneous cohorts and relatively short follow-ups. The authors' objectives herein were to identify risk factors for PJF and to assess its long-term incidence and revision rates in a homogeneous cohort. The authors reviewed data from the Adult Symptomatic Lumbar Scoliosis 1 trial (ASLS-1), a National Institutes of Health-sponsored prospective multicenter study. Inclusion criteria were an age ≥ 40 years, ASLS (Cobb angle ≥ 30° and Oswestry Disability Index [ODI] ≥ 20 or Scoliosis Research Society revised 22-item questionnaire [SRS-22r] score ≤ 4.0 in pain, function, or self-image domains), and primary thoracolumbar fusion/fixation to the sacrum/pelvis of ≥ 7 levels. PJF was defined as a postoperative proximal junctional angle (PJA) change > 20°, fracture of the uppermost instrumented vertebra (UIV) or UIV+1 with > 20% vertebral height loss, spondylolisthesis of UIV/UIV+1 > 3 mm, or UIV screw dislodgment. One hundred sixty patients (141 women) were included in this analysis and had a median age of 62 years and a mean follow-up of 4.3 years (range 0.1-6.1 years). Forty-six patients (28.8%) had PJF at a median of 0.92 years (IQR 0.14, 1.23 years) following surgery. Based on Kaplan-Meier analyses, PJF rates at 1, 2, 3, and 4 years were 14.4%, 21.9%, 25.9%, and 27.4%, respectively. On univariate analysis, PJF was associated with greater age (p = 0.0316), greater body mass index (BMI; p = 0.0319), worse baseline patient-reported outcome measures (PROMs; ODI, SRS-22r, and SF-12 Physical Component Summary [PCS]; all p < 0.04), the use of posterior column osteotomies (PCOs; p = 0.0039), and greater postoperative thoracic kyphosis (TK; p = 0.0031) and PJA (p < 0.001). The use of UIV hooks was protective against PJF (p = 0.0340). On regression analysis (without postoperative measures), PJF was associated with greater BMI (HR 1.077, 95% CI 1.007-1.153, p = 0.0317), lower preoperative PJA (HR 0.607, 95% CI 0.407-0.906, p = 0.0146), and greater preoperative TK (HR 1.362, 95% CI 1.082-1.715, p = 0.0085). Patients with PJF had worse PROMs at the last follow-up (ODI, SRS-22r subscore and self-image, and SF-12 PCS; p < 0.04). Sixteen PJF patients (34.8%) underwent revision, and PJF recurred in 3 (18.8%). Among 160 primary ASLS patients with a median age of 62 years and predominant coronal deformity, the PJF rate was 28.8% at a mean 4.3-year follow-up, with a revision rate of 34.8%. On univariate analysis, PJF was associated with a greater age and BMI, worse baseline PROMs, the use of PCOs, and greater postoperative TK and PJA. The use of UIV hooks was protective against PJF. On multivariate analysis (without postoperative measures), a higher risk of PJF was associated with greater BMI and preoperative TK and lower preoperative PJA.


Fluorescent Protein Approaches in Alpha Herpesvirus Research.
In the nearly two decades since the popularization of green fluorescent protein (GFP), fluorescent protein-based methodologies have revolutionized molecular and cell biology, allowing us to literally see biological processes as never before. Naturally, this revolution has extended to virology in general, and to the study of alpha herpesviruses in particular. In this review, we provide a compendium of reported fluorescent protein fusions to herpes simplex virus 1 (HSV-1) and pseudorabies virus (PRV) structural proteins, discuss the underappreciated challenges of fluorescent protein-based approaches in the context of a replicating virus, and describe general strategies and best practices for creating new fluorescent fusions. We compare fluorescent protein methods to alternative approaches, and review two instructive examples of the caveats associated with fluorescent protein fusions, including describing several improved fluorescent capsid fusions in PRV. Finally, we present our future perspectives on the types of powerful experiments these tools now offer.