Time course of Gag protein assembly in HIV-1-infected cells: a study by immunoelectron microscopy.
Recent biochemical studies have identified high molecular complexes of the HIV Gag precursor in the cytosol of infected cells. Using immunoelectron microscopy we studied the time course of the synthesis and assembly of a HIV Gag precursor protein (pr55gag) in Sf9 cells infected with recombinant baculovirus expressing the HIV gag gene. We also immunolabeled for pr55gag human T4 cells acutely or chronically infected with HIV-1. In Sf9 cells, the time course study showed that the first Gag protein appeared in the cytoplasm at 28-30 h p.i. and that budding started 6-8 h later. Colloidal gold particles, used to visualize the Gag protein, were first scattered randomly throughout the cytoplasm, but soon clusters representing 100 to 1000 copies of pr55gag were also observed. By contrast, in cells with budding or released virus-like particles the cytoplasm was virtually free of gold particles while the released virus-like particles were heavily labeled. Statistical analysis showed that between 80 and 90% of the gold particles in the cytoplasm were seen as singles, as doublets, or in small groups of up to five particles probably representing small oligomers. Clusters of gold particles were also observed in acutely infected lymphocytes as well as in multinuclear cells of chronically infected cultures of T4 cells. In a few cases small aggregates of gold particles were found in the nuclei of T4 lymphocytes. These observations suggest that the Gag polyprotein forms small oligomers in the cytoplasm of expressing cells but that assembly into multimeric complexes takes place predominantly at the plasma membrane. Large accumulations of Gag protein in the cytoplasm may represent misfolded molecules destined for degradation.


Pulmonary effects in workers exposed to indium metal: A cross-sectional study.
Indium was added to the list of substances regulated by the Ordinance on Prevention of Hazards due to Specified Chemical Substances (OPHSCS) in 2013. Indium metal (IM), however, is not regulated by the OPHSCS due to insufficient information on pulmonary effects following exposure. From 2011 to 2013, a cross-sectional study was conducted on 141 IM-exposed workers at 11 factories. Subjective symptoms were assessed, including levels of serum biomarkers, spirometry readings and total and diffuse lung capacity. Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D) were selected as biomarkers of interstitial pneumonia. Indium serum concentration (In-S) and personal air sampling data were used to estimate exposure. Subjects were categorized into 5 groups based on occupation and type of exposure: smelting, soldering, dental technician, bonding and other. The highest level of In-S was 25.4 µg/l, and the mean In-S level was significantly higher in the smelting group than in other groups. In the smelting group, the prevalence of increased In-S levels was 9.1%, while that of abnormal KL-6 was 15.2%. A significant dose-effect relationship was observed between the In-S and KL-6 levels. No marked differences were observed between any of the groups in SP-D values, pulmonary symptoms, or pulmonary function test results. A total of 31% of the subjects worked in an environment with IM levels exceeding 0.3 µg/m(3), which requires a protective mask to be worn. For workers exposed to IM, work environments should be monitored, appropriate protective masks should be worn, and medical monitoring should be conducted according to the OPHSCS.


Transgenic expression of the dicotyledonous pattern recognition receptor EFR in rice leads to ligand-dependent activation of defense responses.
Plant plasma membrane localized pattern recognition receptors (PRRs) detect extracellular pathogen-associated molecules. PRRs such as Arabidopsis EFR and rice XA21 are taxonomically restricted and are absent from most plant genomes. Here we show that rice plants expressing EFR or the chimeric receptor EFR::XA21, containing the EFR ectodomain and the XA21 intracellular domain, sense both Escherichia coli- and Xanthomonas oryzae pv. oryzae (Xoo)-derived elf18 peptides at sub-nanomolar concentrations. Treatment of EFR and EFR::XA21 rice leaf tissue with elf18 leads to MAP kinase activation, reactive oxygen production and defense gene expression. Although expression of EFR does not lead to robust enhanced resistance to fully virulent Xoo isolates, it does lead to quantitatively enhanced resistance to weakly virulent Xoo isolates. EFR interacts with OsSERK2 and the XA21 binding protein 24 (XB24), two key components of the rice XA21-mediated immune response. Rice-EFR plants silenced for OsSERK2, or overexpressing rice XB24 are compromised in elf18-induced reactive oxygen production and defense gene expression indicating that these proteins are also important for EFR-mediated signaling in transgenic rice. Taken together, our results demonstrate the potential feasibility of enhancing disease resistance in rice and possibly other monocotyledonous crop species by expression of dicotyledonous PRRs. Our results also suggest that Arabidopsis EFR utilizes at least a subset of the known endogenous rice XA21 signaling components.


Immunohistochemical analysis of in vivo patterns of Bak expression, a proapoptotic member of the Bcl-2 protein family.
The in vivo patterns of bak gene expression were determined in human tissues using an immunohistochemical approach. Polyclonal antisera were raised in rabbits against a synthetic peptide corresponding to amino acids 14-36 of the human Bak protein, and were shown to be specific by immunoblot analysis of various human tissues and cell lines. Bak immunoreactivity was detected in a wide variety of cell types and was typically present within the cytosol in a punctuate pattern suggestive of association with intracellular organelles. Consistent with a proapoptotic role for the Bak protein, gradients of Bak protein production were observed in the complex epithelia of the nasopharynx, esophagus, colon, and bladder, with Bak immunointensity being highest in the upper layers and relatively low in the basal portions of these epithelia. Similarly, in the myeloid series of hematopoietic cells, Bak immunoreactivity was strongest in the terminally differentiated granulocytes, with only weak immunostaining occurring in most progenitor cells in the bone marrow. Among the other cell types and tissues with prominent Bak immunostaining were: (a) cardiomyocytes; (b) vascular and visceral smooth muscle cells; (c) basal cells of the prostate glands; (d) myoepithelial cells of the mammary glands; (e) distal convoluted tubules of the kidney; (f) epidermal keratinocytes; (g) enterocytes of the small intestine; (h) Sertoli and Leidig cells of the testes; (i) theca interna cells in the ovary; and (j) adrenal cortex (but not adrenal medulla). Nearly all neurons and glial cells of the central nervous system did not contain immunodetectable Bak protein, whereas sympathetic neurons as well as neurons in dorsal root ganglia and their axons were Bak immunopositive. Most circulating peripheral blood lymphocytes were negative for Bak immunostaining, whereas strong Bak immunoreactivity was found frequently in lymphocytes in the nodes and spleen. Overall, these patterns of bak expression are unique compared to other members of the bcl-2 gene family, and suggest that bak regulates cell death at specific stages of cell differentiation through tissue-specific control of its expression.


Resonance enhancement of terahertz metamaterials by liquid crystals/indium tin oxide interfaces.
This work fabricates a terahertz (THz) metamaterial device, whose structure consists of split ring resonator array/ plastic substrate/ Indium Tin Oxide (ITO) film/ liquid crystals/ ITO film/ plastic substrate. Experiment results show that the resonance of the THz metamaterial device can be enhanced as voltage is applied to the liquid crystals. The enhancement will be more significant as higher voltage applied. The resonance enhancement is attributed to the fact that the liquid crystals/ITO interfaces exhibit the large difference in terms of refractive index between the two materials in THz regime. The interfaces reflect the incident electromagnetic wave and cause the reflected wave to enhance the resonance of the metamaterials. As those frequency-tunable metamaterial devices show different resonant transmittance at different frequencies, which is undesired, the liquid crystals/ITO interfaces can improve those frequency-tunable metamaterial devices with a constant transmittance at different frequencies.


Inhibition of tumor angiogenesis by Brahma Rasayana (BR).
The current therapy for prostate cancer includes radical prostatectomy, radiation therapy and hormonal ablation. Chemotherapy also provides beneficial results for some patients with advanced prostate cancer but with several harmful side effects. Hence there is a need to identify and develop alternate therapies, which can reduce the disease progression with minimal or few side effects. Earlier studies from our laboratory have shown that a Polyherbal mixture, Brahma Rasayna (BR) rich in anti-oxidant principles has a potential to be an anti-tumor agent. BR treatment of MAT-LyLu cell inoculated Copenhagen rats resulted in a decrease of palpable tumor incidence, delay in tumor occurrence and lower mean tumor volumes. Also, a significant reduction in tumor weight and lung metastasis was observed in BR treated animals in comparison to untreated controls. In the present study, we focused to examine the effect of BR on angiogenesis and regulation of molecular markers involved in angiogenesis using in-vivo and in-vitro models. BR treatment showed a significant reduction in Factor VIII expression compared to control indicating reduced angiogenesis. BR treated tumor specimens showed a decrease in the pro-angiogenic factors like VEGF, MMP-9 and MMP-2. Methanolic extract of BR was found to inhibit the proliferation, tube formation, cell migration and attachment of HUVEC on matrigel in a dose dependant manner. These findings suggest the possible mechanism(s) of action of BR in the reduction of tumor growth and metastatic spread.


Reduced rates of HIV acquisition during unprotected sex by Kenyan female sex workers predating population declines in HIV prevalence.
Female sex workers (FSWs) form a core group at high risk of both sexual HIV acquisition and secondary transmission. The magnitude of these risks may vary by sexual risk taking, partner HIV prevalence, host immune factors and genital co-infections. We examined temporal trends in HIV prevalence and per-act incidence, adjusted for behavioral and other variables, in FSWs from Nairobi, Kenya. An open cohort of FSWs followed since 1985. Behavioral and clinical data were collected six monthly from 1985 to 2005, and sexually transmitted infection (STI) diagnostics and HIV serology performed. A Cox proportional hazards model with time-dependent covariables was used to estimate infection risk as a function of calendar time. HIV prevalence in new FSW enrollees peaked at 81% in 1986, and was consistently below 50% after 1997. Initially uninfected FSWs remained at high risk of acquiring HIV throughout the study period, but the rate of HIV acquisition during unprotected sex with a casual client declined by over four-fold. This reduction correlated closely with decreases in gonorrhea prevalence, and predated reductions in the Kenyan HIV population prevalence by over a decade. The per-act rate of HIV acquisition in high-risk Nairobi FSWs fell dramatically between 1985 and 2005. This decline may represent the impact of improved STI prevention/therapy, immunogenetic shifts in at-risk women, or changes in the proportion of HIV exposures occurring with clients who had acute HIV infection. Declining HIV incidence in high-risk cohorts may predict and/or be causally related to future reductions in population prevalence.


Utility of Various Ultrafast Magnetic Resonance Sequences in the Detection of Fetal Intracranial Hemorrhage.
The aim of this study is to compare the images obtained from standard ultrafast magnetic resonance (MR) imaging sequences with gradient (GRE) sequence images in identifying fetal intracranial hemorrhage (ICH). MR images of fetal brains with ICH done between October 2012 and September 2015 were reviewed. The images obtained from four ultrafast MR sequences- Turbo Fast Low Angle Shot (Turbo FLASH) T1-weighted images, Half Fourier Acquisition single-shot turbo spin echo (HASTE) T2-weighted images, b0 images of diffusion-weighted imaging (DWI) and b800 images of DWI were compared with images obtained from GRE sequence in depicting fetal ICH. Out of the 212 fetuses during the study period, 15 fetuses had ICH. In the 15 fetuses with ICH as detected on GRE, Grade1 germinal matrix hemorrhage was seen in 5 fetuses, Grade 2 in 4 fetuses, Grade 3 in 3 fetuses, and Grade 4 in two fetuses. Subdural hemorrhage was seen in 1 fetus. In comparison to GRE sequence, b0 of DWI sequence was almost equal in the depiction of ICH. T2 HASTE sequence also delineated hemorrhage, although not as effectively as GRE and b0 images of images DWI. T1 Turbo FLASH and b800 images of DWI were less reliable in the depiction of fetal ICH but were useful in predicting the stage of hemorrhage. As compared to GRE sequence, b0 images of DWI followed by HASTE are the two preferred ultrafast sequences in the diagnosis of fetal ICH.


Feedback regulation of MAPK signalling by an RNA-binding protein.
Mitogen-activated protein kinases (MAPKs) are evolutionarily conserved enzymes that convert extracellular signals into various outputs such as cell growth, differentiation and cell death. MAPK phosphatases selectively inactivate MAPKs by dephosphorylating critical phosphothreonine and phosphotyrosine residues. The transcriptional induction of MAPK phosphatase expression by various stimuli, including MAPK activation, has been well documented as a negative-feedback mechanism of MAPK signalling. Here we show that Rnc1, a novel K-homology-type RNA-binding protein in fission yeast, binds and stabilizes Pmp1 messenger RNA, the MAPK phosphatase for Pmk1 (refs 10, 11). Rnc1 therefore acts as a negative regulator of Pmk1 signalling. Notably, Pmk1 phosphorylates Rnc1, causing enhancement of the RNA-binding activity of Rnc1. Thus, Rnc1 is a component of a new negative-feedback loop that regulates the Pmk1 pathway through its binding to Pmp1 mRNA. Our findings--the post-transcriptional mRNA stabilization of a MAPK phosphatase mediated by an RNA-binding protein--provide an additional regulatory mechanism for fine-tuning of MAPK signalling pathways.


Ventricular tachycardia late after repair of congenital heart disease: efficacy of combination therapy with radiofrequency catheter ablation and class III antiarrhythmic agents and long-term outcome.
This study investigated the treatment of ventricular tachycardia (VT) after repair of tetralogy of Fallot or double outlet of the right ventricle. The ideal antiarrhythmic therapy for VT in patients after repair of congenital heart disease, especially without left ventricular dysfunction, has not yet been established. Seven consecutive patients (2 women and 5 men) with stable monomorphic sustained VT were investigated. The mean age was 25 +/- 7 years (range, 16-35 years). Four patients had undergone surgical repair of tetralogy of Fallot, and 3 had surgical correction of double outlet of the right ventricle at the mean age of 18 +/- 7 years (range, 9-27 years) before documentation of the arrhythmia. The mean ejection fraction of the left ventricle was 60% +/- 8% (range, 50-72). Fourteen sustained monomorphic VTs were induced in 7 patients using programmed electrical stimulation. The mean cycle length of tachycardia was 346 +/- 77 milliseconds (range, 260-480 seconds). The site of the surgical correction of the right ventricle was associated with the origin of VT in all patients. Radiofrequency catheter ablation was attempted in 8 VTs in 7 patients: 7 clinical and 1 nonclinical VTs. In 6 patients, class III antarrhythmic agents were added because VT remained inducible after ablation. During a follow-up of 61 +/- 29 months (range, 15-110 months), there were no recurrences of VT. In patients with drug-refractory VT originating from the right ventricle late after congenital heart disease, and when their left ventricular function do not deteriorate, combined therapy for radiofrequency catheter ablation with class III antiarrhythmic agents might effective and should be considered as a therapeutic option.


Health and ill health of asylum seekers in Switzerland: an epidemiological study.
Although the focus of health care for people seeking asylum in Western European countries is usually on communicable diseases, there is little data about the general health care need of this population. In this study, we investigated the actual burden of disease among asylum seekers. Data were collected from a Swiss Health Maintenance Organisation (HMO; a type of managed care organization in which physicians act as gate keepers) that was set up specifically to provide health care for asylum seekers. The data included socio-demographic characteristics, international classification of diseases (ICD-10) diagnoses and number of clinic visits. Descriptive statistics were used to assess the types of health problems and the number of clinic visits. Logistic regression analysis was used to determine whether age, gender or country or region of origin was predictive in terms of incidence of disease as diagnosed by using ICD classifications. The total number of asylum seekers (mean age 22 years; 38% women) enrolled in the HMO from 2000 through 2003 was 979. Half of this group came from the former country of Yugoslavia. The remainder came primarily from sub-Saharan Africa, Turkey, Iraq and Sri Lanka. The most common health problems encountered in the population included musculoskeletal diseases, respiratory diseases, depression and post-traumatic stress disorder. The prevalence of all disease clusters was significantly associated with age. One-fifth of the population did not request health care at all during the time they were enrolled in the HMO. It is not known whether those who did not visit the medical clinic did not require health care or just chose not to request clinic services. The most frequent health problems encountered in the study population were chronic medical conditions, not communicable acute diseases. Although health care services provided to asylum seekers usually focus on episodic acute care, what this group actually needs is continuity of care.


Comparison of fracture risk prediction among individuals with reduced and normal kidney function.
The Fracture Risk Assessment Tool (FRAX) is widely used to predict the 10-year probability of fracture; however, the clinical utility of FRAX in CKD is unknown. This study assessed the predictive ability of FRAX in individuals with reduced kidney function compared with individuals with normal kidney function. The discrimination and calibration (defined as the agreement between observed and predicted values) of FRAX were examined using data from the Canadian Multicentre Osteoporosis Study (CaMos). This study included individuals aged ≥40 years with an eGFR value at year 10 of CaMos (defined as baseline). The cohort was stratified by kidney function at baseline (eGFR<60 ml/min per 1.73 m(2) [72.2% stage 3a, 23.8% stage 3b, and 4.0% stage 4/5] versus ≥60 ml/min per 1.73 m(2)) and followed individuals for a mean of 4.8 years for an incident major osteoporotic fracture (clinical spine, hip, forearm/wrist, or humerus). There were 320 individuals with an eGFR<60 ml/min per 1.73 m(2) and 1787 with an eGFR≥60 ml/min per 1.73 m(2). The mean age was 67±10 years and 71% were women. The 5-year observed major osteoporotic fracture risk was 5.3% (95% confidence interval [95% CI], 3.3% to 8.6%) in individuals with an eGFR<60 ml/min per 1.73 m(2), which was comparable to the FRAX-predicted fracture risk (6.4% with bone mineral density; 8.2% without bone mineral density). A statistically significant difference was not observed in the area under the curve values for FRAX in individuals with an eGFR<60 ml/min per 1.73 m(2) versus ≥60 ml/min per 1.73 m(2) (0.69 [95% CI, 0.54 to 0.83] versus 0.76 [95% CI, 0.70 to 0.82]; P=0.38). This study showed that FRAX was able to predict major osteoporotic fractures in individuals with reduced kidney function; further study is needed before FRAX should be routinely used in individuals with reduced kidney function.


Factors associated with experiencing sexual violence among female gender-based violence survivors in conflict-afflicted eastern Ukraine.
Since 2014, over 1.6 million people have been forcibly displaced by the conflict in eastern Ukraine. In 2014, 8% of reproductive-aged women in Ukraine had ever experienced sexual violence, compared to 5% in 2007. This increase was driven by non-domestic sexual violence. Our study examined characteristics of women in eastern Ukraine receiving psychosocial services following sexual violence compared to survivors of other forms of gender-based violence. Intake data collected between February 2016 and June 2017 by psychosocial service providers in five conflict-affected areas of Ukraine from women, aged 15-49, (N = 8525), was analyzed. Descriptive analysis and covariate adjusted logistic and negative binomial regressions were used to identify socioeconomic, incident and access to services factors associated with having experienced sexual violence compared to other forms of violence. Among this sample of survivors receiving psychosocial services, 2.6% (n = 220) reported experiencing sexual violence. A majority of sexual violence acts reported were committed by non-domestic perpetrators (61.4%); followed by intimate partners (25.9%). Almost half of sexual violence cases occurred at home (49.1%). Experiencing sexual violence was positively associated with being younger, single and internally displaced, and negatively with engaging in unpaid labor, such as childcare. Women who experienced sexual violence delayed seeking care by 4 days compared to other gender-based violence survivors. Sexual violence survivors were less likely than physical violence survivors to have reported the incident prior to receiving care (adjusted odds ratio = 0.39; 95% confidence interval = 0.28-0.54). Non-domestic and intimate partner sexual violence were both prevalent in our sample. Compared to survivors disclosing other types of gender-based violence, sexual violence survivors appear to face unique barriers to reporting and accessing timely care. Prevention and outreach programs tailored to the specific vulnerabilities, such as displacement status, and needs of sexual violence survivors in conflict settings are urgently needed.


KRAS Suppression-Induced Degradation of MYC Is Antagonized by a MEK5-ERK5 Compensatory Mechanism.
Our recent ERK1/2 inhibitor analyses in pancreatic ductal adenocarcinoma (PDAC) indicated ERK1/2-independent mechanisms maintaining MYC protein stability. To identify these mechanisms, we determined the signaling networks by which mutant KRAS regulates MYC. Acute KRAS suppression caused rapid proteasome-dependent loss of MYC protein, through both ERK1/2-dependent and -independent mechanisms. Surprisingly, MYC degradation was independent of PI3K-AKT-GSK3β signaling and the E3 ligase FBWX7. We then established and applied a high-throughput screen for MYC protein degradation and performed a kinome-wide proteomics screen. We identified an ERK1/2-inhibition-induced feedforward mechanism dependent on EGFR and SRC, leading to ERK5 activation and phosphorylation of MYC at S62, preventing degradation. Concurrent inhibition of ERK1/2 and ERK5 disrupted this mechanism, synergistically causing loss of MYC and suppressing PDAC growth.


The ZInEP Epidemiology Survey: background, design and methods.
This article introduces the design, sampling, field procedures and instruments used in the ZInEP Epidemiology Survey. This survey is one of six ZInEP projects (Zürcher Impulsprogramm zur nachhaltigen Entwicklung der Psychiatrie, i.e. the "Zurich Program for Sustainable Development of Mental Health Services"). It parallels the longitudinal Zurich Study with a sample comparable in age and gender, and with similar methodology, including identical instruments. Thus, it is aimed at assessing the change of prevalence rates of common mental disorders and the use of professional help and psychiatric sevices. Moreover, the current survey widens the spectrum of topics by including sociopsychiatric questionnaires on stigma, stress related biological measures such as load and cortisol levels, electroencephalographic (EEG) and near-infrared spectroscopy (NIRS) examinations with various paradigms, and sociophysiological tests. The structure of the ZInEP Epidemiology Survey entails four subprojects: a short telephone screening using the SCL-27 (n of nearly 10,000), a comprehensive face-to-face interview based on the SPIKE (Structured Psychopathological Interview and Rating of the Social Consequences for Epidemiology: the main instrument of the Zurich Study) with a stratified sample (n = 1500), tests in the Center for Neurophysiology and Sociophysiology (n = 227), and a prospective study with up to three follow-up interviews and further measures (n = 157). In sum, the four subprojects of the ZInEP Epidemiology Survey deliver a large interdisciplinary database.


Fingolimod additionally acts as immunomodulator focused on the innate immune system beyond its prominent effects on lymphocyte recirculation.
Growing evidence emphasizes the relevance of sphingolipids for metabolism and immunity of antigen-presenting cells (APC). APCs are key players in balancing tolerogenic and encephalitogenic responses in immunology. In contrast to the well-known prominent effects of sphingosine-1-phosphate (S1P) on lymphocyte trafficking, modulatory effects on APCs have not been fully characterized. Frequencies and activation profiles of dendritic cell (DC) subtypes, monocytes, and T cell subsets in 35 multiple sclerosis (MS) patients were evaluated prior and after undergoing fingolimod treatment for up to 24 months. Impact of fingolimod and S1P on maturation and activation profile, pro-inflammatory cytokine release, and phagocytotic capacity was assessed in vitro and ex vivo. Modulation of DC-dependent programming of naïve CD4+ T cells, as well as CD4+ and CD8+ T cell proliferation, was also investigated in vitro and ex vivo. Fingolimod increased peripheral slanDC count-CD1+ DC, and monocyte frequencies remained stable. While CD4+ T cell count decreased, ratio of Treg/Th17 significantly increased in fingolimod-treated patients over time. CD83, CD150, and HLADR were all inhibited, but CD86 was upregulated in DCs after incubation in the presence of fingolimod. Fingolimod but not S1P was associated with reduced release of pro-inflammatory cytokines from DCs and monocytes in vitro and ex vivo. Fingolimod also inhibited phagocytic capacity of slanDCs and monocytes. After fingolimod, slanDCs demonstrated reduced potential to induce interferon-gamma-expressing Th1 or IL-17-expressing Th17 cells and DC-dependent T cell proliferation in vitro and in fingolimod-treated patients. We present the first evidence that S1P-directed therapies can act additionally as immunomodulators that decrease the pro-inflammatory capabilities of APCs, which is a crucial element in DC-dependent T cell activation and programming.


Same, same but different: symbiotic bacterial associations in GBR sponges.
Symbioses in marine sponges involve diverse consortia of microorganisms that contribute to the health and ecology of their hosts. The microbial communities of 13 taxonomically diverse Great Barrier Reef (GBR) sponge species were assessed by DGGE and 16S rRNA gene sequencing to determine intra and inter species variation in bacterial symbiont composition. Microbial profiling revealed communities that were largely conserved within different individuals of each species with intra species similarity ranging from 65-100%. 16S rRNA gene sequencing revealed that the communities were dominated by Proteobacteria, Chloroflexi, Acidobacteria, Actinobacteria, Nitrospira, and Cyanobacteria. Sponge-associated microbes were also highly host-specific with no operational taxonomic units (OTUs) common to all species and the most ubiquitous OTU found in only 5 of the 13 sponge species. In total, 91% of the OTUs were restricted to a single sponge species. However, GBR sponge microbes were more closely related to other sponge-derived bacteria than they were to environmental communities with sequences falling within 50 of the 173 previously defined sponge-(or sponge-coral) specific sequence clusters (SC). These SC spanned the Acidobacteria, Actinobacteria, Proteobacteria, Bacteroidetes, Chloroflexi, Cyanobacteria, Gemmatimonadetes, Nitrospira, and the Planctomycetes-Verrucomicrobia-Chlamydiae superphylum. The number of sequences assigned to these sponge-specific clusters across all species ranged from 0 to 92%. No relationship between host phylogeny and symbiont communities were observed across the different sponge orders, although the highest level of similarity was detected in two closely related Xestospongia species. This study identifies the core microbial inhabitants in a range of GBR sponges thereby providing the basis for future studies on sponge symbiotic function and research aiming to predict how sponge holobionts will respond to environmental perturbation.


Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma.
Squamous cell carcinomas (SCCs) are one of the most frequent forms of human malignancy, but, other than TP53 mutations, few causative somatic aberrations have been identified. We identified NOTCH1 or NOTCH2 mutations in ~75% of cutaneous SCCs and in a lesser fraction of lung SCCs, defining a spectrum for the most prevalent tumor suppressor specific to these epithelial malignancies. Notch receptors normally transduce signals in response to ligands on neighboring cells, regulating metazoan lineage selection and developmental patterning. Our findings therefore illustrate a central role for disruption of microenvironmental communication in cancer progression. NOTCH aberrations include frameshift and nonsense mutations leading to receptor truncations as well as point substitutions in key functional domains that abrogate signaling in cell-based assays. Oncogenic gain-of-function mutations in NOTCH1 commonly occur in human T-cell lymphoblastic leukemia/lymphoma and B-cell chronic lymphocytic leukemia. The bifunctional role of Notch in human cancer thus emphasizes the context dependency of signaling outcomes and suggests that targeted inhibition of the Notch pathway may induce squamous epithelial malignancies.


-Book-shaped decellularized tendon matrix scaffold combined with bone marrow mesenchymal stem cells-sheets for repair of achilles tendon defect in rabbit.
Tissue-engineering approaches have great potential to improve the treatment of tendon injuries which are major musculoskeletal disorders. The purpose of this study was to assess the tissue engineering potential of a novel multilayered decellularized tendon "book" scaffold with bone marrow mesenchymal stem cells (BMSCs) sheets for repair of an Achilles tendon defect in a rabbit model. In this study, we developed a novel book-shaped decellularized scaffold derived from the extracellular matrix of tendon tissues from New Zealand white rabbits. Hematoxylin and eosin (H&E) staining, 4', 6-diamidino-2-phenylindole (DAPI) staining, DNA quantitation, and scanning electron microscopy (SEM) confirmed the efficiency of decellularization. After culturing BMSCs on decellularized scaffolds, 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, SEM, quantitative real time polymerase chain reaction (qRT-PCR), and immunofluorescence analysis demonstrated that decellularized scaffolds have the capacity to yield homogeneous distribution and alignment of BMSCs, as well as support their differentiation into tendon. Tenomodulin and Alpha-1 collagen type I are important indicators for evaluating tenogenic differentiation of BMSCs. When decellularized "book" scaffolds with BMSCs sheets were used to repair a 1 mm Achilles tendon defect, histomorphological analysis, immunohistochemical assessment, and biomechanical testing showed that the book-shaped decellularized tendon matrix scaffold and BMSCs sheets could promote the regeneration of type I collagen at the wound site during healing, and improve the mechanical properties of the repaired tendon. Therefore, the results of this study suggest that the novel decellularized "book" tendon scaffolds combined with BMSCs sheets have therapeutic effects on improving the healing quality of the Achilles tendon. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 9999:1-11, 2019.


Associations Between Systolic Interarm Differences in Blood Pressure and Cardiovascular Disease Outcomes and Mortality: Individual Participant Data Meta-Analysis, Development and Validation of a Prognostic Algorithm: The INTERPRESS-IPD Collaboration.
Systolic interarm differences in blood pressure have been associated with all-cause mortality and cardiovascular disease. We undertook individual participant data meta-analyses to (1) quantify independent associations of systolic interarm difference with mortality and cardiovascular events; (2) develop and validate prognostic models incorporating interarm difference, and (3) determine whether interarm difference remains associated with risk after adjustment for common cardiovascular risk scores. We searched for studies recording bilateral blood pressure and outcomes, established agreements with collaborating authors, and created a single international dataset: the Inter-arm Blood Pressure Difference - Individual Participant Data (INTERPRESS-IPD) Collaboration. Data were merged from 24 studies (53 827 participants). Systolic interarm difference was associated with all-cause and cardiovascular mortality: continuous hazard ratios 1.05 (95% CI, 1.02-1.08) and 1.06 (95% CI, 1.02-1.11), respectively, per 5 mm Hg systolic interarm difference. Hazard ratios for all-cause mortality increased with interarm difference magnitude from a ≥5 mm Hg threshold (hazard ratio, 1.07 [95% CI, 1.01-1.14]). Systolic interarm differences per 5 mm Hg were associated with cardiovascular events in people without preexisting disease, after adjustment for Atherosclerotic Cardiovascular Disease (hazard ratio, 1.04 [95% CI, 1.00-1.08]), Framingham (hazard ratio, 1.04 [95% CI, 1.01-1.08]), or QRISK cardiovascular disease risk algorithm version 2 (QRISK2) (hazard ratio, 1.12 [95% CI, 1.06-1.18]) cardiovascular risk scores. Our findings confirm that systolic interarm difference is associated with increased all-cause mortality, cardiovascular mortality, and cardiovascular events. Blood pressure should be measured in both arms during cardiovascular assessment. A systolic interarm difference of 10 mm Hg is proposed as the upper limit of normal. Registration: URL: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42015031227.


Deep brain stimulation abolishes slowing of reactions to unlikely stimuli.
The cortico-basal-ganglia circuit plays a critical role in decision making on the basis of probabilistic information. Computational models have suggested how this circuit could compute the probabilities of actions being appropriate according to Bayes' theorem. These models predict that the subthalamic nucleus (STN) provides feedback that normalizes the neural representation of probabilities, such that if the probability of one action increases, the probabilities of all other available actions decrease. Here we report the results of an experiment testing a prediction of this theory that disrupting information processing in the STN with deep brain stimulation should abolish the normalization of the neural representation of probabilities. In our experiment, we asked patients with Parkinson's disease to saccade to a target that could appear in one of two locations, and the probability of the target appearing in each location was periodically changed. When the stimulator was switched off, the target probability affected the reaction times (RT) of patients in a similar way to healthy participants. Specifically, the RTs were shorter for more probable targets and, importantly, they were longer for the unlikely targets. When the stimulator was switched on, the patients were still faster for more probable targets, but critically they did not increase RTs as the target was becoming less likely. This pattern of results is consistent with the prediction of the model that the patients on DBS no longer normalized their neural representation of prior probabilities. We discuss alternative explanations for the data in the context of other published results.


Molecular diagnostic for boll weevil (Coleoptera: Curculionidae) based on amplification of three species-specific microsatellites.
The boll weevil, Anthonomus grandis grandis Boheman (Coleoptera: Curculionidae), is a serious pest of cultivated cotton, Gossypium hirsutum L., in the Americas, and reinfestation of zones from which they have been eradicated is of perpetual concern. Extensive arrays of pheromone traps monitor for reintroductions, but occasionally the traps collect nontarget weevils that can be misidentified by scouts. For example, the congeneric pepper weevil, Anthonomus eugenii Cano, and other superficially similar weevils are attracted to components of the boll weevil lure or trap color. Although morphologically distinguishable by trained personnel, the potential for misidentification is compounded when captured weevils are dismembered or partially consumed by ants or ground beetles that sometimes feed on them in the traps. Because misidentification can have expensive consequences, a molecular diagnostic tool would be of great value to eradication managers. We demonstrate that a cocktail of three primer pairs in a single polymerase chain reaction (PCR) amplify species-specific microsatellites that unambiguously distinguish the boll weevil from three other weevil species tested, including pepper weevil; cranberry weevil, Anthonomus eugenii musculus Say; and pecan weevil, Curculio caryae Horn. However, it does not distinguish the boll weevil from the subspecific "thurberia" weevil. A universal internal transcribed spacer primer pair included in the cocktail cross-amplifies DNA from all species, serving as a positive control. Furthermore, the diagnostic primers amplified the target microsatellites from various boll weevil adult body parts, indicating that the PCR technology using the primer cocktail is sensitive enough to positively identify a boll weevil even when the body is partly degraded.


Barriers and facilitators of a near real-time feedback approach for measuring patient experiences of hospital care.
To contribute towards the current policy directive and recommendations outlined in the Francis Report (1) to strengthen relational aspects of hospital care and increase the use of a near real-time feedback (RTF) approach. This article offers insight into the challenges and enablers faced when collecting near real-time feedback of patient experiences with trained volunteers; and using the data to facilitate improvements. Feedback was collected from staff and volunteers before, during and after a patient experience data collection. This took the form of both formal mixed methods data collections via interviews, surveys and a diary; and informal anecdotal evidence, collected from meetings, workshops, support calls and a networking event. Various challenges and enablers associated with the RTF approach were identified. These related to technology, the setting, volunteer engagement and staff engagement. This article presents the key barriers experienced followed by methods suggested and utilised by staff and volunteers in order to counteract the difficulties faced. The results from this evaluation suggest that a near real-time feedback approach, when used in a hospital setting with trained volunteers, benefits from various support structures or systems to minimise the complications or burden placed on both staff and volunteers.


IL-10 production is enhanced in human T cells by IL-12 and IL-6 and in monocytes by tumor necrosis factor-alpha.
IL-10, an immunoregulatory cytokine produced by T cells and monocytes, inhibits the expression of inflammatory and hemopoietic cytokines as well as its own expression. To evaluate the regulation of IL-10 production by T cells and monocytes, we measured IL-10 levels by ELISA in supernatants of PHA-stimulated PBMC following depletion of either T cells or monocytes. IL-10 production was significantly down-regulated in both T cell- and monocyte-depleted PBMC compared with undepleted PBMC, and IL-10 production could be restored by the addition of monocyte-conditioned medium (supernatant of PHA-stimulated, T cell-depleted PBMC), suggesting that IL-10 production by T cells is regulated by a monokine(s) produced by activated monocytes. To further clarify the monokine(s) responsible for IL-10 induction, we stimulated monocyte-depleted PBMC, purified CD4+, and CD8+ T cells with PHA and measured IL-10 production by ELISA and semiquantitative reverse transcriptase-PCR following monokine(s) addition. Addition of IL-6 and IL-12 enhanced IL-10 production in monocyte-depleted PBMC in a dose-dependent and additive manner. Furthermore, anti-IL-6 and anti-IL-12 Abs neutralized the IL-10-inductive effect of monocyte-conditioned medium. Similarly, IL-12 and IL-6 induced IL-10 production by purified CD4+ and CD8+ T cells. With respect to regulation of IL-10 produced by monocytes, TNF-alpha was found to induce IL-10 production by resting as well as by LPS-stimulated purified monocytes/macrophages. Taken together, these findings suggest that IL-10 production by human T cells and monocytes is differentially regulated. IL-12 and/or IL-6 can induce the expression of IL-10 by PHA-stimulated T cells, whereas TNF-alpha induces IL-10 production by monocytes. Since IL-10 inhibits the production of IL-6, IL-12, and TNF-alpha, these results may indicate a potential mechanism of negative feedback regulation of the immune response.


Population-level cost-effectiveness of implementing evidence-based practices into routine care.
The objective of this research was to apply a new methodology (population-level cost-effectiveness analysis) to determine the value of implementing an evidence-based practice in routine care. Data are from sequentially conducted studies: a randomized controlled trial and an implementation trial of collaborative care for depression. Both trials were conducted in the same practice setting and population (primary care patients prescribed antidepressants). The study combined results from a randomized controlled trial and a pre-post-quasi-experimental implementation trial. The randomized controlled trial collected quality-adjusted life years (QALYs) from survey and medication possession ratios (MPRs) from administrative data. The implementation trial collected MPRs and intervention costs from administrative data and implementation costs from survey. In the randomized controlled trial, MPRs were significantly correlated with QALYs (p = .03). In the implementation trial, patients at implementation sites had significantly higher MPRs (p = .01) than patients at control sites, and by extrapolation higher QALYs (0.00188). Total costs (implementation, intervention) were nonsignificantly higher ($63.76) at implementation sites. The incremental population-level cost-effectiveness ratio was $33,905.92/QALY (bootstrap interquartile range -$45,343.10/QALY to $99,260.90/QALY). The methodology was feasible to operationalize and gave reasonable estimates of implementation value.


An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome.
Bronchiolitis obliterans syndrome (BOS) is a major complication of lung transplantation that is associated with poor survival. The International Society for Heart and Lung Transplantation, American Thoracic Society, and European Respiratory Society convened a committee of international experts to describe and/or provide recommendations for 1) the definition of BOS, 2) the risk factors for developing BOS, 3) the diagnosis of BOS, and 4) the management and prevention of BOS. A pragmatic evidence synthesis was performed to identify all unique citations related to BOS published from 1980 through to March, 2013. The expert committee discussed the available research evidence upon which the updated definition of BOS, identified risk factors and recommendations are based. The committee followed the GRADE (Grading of Recommendation, Assessment, Development and Evaluation) approach to develop specific clinical recommendations. The term BOS should be used to describe a delayed allograft dysfunction with persistent decline in forced expiratory volume in 1 s that is not caused by other known and potentially reversible causes of post-transplant loss of lung function. The committee formulated specific recommendations about the use of systemic corticosteroids, cyclosporine, tacrolimus, azithromycin and about re-transplantation in patients with suspected and confirmed BOS. The diagnosis of BOS requires the careful exclusion of other post-transplant complications that can cause delayed lung allograft dysfunction, and several risk factors have been identified that have a significant association with the onset of BOS. Currently available therapies have not been proven to result in significant benefit in the prevention or treatment of BOS. Adequately designed and executed randomised controlled trials that properly measure and report all patient-important outcomes are needed to identify optimal therapies for established BOS and effective strategies for its prevention.


Measuring the quality of medication use in older adults.
The quality of health care in the United States continues to fall short of expectations. A contributing factor is the suboptimal use of medications, a problem that is causing significant morbidity and mortality and costing the healthcare industry billions of dollars each year. Older adults are especially vulnerable to suboptimal quality medication use because of their concurrent medical conditions, multiple medications, and the physiological effects of aging on the use of drug therapy. In addition, older adults and their caregivers are often responsible for managing complex medication regimens. Efforts to measure the quality of medication use in older adults have traditionally focused on inappropriate medications and doses, select indicators of medication appropriateness, or diseases rather than the unique medication needs of individual patients. The goal is to move toward a measure that can account for the complexities of an individual's medication regimen and that is responsive to individual patient values and needs. The purpose of this article is to discuss the benefits and limitations of current strategies to measure the quality of medication use in older adults and, using a case study, illustrate the variations in quality measurement using existing measures. The article concludes with recommendations for moving toward a more-comprehensive approach to measuring the quality of medication use in older adults.


Multi-state modelling of repeated hospitalisation and death in patients with heart failure: The use of large administrative databases in clinical epidemiology.
In chronic diseases like heart failure (HF), the disease course and associated clinical event histories for the patient population vary widely. To improve understanding of the prognosis of patients and enable health care providers to assess and manage resources, we wish to jointly model disease progression, mortality and their relation with patient characteristics. We show how episodes of hospitalisation for disease-related events, obtained from administrative data, can be used as a surrogate for disease status. We propose flexible multi-state models for serial hospital admissions and death in HF patients, that are able to accommodate important features of disease progression, such as multiple ordered events and competing risks. Fully parametric and semi-parametric semi-Markov models are implemented using freely available software in R. The models were applied to a dataset from the administrative data bank of the Lombardia region in Northern Italy, which included 15,298 patients who had a first hospitalisation ending in 2006 and 4 years of follow-up thereafter. This provided estimates of the associations of age and gender with rates of hospital admission and length of stay in hospital, and estimates of the expected total time spent in hospital over five years. For example, older patients and men were readmitted more frequently, though the total time in hospital was roughly constant with age. We also discuss the relative merits of parametric and semi-parametric multi-state models, and model assessment and comparison.


Nucleotide sequence of the 26 S mRNA of the virulent Trinidad donkey strain of Venezuelan equine encephalitis virus and deduced sequence of the encoded structural proteins.
A cDNA clone containing all of the 26 S mRNA coding region of the RNA genome of Venezuelan equine encephalitis (VEE) virus, virulent strain Trinidad donkey (TRD), has been constructed and sequenced. The nucleotide and deduced amino acid sequences of the 26 S RNA of VEE virus conform to the general organization of the alphavirus subgenomic mRNA. Excluding the poly(A) tail, the VEE 26 S RNA is 3913 nucleotides long with a protein coding region of 3762 nucleotides. Codon usage in the translated region is nonrandom and correlates well with that reported for Sindbis (SIN), Semliki Forest (SF), and Ross River (RR) alphaviruses. Highly conserved sequences of 19 to 22 nucleotides representing putative replicase recognition sites occur at the 26 S RNA junction region of the 42 S genomic RNA and at the 3' terminus immediately preceding the poly(A) tail. The conserved sequence at the 26 S/42 S junction region of VEE virus differs from that of other alphaviruses in that an ochre termination codon (UAA) is substituted for a GGU (Gly) codon present in the other viruses. The 5' and 3' noncoding regions (30 and 121 nucleotides, respectively) of the VEE 26 S RNA are shorter than has been reported for several other alphaviruses. The approximate transmembrane domains of the VEE E1 and E2 envelope glycoproteins have been identified. VEE E1 contains a single asparagine-linked glycosylation site, whereas E2 has three such sites, all of which are apparently glycosylated. The deduced amino acid sequence of the VEE polyprotein shows an overall homology of 44 to 46% with the precursor polyproteins of SIN, SF, and RR viruses. VEE virus capsid, E1, and E2 structural proteins show 43 to 46%, 50 to 53%, and 36 to 41% homology, respectively, with the cognate proteins of SIN, SF, and RR viruses.


Lawyer control of the tobacco industry's external research program. The Brown and Williamson documents.
To examine the involvement of tobacco industry lawyers in the selection of tobacco industry scientific research projects and to examine how the research was used to influence public policy. Documents from Brown and Williamson Tobacco Corporation, the British American Tobacco Company (BAT), and other tobacco interests provided by an anonymous source, obtained from Congress, and received from the private papers of a former BAT officer. All available materials, including confidential reports regarding research and internal memoranda exchanged between tobacco industry lawyers. The involvement of tobacco industry lawyers in the selection of scientific projects to be funded is in sharp contrast to the industry's public statements about its review process for its external research program. Scientific merit played little role in the selection of external research projects. The results of the projects were used to generate good publicity for the industry, to deflect attention away from tobacco use as a health danger, and to attempt, sometimes surreptitiously, to influence policymakers.


Analysis of CEPH-accredited DrPH programs in the United States: A mixed-methods study.
Interest has been growing in regard to increasing the public health workforce and standardizing training to ensure there are competent professionals to support rebuilding and reinforcing the public health infrastructure of the United States. The need for public health leaders was recognized as early as the hookworm control campaign during 1909-1914 when it became apparent that prevention of disease should be distinct from clinical medicine and should be conducted by professionally trained, dedicated full-time public health practitioners. In recent years, research on the public health workforce and on standardizing health workforce education has significantly expanded. A key element of such a workforce is public health leadership, and DrPH programs are the means to provide effective public health education for these future health professionals. The purpose of this paper is to analyze the general trend of DrPH programs from past to present and analyze the common themes and variations of 28 Council on Education for Public Health (CEPH)-accredited DrPH programs in the United States. This research utilized a mixed-methods approach, investigating DrPH education at each school or program to improve our understanding of the current status of DrPH programs.


Deep phylogenetic divergence between Scolytoplatypus and Remansus, a new genus of Scolytoplatypodini from Madagascar (Coleoptera, Curculionidae, Scolytinae).
Scolytoplatypodini Blandford is a monotypic tribe of ambrosia beetles found in Asia, Madagascar and Africa. Only three species are currently known from Madagascar and four additional species are here described as new to science. Phylogenetic analyses of morphological and molecular data revealed that four of the seven endemic species are deeply separated from all other species by genetic and distinct morphological characters and therefore placed in a new genus Remansus Jordal. The split between this ancient lineage and Scolytoplatypus Schaufuss was estimated to approximate Palaeocene age (63 Ma), extending the minimum age of ambrosia feeding for this tribe to the beginning of the Palaeocene‒Eocene thermal maximum (PETM). In addition to the ancient origin of Remansus in Madagascar during the Palaeocene, a second origin occurred in Scolytoplatypus no more than 13 Ma. A geographical origin of the latter in South-Eastern Africa was unequivocally inferred from the phylogenies.


Consequences of constitutive and induced variation in plant nutritional quality for immune defence of a herbivore against parasitism.
The mechanisms through which trophic interactions between species are indirectly mediated by distant members in a food web have received increasing attention in the field of ecology of multitrophic interactions. Scarcely studied aspects include the effects of varying plant chemistry on herbivore immune defences against parasitoids. We investigated the effects of constitutive and herbivore-induced variation in the nutritional quality of wild and cultivated populations of cabbage (Brassica oleracea) on the ability of small cabbage white Pieris rapae (Lepidoptera, Pieridae) larvae to encapsulate eggs of the parasitoid Cotesia glomerata (Hymenoptera, Braconidae). Average encapsulation rates in caterpillars parasitised as first instars were low and did not differ among plant populations, with caterpillar weight positively correlating with the rates of encapsulation. When caterpillars were parasitised as second instar larvae, encapsulation of eggs increased. Caterpillars were larger on the cultivated Brussels sprouts plants and exhibited higher levels of encapsulation compared with caterpillars on plants of either of the wild cabbage populations. Observed differences in encapsulation rates between plant populations could not be explained exclusively by differences in host growth on the different Brassica populations. Previous herbivore damage resulted in a reduction in the larval weight of subsequent herbivores with a concomitant reduction in encapsulation responses on both Brussels sprouts and wild cabbage plants. To our knowledge this is the first study demonstrating that constitutive and herbivore-induced changes in plant chemistry act in concert, affecting the immune response of herbivores to parasitism. We argue that plant-mediated immune responses of herbivores may be important in the evaluation of fitness costs and benefits of herbivore diet on the third trophic level.


Clinicopathological characteristics and outcome of Chinese patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: a 9-year retrospective study.
The pathogenesis of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) is unclear and the prognosis is poor. Few studies have been published focusing on Chinese patients with TTP-HUS. We performed a retrospective study on the clinical characteristics and outcome of Chinese patients with TTP-HUS. Patients with TTP-HUS, admitted to our hospital from 1998 to 2006, were retrospectively analyzed. There were 26 females and 6 males in our study. Fifteen patients had systemic lupus erythematosus (SLE)-associated TTP-HUS; 2 had pregnancy-associated TTP-HUS; 1 had antiphospholipid syndrome-associated TTP-HUS; 2 had drug-associated TTP-HUS; 4 had malignant angionephrosclerosis- associated TTP-HUS; 3 had vasculitis-associated TTP-HUS, and the remaining 5 had idiopathic TTP-HUS. Twenty-six patients had acute kidney injury and 21 had nephrotic syndrome. Hypertension was found in 31 patients. For the treatment, 15 patients had plasmapheresis, 12 had continuous veno-venous hemodiafiltration and 14 had hemodialysis. Eighteen patients were treated with intravenous immunoglobulin. Corticosteroids were used in patients with idiopathic TTP-HUS. For the patients with SLE-associated TTP-HUS, corticosteroids and immunosuppressant were used. Outcome was poor: 6 patients died; 17 recovered from renal insufficiency; 5 progressed to chronic renal failure, and 4 were dependent on hemodialysis. Most of our patients had secondary TTP-HUS. SLE-associated TTP-HUS is the most common form of TTP-HUS. Early diagnosis and treatment can improve prognosis. An immunosuppressant together with corticosteroids could improve prognosis in some patients.


Estimating outcome probabilities from early symptom changes in cognitive therapy for recurrent depression.
Acute-phase cognitive therapy (CT) is an efficacious treatment for major depressive disorder (MDD) producing benefits comparable to pharmacotherapy, but not all patients respond or remit. The purpose of the current analyses was to estimate CT patients' probability of nonresponse and remission from symptom improvement early in treatment. Data from 2 clinical trials of acute-phase CT for recurrent depression were pooled for analysis (N = 679). Adult outpatients received 16- or 20-session CT protocols. Symptoms were measured repeatedly with the clinician-report Hamilton Rating Scale for Depression (HRSD) and Inventory of Depressive Symptomatology-Self-Report (IDS-SR). Outcomes at exit from CT were nonresponse (<50% reduction in HRSD scores) and remission (no MDD and HRSD score ≤6). The nonresponse rate was 45.7%, and the remission rate was 33.4%. In logistic regression models, improvements on the HRSD or IDS-SR from intake to CT Sessions 3, 5, 7, 9, or 11 significantly predicted both outcomes, with prediction gaining in accuracy in later sessions. Clinician and self-report assessments yielded similar results. Prediction of outcomes replicated across data sets. Patients with no symptom improvement by CT Session 9 (Week 5) had ≤10% probability of remission and >75% probability of nonresponse. Outcomes of CT for depression are predictable from early symptom changes. Clinicians may find nonresponse and remission probability estimates useful in the informed consent process and in choosing whether to continue, augment, or switch treatments for CT patients with recurrent MDD. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Establishing the research priorities of paediatric emergency medicine clinicians in the UK and Ireland.
Paediatric Emergency Research in the UK and Ireland (PERUKI) is a collaborative clinical studies group established in August 2012. It consists of a network of 43 centres from England, Ireland, Northern Ireland, Scotland and Wales, and aims to improve the emergency care of children through the performance of robust collaborative multicentre research within emergency departments. A study was conducted regarding the research priorities of PERUKI, to establish the research agenda for paediatric emergency medicine in the UK and Ireland. A two-stage modified Delphi survey was conducted of PERUKI members via an online survey platform. Stage 1 allowed each member to submit up to 12 individual questions that they identified as priorities for future research. In stage 2, the shortlisted questions were each rated on a seven-point Likert scale of relative importance. Members of PERUKI, including clinical specialists, academics, trainees and research nurses. Stage 1 surveys were submitted by 46/91 PERUKI members (51%). A total of 249 research questions were generated and, following the removal of duplicate questions and shortlisting, 60 questions were carried forward for stage 2 ranking. Stage 2 survey responses were submitted by 58/95 members (61%). For the 60 research questions that were rated, the mean score of 'relative degree of importance' was 4.70 (range 3.36-5.62, SD 0.55). After ranking, the top 10 research priorities included questions on biomarkers for serious bacterial illness, major trauma, intravenous bronchodilators for asthma and decision rules for fever with petechiae, head injury and atraumatic limp. Research priorities of PERUKI members have been identified. By sharing these results with clinicians, academics and funding bodies, future research efforts can be focused to the areas of greatest need.


Comprehending Mental Health in Indonesian's Adolescents through Mental, Emotional, and Social Well-Being.
Many problems occur at the age of adolescence, especially mental health disorders. Teens experiencing life changes could be at risk for mental health disorders. Adolescents with flourishing/good mental health can become adults who are optimistic, independent, creative, and able to adequately contribute to their surroundings by optimally using their capacities. This study aims to describe an overview of the psychological, emotional, and social well-being of adolescents; thus, it can be used to create a national picture of adolescents' mental health in Indonesia. This is a descriptive study with a cross-sectional design. The study sample included 972 adolescents in grades 7 and 8 in public and private junior high schools in Depok, Jakarta, Tangerang, and Denpasar who were selected by stratified random sampling. Adolescents possess a high degree of psychological, emotional, and social well-being, and 46.3% of the adolescents were discovered to have flourishing mental health while the others had moderate and languishing/weak mental health. It is necessary to maintain and enhance the involvement of adolescents' support systems to maintain their mental health. Moreover, adolescents should explore their potential in order to learn adaptive coping mechanisms to help them solve problems appropriately.


Evolution of the globin gene family in deuterostomes: lineage-specific patterns of diversification and attrition.
In the Metazoa, globin proteins display an underlying unity in tertiary structure that belies an extraordinary diversity in primary structures, biochemical properties, and physiological functions. Phylogenetic reconstructions can reveal which of these functions represent novel, lineage-specific innovations, and which represent ancestral functions that are shared with homologous globin proteins in other eukaryotes and even prokaryotes. To date, our understanding of globin diversity in deuterostomes has been hindered by a dearth of genomic sequence data from the Ambulacraria (echinoderms + hemichordates), the sister group of chordates, and the phylum Xenacoelomorpha, which includes xenoturbellids, acoelomorphs, and nemertodermatids. Here, we report the results of a phylogenetic and comparative genomic analysis of the globin gene repertoire of deuterostomes. We first characterized the globin genes of the acorn worm, Saccoglossus kowalevskii, a representative of the phylum Hemichordata. We then integrated genomic sequence data from the acorn worm into a comprehensive analysis of conserved synteny and phylogenetic relationships among globin genes from representatives of the eight lineages that comprise the superphylum Deuterostomia. The primary aims were 1) to unravel the evolutionary history of the globin gene superfamily in deuterostomes and 2) to use the estimated phylogeny to gain insights into the functional evolution of deuterostome globins. Results of our analyses indicate that the deuterostome common ancestor possessed a repertoire of at least four distinct globin paralogs and that different subsets of these ancestral genes have been retained in each of the descendant organismal lineages. In each major deuterostome group, a different subset of ancestral precursor genes underwent lineage-specific expansions of functional diversity through repeated rounds of gene duplication and divergence. By integrating results of the phylogenetic analysis with available functional data, we discovered that circulating oxygen-transport hemoglobins evolved independently in several deuterostome lineages and that intracellular nerve globins evolved independently in chordates and acoelomorph worms.


When cognition kicks in: working memory and speech understanding in noise.
Perceptual load and cognitive load can be separately manipulated and dissociated in their effects on speech understanding in noise. The Ease of Language Understanding model assumes a theoretical position where perceptual task characteristics interact with the individual's implicit capacities to extract the phonological elements of speech. Phonological precision and speed of lexical access are important determinants for listening in adverse conditions. If there are mismatches between the phonological elements perceived and phonological representations in long-term memory, explicit working memory (WM)-related capacities will be continually invoked to reconstruct and infer the contents of the ongoing discourse. Whether this induces a high cognitive load or not will in turn depend on the individual's storage and processing capacities in WM. Data suggest that modulated noise maskers may serve as triggers for speech maskers and therefore induce a WM, explicit mode of processing. Individuals with high WM capacity benefit more than low WM-capacity individuals from fast amplitude compression at low or negative input speech-to-noise ratios. The general conclusion is that there is an overarching interaction between the focal purpose of processing in the primary listening task and the extent to which a secondary, distracting task taps into these processes.


Maintenance of muscle mass and load-induced growth in Muscle RING Finger 1 null mice with age.
Age-related loss of muscle mass occurs to varying degrees in all individuals and has a detrimental effect on morbidity and mortality. Muscle RING Finger 1 (MuRF1), a muscle-specific E3 ubiquitin ligase, is believed to mediate muscle atrophy through the ubiquitin proteasome system (UPS). Deletion of MuRF1 (KO) in mice attenuates the loss of muscle mass following denervation, disuse, and glucocorticoid treatment; however, its role in age-related muscle loss is unknown. In this study, skeletal muscle from male wild-type (WT) and MuRF1 KO mice was studied up to the age of 24 months. Muscle mass and fiber cross-sectional area decreased significantly with age in WT, but not in KO mice. In aged WT muscle, significant decreases in proteasome activities, especially 20S and 26S β5 (20-40% decrease), were measured and were associated with significant increases in the maladaptive endoplasmic reticulum (ER) stress marker, CHOP. Conversely, in aged MuRF1 KO mice, 20S or 26S β5 proteasome activity was maintained or decreased to a lesser extent than in WT mice, and no increase in CHOP expression was measured. Examination of the growth response of older (18 months) mice to functional overload revealed that old WT mice had significantly less growth relative to young mice (1.37- vs. 1.83-fold), whereas old MuRF1 KO mice had a normal growth response (1.74- vs. 1.90-fold). These data collectively suggest that with age, MuRF1 plays an important role in the control of skeletal muscle mass and growth capacity through the regulation of cellular stress.


Assortative sociality, limited dispersal, infectious disease and the genesis of the global pattern of religion diversity.
Why are religions far more numerous in the tropics compared with the temperate areas? We propose, as an answer, that more religions have emerged and are maintained in the tropics because, through localized coevolutionary races with hosts, infectious diseases select for three anticontagion behaviours: in-group assortative sociality; out-group avoidance; and limited dispersal. These behaviours, in turn, create intergroup boundaries that effectively fractionate, isolate and diversify an original culture leading to the genesis of two or more groups from one. Religion is one aspect of a group's culture that undergoes this process. If this argument is correct then, across the globe, religion diversity should correlate positively with infectious disease diversity, reflecting an evolutionary history of antagonistic coevolution between parasites and hosts and subsequent religion genesis. We present evidence that supports this model: for a global sample of traditional societies, societal range size is reduced in areas with more pathogens compared with areas with few pathogens, and in contemporary countries religion diversity is positively related to two measures of parasite stress.


Authentication of Chinese Materia Medica decoction dregs, part 1: comparison of morphological and microscopic features of four Chinese Materia Medica before and after decoction.
Chinese Materia Medica (CMM) decoction dregs are the residues of medicinal materials after decoction. Accurate identification of CMM in decoction dregs will be helpful for exploring the causes of poisoning or other medical incidents arising after the ingestion of CMM decoctions. To determine how decoction affects the characteristics used to authenticate specific CMM, a systematic study was carried out. In this study, two pairs of Materia Medica that are commonly confused-namely, Baizhu (Atractylodis Macrocephalae Rhizoma) and Cangzhu (Atractylodis Rhizoma), Baishao (Paeoniae Alba Radix) and Chishao (Paeoniae Rubra Radix)-were chosen for investigation. Each pair of Materia Medica has similar morphology in appearance, but they have different functions in Chinese clinic. After decoction, with regard to gross morphological characters, the results showed that bark and wood could be easily distinguished. The striation of vessels and fibers became more prominent because of the contraction of parenchymatous cells, but the lignified cells did not. As for the microscopic characteristics, the cells with thickened walls, such as stone cells and fibers, were basically stable. Most of the parenchymatous cells were broken. Crystals of calcium oxalate showed no changes as they were insoluble in water. Starch granules were gelatinized and aggregated in parenchymatous cells. Inulins were substantially reduced in number as they dissolved in water during decoction. According to these changes in morphological and microscopic characteristics after decoction, the dregs of two pairs of Materia Medica could be distinguished.


All-optical phase locking of two femtosecond Ti:sapphire lasers: a passive coupling mechanism beyond the slowly varying amplitude approximation.
Two independently tunable femtosecond Ti:sapphire lasers are passively synchronized with a stable relative carrier-envelope offset phase. By heterodyning the spectral overlap of the two frequency combs, we observe multiple regimes for the cavity length difference in which the relative round-trip phase slip is effectively locked to zero. The strong correlation of the femtosecond pulse trains is maintained over minutes without any external stabilization, and relative cavity length variations of 50 nm are compensated. The phase synchronization relies on phase-dependent cross-phase modulation, taking full advantage of the nonresonant optical nonlinearity of the shared gain medium, which is much faster than the optical cycle.


Transgene silencing of sucrose synthase in alfalfa (Medicago sativa L.) stem vascular tissue suggests a role for invertase in cell wall cellulose synthesis.
Alfalfa (Medicago sativa L.) is a widely adapted perennial forage crop that has high biomass production potential. Enhanced cellulose content in alfalfa stems would increase the value of the crop as a bioenergy feedstock. We examined if increased expression of sucrose synthase (SUS; EC 126.96.36.199) would increase cellulose in stem cell walls. Alfalfa plants were transformed with a truncated alfalfa phosphoenolpyruvate carboxylase gene promoter (PEPC7-P4) fused to an alfalfa nodule-enhanced SUS cDNA (MsSUS1) or the β-glucuronidase (GUS) gene. Strong GUS expression was detected in xylem and phloem indicating that the PEPC7-P4 promoter was active in stem vascular tissue. In contrast to expectations, MsSUS1 transcript accumulation was reduced 75-90 % in alfalfa plants containing the PEPC7-P4::MsSUS1 transgene compared to controls. Enzyme assays indicated that SUS activity in stems of selected down-regulated transformants was reduced by greater than 95 % compared to the controls. Although SUS activity was detected in xylem and phloem of control plants by in situ enzyme assays, plants with the PEPC7-P4::MsSUS1 transgene lacked detectable SUS activity in post-elongation stem (PES) internodes and had very low SUS activity in elongating stem (ES) internodes. Loss of SUS protein in PES internodes of down-regulated lines was confirmed by immunoblots. Down-regulation of SUS expression and activity in stem tissue resulted in no obvious phenotype or significant change in cell wall sugar composition. However, alkaline/neutral (A/N) invertase activity increased in SUS down-regulated lines and high levels of acid invertase activity were observed. In situ enzyme assays of stem tissue showed localization of neutral invertase in vascular tissues of ES and PES internodes. These results suggest that invertases play a primary role in providing glucose for cellulose biosynthesis or compensate for the loss of SUS1 activity in stem vascular tissue.


The Schistosoma japonicum egg granuloma. II. Cellular composition, granuloma size, and immunologic concomitants.
Studies of granulomatous hypersensitivity to Schistosoma japonicum eggs were performed at various time periods up to 20 wk after the induction of light infections in mice. Cell populations which were determined in granulomas isolated from the livers revealed a maximum in the total number of cells at 6 wk with a decline of 36% by 20 wk. Large mononuclear cells were predominant at all time periods, with eosinophils being the second most common cell. Measurements of granuloma diameters around single viable eggs in the livers also revealed peak size at 6 wk with a decline of 51% between 16 and 24 wk. Immunodiffusion analysis demonstrated the presence of precipitating antibodies as early as 7 wk after infection. Investigations of lymphocyte blastogenesis revealed a profound depression in response to T-cell mitogens by 8 wk of infection. Studies of footpad swelling to soluble S. japonicum egg antigens revealed massive immediate reactions starting at 6 wk. but no delayed reactivity over a period from 3 to 20 wk. All of these results are related to differences in the biology of S. japonicum in comparison with S. mansoni with respect to the earlier onset of egg production, the much larger numbers of eggs produced, and the possibility of differences in the antigens emitted by the eggs.


Morbidity and mortality in the antiphospholipid syndrome during a 5-year period: a multicentre prospective study of 1000 patients.
To identify the main causes of morbidity and mortality in patients with antiphospholipid syndrome (APS) during a 5-year period and to determine clinical and immunological parameters with prognostic significance. The clinical and immunological features of a cohort of 1000 patients with APS from 13 European countries who had been followed up from 1999 to 2004 were analysed. 200 (20%) patients developed APS-related manifestations during the 5-year study period. Recurrent thrombotic events appeared in 166 (16.6%) patients and the most common were strokes (2.4% of the total cohort), transient ischaemic attacks (2.3%), deep vein thromboses (2.1%) and pulmonary embolism (2.1%). When the thrombotic events occurred, 90 patients were receiving oral anticoagulants and 49 were using aspirin. 31/420 (7.4%) patients receiving oral anticoagulants presented with haemorrhage. 3/121 (2.5%) women with only obstetric APS manifestations at the start of the study developed a new thrombotic event. A total of 77 women (9.4% of the female patients) had one or more pregnancies and 63 (81.8% of pregnant patients) had one or more live births. The most common fetal complications were early pregnancy loss (17.1% of pregnancies) and premature birth (35% of live births). 53 (5.3% of the total cohort) patients died. The most common causes of death were bacterial infection (21% of deaths), myocardial infarction (19%) and stroke (13%). No clinical or immunological predictor of thrombotic events, pregnancy morbidity or mortality was detected. Patients with APS still develop significant morbidity and mortality despite current treatment (oral anticoagulants or antiaggregants, or both).


Effects and Location of Coplanar and Noncoplanar PCB in a Lipid Bilayer: A Solid-State NMR Study.
Coplanar and noncoplanar polychlorinated biphenyls (PCBs) are known to have different routes and degree of toxicity. Here, the effects of noncoplanar PCB 52 and coplanar PCB 77 present at 2 mol % in a model system consisting of POPC liposomes (50% hydrated) are investigated by solid-state (13)C and (31)P NMR at 298 K. Both PCBs intercalate horizontally in the outer part of the bilayer, near the segments of the acyl chain close to the glycerol group. Despite similar membrane locations, the coplanar PCB 77 shows little effect on the bilayer properties overall, except for the four nearest neighboring lipids, while the effect of PCB 52 is more dramatic. The first ∼2 layers of lipids around each PCB 52 in the bilayer form a high fluidity lamellar phase, whereas lipids beyond these layers form a lamellar phase with a slight increase in fluidity compared to a bilayer without PCB 52. Further, a third high mobility domain is observed. The explanation for this is the interference of several high fluidity lamellar phases caused by interactions of PCB 52 molecules in different leaflets of the model bilayer. This causes formation of high curvature toroidal region in the bilayer and might induce formation of channels.


Caregiver preparedness for death in dementia: an evaluation of existing tools.
Objectives: Death preparedness amongst family caregivers (CG) is a valuable and measurable concept. Preparedness predicts CG outcomes in bereavement and is modifiable through a palliative approach which includes advance care planning (ACP) interventions. Improving death preparedness is important for CGs of persons with dementia (PwD) whom are more likely to develop negative outcomes in bereavement, and experience less than adequate palliative care. However, the adequacy of existing tools to measure death preparedness in CGs of PwD is unknown, which limits intervention design and prospective evaluation of ACP effectiveness.Methods: We conducted a review and evaluation of existing tools measuring the attribute domains and traits of CG death preparedness. Literature was searched for articles describing caregiving at end of life (EOL). Measurement tools were extracted, screened for inclusion criteria, and data extracted regarding: conceptual basis, population of development, and psychometrics. Tool content was compared to preparedness domains/traits to assess congruency and evaluate the adequacy of tools as measures of death preparedness for CGs of PwD.Results: Authors extracted 569 tools from articles, retaining seven tools for evaluation. The majority of tools, n = 5 (70%) did not sample all preparedness domains/traits. Few tools had items specific to EOL; only one tool had a specific item questioning CG preparedness for death, and only one tool had items specific to dementia.Conclusion: Limitations in existing tools suggest they are not adequate measures of death preparedness for CGs of PwD. Consequently, the authors are currently developing a questionnaire to be titled, 'Caring Ahead' for this purpose.


[Relationship between interleukin-8 levels in expressed prostatic secretion and expressions of bFGF and Bcl-2 in benign prostatic hyperplasia].
To investigate the relationship between interleukin-8 levels in expressed prostatic secretion and expressions of basic fibroblast growth factor (bFGF) and Bcl-2 in benign prostatic hyperplasia (BPH). A series of 50 consecutive patients diagnosed with BPH and scheduled for transurethral resection of the prostate (TURP) were included. Patients were divided into two groups, simple BPH and BPH with chronic prostatitis (CP). The grade of inflammatory changes in the prostate was then determined blindly by two experienced pathologists, according to the classification system. Expressed prostatic secretion (EPS) was collected right before TURP for IL-8 detection using ELISA kits. The resected prostatic tissue was harvested for immunohistochemistry to measure the expression of Bcl-2 and bFGF. A total of 30 (60%) patients were confirmed to have prostatic histologic inflammation. The volume of the prostate in BPH with CP was obviously larger than that in simple BPH (P=0.022). The NIH chronic prostatitis symptom index (NIH-CPSI) and international prostate symptom score (IPSS) of BPH with CP were both higher than those of simple BPH (P<0.05). Significantly increased levels of IL-8 were observed in EPS obtained from BPH patients with CP (mean level, 43.29 ng/L), compared with patients with simple BPH (mean level, 36.90 ng/L) (P=0.003). The expression of Bcl-2 in BPH with CP (mean level, 6.17) increased significantly, compared with those in simple BPH (mean level, 2.45) (P=0.013). The expression of bFGF in BPH with CP (mean level, 7.57) also obviously elevated, compared with those in simple BPH (mean level, 5.05) (P=0.008). Correlation coefficients of IL-8 levels in EPS and expression of Bcl-2 or bFGF indicated that IL-8 had strong correlation with Bcl-2 and bFGF respectively both in simple BPH and BPH with CP (0<R<1, P<0.05). IL-8, Bcl-2 and bFGF are significantly up-regulated in BPH with CP patients, compared with simple BPH patients. Inflammation might play an important role in the outcome and development of benign prostatic hyperplasia and makes it more severe.


The role of "cell therapy" in osteonecrosis of the femoral head. A systematic review of the literature and meta-analysis of 7 studies.
The value of core decrompression for treatment of osteonecrosis of the femoral head (ONFH) is unclear. We investigated by a literature review whether implantation of autologous bone marrow aspirate, containing high concentrations of pluripotent mesenchymal stem cells, into the core decompression track would improve the clinical and radiological results compared with the classical method of core decompression alone. The primary outcomes of interest were structural failure (collapse) of the femoral head and conversion to total hip replacement (THR). All randomized and non-randomized control trials comparing simple core decompression with autologous bone marrow cell implantation into the femoral head for the treatment of ONFH were considered eligible for inclusion. The methodological quality of the studies included was assessed independently by 2 reviewers using the Cochrane Collaboration tool for assessing risk of bias in randomized studies. Of 496 relevant citations identified, 7 studies formed the basis of this review. The pooled estimate of effect size for structural failure of the femoral head favored the cell therapy group, as, in this treatment group, the odds of progression of the femoral head to the collapse stage were reduced by a factor of 5 compared to the CD group (odds ratio (OR) = 0.2, 95% CI: 0.08-0.6; p = 0.02). The respective summarized estimate of effect size yielded halved odds for conversion to THR in the cell therapy group compared to CD group (OR = 0.6, 95% CI: 0.3-1.02; p = 0.06). Our findings suggest that implantation of autologous mesenchymal stem cells (MSCs) into the core decompression track, particularly when employed at early (pre-collapse) stages of ONFH, would improve the survivorship of femoral heads and reduce the need for hip arthroplasty.


Free spectral range measurement of a fiberized Fabry-Perot etalon with sub-Hz accuracy.
In this work a narrow linewidth (1 kHz) laser source is used to measure the free spectral range of a fiberized Fabry-Perot etalon with sub-Hz accuracy (10(-8)). A previously demonstrated technique based on the Pound-Drever-Hall error signal is improved in accuracy by the use of a narrow linewidth laser swept in frequency via an acousto-optic modulator, or single sideband generation. The sub-Hz (10(-8)) accuracy attained enables the characterization of both the long-term drift and the polarization dependence of the free spectral range of the fiberized etalon.


Transport of Strontium-90 in Runoff.
Only a small portion of the strontium-90 that fell on cultivated soils was removed in runoff. The concentration of strontium-90 was usually about 10 times higher in the soil carried by the runoff than in the soil from the plow layer of the plots. Thus, a considerable concentration of Sr(90) could occur in areas where runoff sediments accumulate.


YAP and TAZ regulate adherens junction dynamics and endothelial cell distribution during vascular development.
Formation of blood vessel networks by sprouting angiogenesis is critical for tissue growth, homeostasis and regeneration. How endothelial cells arise in adequate numbers and arrange suitably to shape functional vascular networks is poorly understood. Here we show that YAP/TAZ promote stretch-induced proliferation and rearrangements of endothelial cells whilst preventing bleeding in developing vessels. Mechanistically, YAP/TAZ increase the turnover of VE-Cadherin and the formation of junction associated intermediate lamellipodia, promoting both cell migration and barrier function maintenance. This is achieved in part by lowering BMP signalling. Consequently, the loss of YAP/TAZ in the mouse leads to stunted sprouting with local aggregation as well as scarcity of endothelial cells, branching irregularities and junction defects. Forced nuclear activity of TAZ instead drives hypersprouting and vascular hyperplasia. We propose a new model in which YAP/TAZ integrate mechanical signals with BMP signaling to maintain junctional compliance and integrity whilst balancing endothelial cell rearrangements in angiogenic vessels.


Cognitive and psychosocial development concerns in children born small for gestational age.
Outcome information for infants born small for gestational age (SGA), whether term or premature, suggests poorer cognitive function compared with appropriate size for gestational age (AGA) infants. Poorer outcome is associated with smaller size for gestational age and with lack of catch-up growth after birth. Such data have been reported from early childhood to young adulthood. Diminished head circumference at birth and growth thereafter has also been associated with poor outcome. Based on available reports, the impact of SGA birth upon psychosocial development remains unclear. While it has not been shown that growth hormone (GH) therapy impacts either cognitive or psychosocial outcome, increased head circumference standard deviation scores have been shown to occur with GH therapy. These data need to be interpreted with caution since study populations do not define etiology of SGA and definitions of SGA vary. Further, generalized group data are not applicable to individuals.


Central effects of 1,4-butanediol are mediated by GABA(B) receptors via its conversion into gamma-hydroxybutyric acid.
The aliphatic alcohol 1,4-butanediol in converted into gamma-hydroxybutyric acid (GHB) via two enzymatic steps: first, it is oxidised by alcohol dehydrogenase in gamma-hydroxybutyraldehyde; second, the latter is transformed, likely by aldehyde dehydrogenase, into GHB. Initially, the present study compared the sedative/hypnotic effect of GHB and 1,4-butanediol, measured as loss of righting reflex. 1,4-Butanediol was more potent than GHB, presumably because of a more rapid penetration of the blood brain barrier. Further alcohol dehydrogenase inhibitors, 4-methylpyrazole and ethanol, totally prevented the sedative/hypnotic effect of 1,4-butanediol; the aldehyde dehydrogenase inhibitor disulfiram partially blocked the sedative/hypnotic effect of 1,4-butanediol. Finally, the sedative/hypnotic effect of 1,4-butanediol was antagonised by the GABA(B) receptor antagonists, SCH 50911 [(2S)(+)-5,5-dimethyl-2-morpholineacetic acid] and CGP 46381 [(3-aminopropyl)(cyclohexylmethyl)phosphinic acid], but not by the putative GHB receptor antagonist NCS-382 (6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylideneacetic acid), indicating that it is mediated by GABA(B) but not GHB receptors. Taken together, these results suggest that the sedative/hypnotic effect of 1,4-butanediol is mediated by its conversion in vivo into GHB which, in turn, binds to GABA(B) receptors. Accordingly 1,4-butanediol, unlike GHB, failed to displace [(3)H]GHB and [(3)H]baclofen in brain membranes.


Tubular adenoma with high-grade dysplasia in the ileal segment 34 years after augmentation ileocystoplasty: report of a first case.
Neoplasms of the urinary bladder following augmentation ileocystoplasty are rare. We present the case of a 39-year-old male with a tubular adenoma with high-grade dysplasia in the ileal segment 34 years after augmentation ileocystoplasty to enlarge a post-chemoradiation-induced shrunken bladder. He presented with gross hematuria. Cystoscopy revealed a papillary tumor at the site of ileovesical anastomosis, and transurethral resection was performed. Histologic examination revealed a tubular adenoma with high-grade dysplasia. There are only two previous reports of tubulovillous adenoma in ileal segment after ileocystoplasty, both without high-grade dysplasia. Our observation supports the hypothesis that an ileal neobladder may undergo all the morphologic and molecular changes observed in the development of gastrointestinal adenocarcinoma. Therefore, patients who had an ileal neobladder created should be closely followed.


Developmental profile of SK2 channel expression and function in CA1 neurons.
We investigated the temporal and spatial expression of SK2 in the developing mouse hippocampus using molecular and biochemical techniques, quantitative immunogold electron microscopy, and electrophysiology. The mRNA encoding SK2 was expressed in the developing and adult hippocampus. Western blotting and immunohistochemistry showed that SK2 protein increased with age. This was accompanied by a shift in subcellular localization. Early in development (P5), SK2 was predominantly localized to the endoplasmic reticulum in the pyramidal cell layer. But by P30 SK2 was almost exclusively expressed in the dendrites and spines. The level of SK2 at the postsynaptic density (PSD) also increased during development. In the adult, SK2 expression on the spine plasma membrane showed a proximal-to-distal gradient. Consistent with this redistribution and gradient of SK2, the selective SK channel blocker apamin increased evoked excitatory postsynaptic potentials (EPSPs) only in CA1 pyramidal neurons from mice older than P15. However, the effect of apamin on EPSPs was not different between synapses in proximal or distal stratum radiatum or stratum lacunosum-moleculare in adult. These results show a developmental increase and gradient in SK2-containing channel surface expression that underlie their influence on neurotransmission, and that may contribute to increased memory acquisition during early development.


Internet addiction: a descriptive clinical study focusing on comorbidities and dissociative symptoms.
Internet addiction (IAD) is an emerging cause of morbidity and has been recently considered to merit inclusion in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Given the paucity of knowledge about IAD, we conducted a descriptive clinical analysis of patients focusing on clinical, demographic features, and comorbidities. The detachment has been suggested as a reason for the attractiveness of the Internet; thus, we assessed dissociative symptoms and their association with IAD disability. A cohort of 50 adult outpatients were screened using the Internet Addiction Scale. Exclusion criterion was using the Internet for only one purpose such as gaming or gambling. Nine women and 6 men constituted the sample of Internet addicts; each of them had a score of 70 or higher on the Internet Addiction Scale. Comorbidities and subthreshold symptoms were screened carefully. Dissociative symptoms were analyzed with the Dissociative Experience Scale, and disability was assessed using the Sheehan Disability Scale. Hours/week spent on the Internet were 42.21 +/- 3.09. Clinical diagnoses included 14% attention deficit and hyperactivity disorder, 7% hypomania, 15% generalized anxiety disorder, 15% social anxiety disorder; 7% dysthymia, 7% obsessive compulsive personality disorder, 14% borderline personality disorder, and 7% avoidant personality disorder. One patient met criteria for binge eating disorder. Severity measures of IAD were associated with higher perception of family disability (r = 0.814; P <or= .001) and with higher Yale-Brown Obsessive Compulsive Severity score (r = 0.771; P <or= .001). Scores for the Dissociative Experience Scale were higher than expected (23.20 +/- 1.83) and were related to higher obsessive compulsive scores (r = 0.618; P <or= .001), hours per week on the Internet (r = 0.749; P <or= .001), and perception of family disability (r = 0.677; P <or= .001). From a phenomenological point of view, IAD in our sample population seems to be more compulsory than rewarding or mood driven. Dissociative symptoms are related to severity and impact of IAD.


An Ru(II)-Fe(III) bimetallic complex as a multifunctional device for detecting, signal amplifying, and degrading oxalate.
A tetranuclear bimetallic complex, [Ru(II)((t)Bubpy)(CN)4]2-[Fe(III)(H2O)3Cl]2·8H2O (1) has been synthesized and characterized. It was found to be a multifunctional device that can detect, signal amplify, and degrade an organic pollutant, oxalate. Results of the chemosensing studies of 1 toward common anions show that only oxalate selectively induces naked-eye colorimetric and luminometric responses with method detection limits down to 78.7 and 5.5 ppm, respectively from 1. Meanwhile, results of the photo-degradation studies of 1 toward oxalate show that the dissolved organic carbon content of oxalate decreased and reached complete mineralization into CO2 within 6 hours. Complex 1 was also found as the catalyst that amplified the detection signal toward oxalate. Through the photoassisted Fenton reaction by 1, methyl orange, an additional coloring agent, could be degraded so that the visual detection limit of 1 toward oxalate was magnified 50 times from 100 to 2 ppm. The detection, degradation, mineralization and signal amplification were found applicable in real water bodies such as river, pond and underground water with excellent recoveries and relative standard deviation.


Event-Based, 6-DOF Camera Tracking from Photometric Depth Maps.
Event cameras are bio-inspired vision sensors that output pixel-level brightness changes instead of standard intensity frames. These cameras do not suffer from motion blur and have a very high dynamic range, which enables them to provide reliable visual information during high-speed motions or in scenes characterized by high dynamic range. These features, along with a very low power consumption, make event cameras an ideal complement to standard cameras for VR/AR and video game applications. With these applications in mind, this paper tackles the problem of accurate, low-latency tracking of an event camera from an existing photometric depth map (i.e., intensity plus depth information) built via classic dense reconstruction pipelines. Our approach tracks the 6-DOF pose of the event camera upon the arrival of each event, thus virtually eliminating latency. We successfully evaluate the method in both indoor and outdoor scenes and show that-because of the technological advantages of the event camera-our pipeline works in scenes characterized by high-speed motion, which are still inaccessible to standard cameras.


Fission yeast Swi5 protein, a novel DNA recombination mediator.
The Schizosaccharomyces pombe Swi5 protein forms two distinct protein complexes, Swi5-Sfr1 and Swi5-Swi2, each of which plays an important role in the related but functionally distinct processes of homologous recombination and mating-type switching, respectively. The Swi5-Sfr1 mediator complex has been shown to associate with the two RecA-like recombinases, Rhp51 (spRad51) and Dmc1, and to stimulate in vitro DNA strand exchange reactions mediated by these proteins. Genetic analysis indicates that Swi5-Sfr1 works independently of another mediator complex, Rhp55-Rhp57, during Rhp51-dependent recombinational repair. In addition, mutations affecting the two mediators generate distinct repair spectra of HO endonuclease-induced DNA double strand breaks, suggesting that these recombination mediators differently regulate recombination outcomes in an independent manner.