Diagnostic accuracy of Xpert MTB/RIF Ultra for tuberculous meningitis in HIV-infected adults: a prospective cohort study.

BACKGROUND: WHO recommends Xpert MTB/RIF as initial diagnostic testing for tuberculous meningitis. However, diagnosis remains difficult, with Xpert sensitivity of about 50-70% and culture sensitivity of about 60%. We evaluated the diagnostic performance of the new Xpert MTB/RIF Ultra (Xpert Ultra) for tuberculous meningitis. METHODS: We prospectively obtained diagnostic cerebrospinal fluid (CSF) specimens during screening for a trial on the treatment of HIV-associated cryptococcal meningitis in Mbarara, Uganda. HIV-infected adults with suspected meningitis (eg, headache, nuchal rigidity, altered mental status) were screened consecutively at Mbarara Regional Referral Hospital. We centrifuged CSF, resuspended the pellet in 2 mL of CSF, and tested 0·5 mL with mycobacteria growth indicator tube culture, 1 mL with Xpert, and cryopreserved 0·5 mL, later tested with Xpert Ultra. We assessed diagnostic performance against uniform clinical case definition or a composite reference standard of any positive CSF tuberculous test. FINDINGS: From Feb 27, 2015, to Nov 7, 2016, we prospectively evaluated 129 HIV-infected adults with suspected meningitis for tuberculosis. 23 participants were classified as probable or definite tuberculous meningitis by uniform case definition, excluding Xpert Ultra results. Xpert Ultra sensitivity was 70% (95% CI 47-87; 16 of 23 cases) for probable or definite tuberculous meningitis compared with 43% (23-66; 10/23) for Xpert and 43% (23-66; 10/23) for culture. With composite standard, we detected tuberculous meningitis in 22 (17%) of 129 participants. Xpert Ultra had 95% sensitivity (95% CI 77-99; 21 of 22 cases) for tuberculous meningitis, which was higher than either Xpert (45% [24-68]; 10/22; p=0·0010) or culture (45% [24-68]; 10/22; p=0·0034). Of 21 participants positive by Xpert Ultra, 13 were positive by culture, Xpert, or both, and eight were only positive by Xpert Ultra. Of those eight, three were categorised as probable tuberculous meningitis, three as possible tuberculous meningitis, and two as not tuberculous meningitis. Testing 6 mL or more of CSF was associated with more frequent detection of tuberculosis than with less than 6 mL (26% vs 7%; p=0·014). INTERPRETATION: Xpert Ultra detected significantly more tuberculous meningitis than did either Xpert or culture. WHO now recommends the use of Xpert Ultra as the initial diagnostic test for suspected tuberculous meningitis. FUNDING: National Institute of Neurologic Diseases and Stroke, Fogarty International Center, National Institute of Allergy and Infectious Disease, UK Medical Research Council/DfID/Wellcome Trust Global Health Trials, Doris Duke Charitable Foundation

Survival of Enterococcus faecalis in root canals ex vivo

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72532/1/j.1365-2591.2005.01009.x.pd

Different secretion patterns of matrix metalloproteinases and IL-8 and effect of corticotropin-releasing hormone in preterm and term cervical fibroblasts

The aims of the present study were to compare the levels of mRNA and protein expression of matrix metalloproteinase (MMP)-1, -3, -8 and -9 in human cervical tissue in preterm and term labor as well as not in labor and to determine if corticotropin-releasing hormone (CRH) has an effect on MMP-1, -3 and interleukin (IL)-8 secretion in both preterm and term cervical fibroblasts. Cervical biopsies were taken from 60 women: 18 at preterm labor, 7 at preterm not in labor, 18 at term labor and 17 at term not in labor. ELISA and Immulite were used for protein and real-time RT–PCR for mRNA analysis. Cervical fibroblast cultures were incubated for 18 h with different CRH concentrations (10−13–10−6 M). The mRNA expression of MMP-1, -3 and -9 was higher in laboring groups compared with term not in labor. Protein levels of MMP-8 and -9 were higher in term in labor group compared with non-laboring groups. There were no significant differences in mRNA and protein expression between the preterm and respective term control groups. CRH significantly increased secretion of IL-8 in preterm and term cervical fibroblasts compared with controls. The secretion of IL-8 and MMP-1 was significantly higher and MMP-3 secretion lower in preterm cervical fibroblasts. In conclusion, cervical ripening at preterm seems to be a similar inflammatory process as at term with CRH involved. However, preterm and term cervical fibroblasts might have different phenotypes based on different secretion patterns of IL-8, MMP-1 and MMP-3

Resolution of inflammation: a new therapeutic frontier

Dysregulated inflammation is a central pathological process in diverse disease states. Traditionally, therapeutic approaches have sought to modulate the pro- or anti-inflammatory limbs of inflammation, with mixed success. However, insight into the pathways by which inflammation is resolved has highlighted novel opportunities to pharmacologically manipulate these processes — a strategy that might represent a complementary (and perhaps even superior) therapeutic approach. This Review discusses the state of the art in the biology of resolution of inflammation, highlighting the opportunities and challenges for translational research in this field

Prolonged labour associated with lower expression of syndecan 3 and connexin 43 in human uterine tissue

BACKGROUND: Prolonged labour is associated with greater morbidity and mortality for mother and child. Connexin 43 is a major myometrial gap junction protein found in human myometrium. Syndecan 3 seems to prevail in the human uterus among heparan sulphate proteoglycans, showing the most significant increase during labour. The aims of the present study were to investigate syndecan 3 and connexin 43 mRNA expressions and protein distributions in human uterine tissue during normal and prolonged labour. METHODS: Uterine isthmic biopsies were collected from non-pregnant (n = 7), term pregnant women not in labour (n = 14), in normal labour (n = 7) and in prolonged labour (n = 7). mRNA levels of syndecan 3 and connexin 43 were determined by real time RT-PCR. The localization and expression were demonstrated by immunohistochemistry and confocal microscopy. RESULTS: In women with prolonged labour, the mRNA expressions of syndecan 3 and Connexin 43 were considerably lower than the expression level at normal labour (p < 0.05). In term-pregnant tissue, the expression of syndecan 3 and connexin 43 did not differ significantly compared to non-pregnant and normal labour. The immunoreactivity of syndecan 3 was strong at normal labour, in contrast to prolonged labour, where both a weaker expression and an irregular distribution were detected. The immunoreactivity of connexin 43 increased until term and further stronger staining occurred at normal labour. At prolonged labour, the immunoreactivity was weaker and more unevenly distributed. At labour, a co-localization of syndecan 3 and connexin 43 could be demonstrated in the smooth muscle by confocal microscopy. CONCLUSION: The high expression of syndecan 3 and connexin 43 and their co-localization to the smooth muscle bundles during normal labour, together with the significant reduction in prolonged labour, may indicate a role for these proteins in the co-ordination of myometrial contractility

Complexity of Many-Body Interactions in Transition Metals via Machine-Learned Force Fields from the TM23 Data Set

This work examines challenges associated with the accuracy of machine-learned force fields (MLFFs) for bulk solid and liquid phases of d-block elements. In exhaustive detail, we contrast the performance of force, energy, and stress predictions across the transition metals for two leading MLFF models: a kernel-based atomic cluster expansion method implemented using sparse Gaussian processes (FLARE), and an equivariant message-passing neural network (NequIP). Early transition metals present higher relative errors and are more difficult to learn relative to late platinum- and coinage-group elements, and this trend persists across model architectures. Trends in complexity of interatomic interactions for different metals are revealed via comparison of the performance of representations with different many-body order and angular resolution. Using arguments based on perturbation theory on the occupied and unoccupied d states near the Fermi level, we determine that the large, sharp d density of states both above and below the Fermi level in early transition metals leads to a more complex, harder-to-learn potential energy surface for these metals. Increasing the fictitious electronic temperature (smearing) modifies the angular sensitivity of forces and makes the early transition metal forces easier to learn. This work illustrates challenges in capturing intricate properties of metallic bonding with current leading MLFFs and provides a reference data set for transition metals, aimed at benchmarking the accuracy and improving the development of emerging machine-learned approximations.Comment: main text: 21 pages, 9 figures, 2 tables. supplementary information: 57 pages, 83 figures, 20 table

CAR T cells targeting tumor endothelial marker CLEC14A inhibit tumor growth

Engineering T cells to express chimeric antigen receptors (CARs) specific for antigens on hematological cancers has yielded remarkable clinical responses, but with solid tumors, benefit has been more limited. This may reflect lack of suitable target antigens, immune evasion mechanisms in malignant cells, and/or lack of T cell infiltration into tumors. An alternative approach, to circumvent these problems, is targeting the tumor vasculature rather than the malignant cells directly. CLEC14A is a glycoprotein selectively overexpressed on the vasculature of many solid human cancers and is, therefore, of considerable interest as a target antigen. Here, we generated CARs from 2 CLEC14A-specific antibodies and expressed them in T cells. In vitro studies demonstrated that, when exposed to their target antigen, these engineered T cells proliferate, release IFN-γ, and mediate cytotoxicity. Infusing CAR engineered T cells into healthy mice showed no signs of toxicity, yet these T cells targeted tumor tissue and significantly inhibited tumor growth in 3 mouse models of cancer (Rip-Tag2, mPDAC, and Lewis lung carcinoma). Reduced tumor burden also correlated with significant loss of CLEC14A expression and reduced vascular density within malignant tissues. These data suggest the tumor vasculature can be safely and effectively targeted with CLEC14A-specific CAR T cells, offering a potent and widely applicable therapy for cancer

Организация бухгалтерского учета основных средств на медеплавильном заводе АО «АГМК»

Объектом исследования является акционерное общество "Алмалыкский ГМК". Целью работы – учет основных производственных фондов акционерного общества "Алмалыкский ГМК", а также разработка рекомендаций по улучшению их использования. Предмет исследования - учет основных средств на АО "Алмалыкский ГМК".The object of research is the joint stock company "Almalyk MMC". The aim of the work is to record fixed assets of Almalyk GMK joint – stock company, as well as to develop recommendations for improving their use. The subject of the research is the accounting of fixed assets at JSC "Almalyk MMC"

Lament as Transitional Justice

Works of human rights literature help to ground the formal rights system in an informal rights ethos. Writers have developed four major modes of human rights literature: protest, testimony, lament, and laughter. Through interpretations of poetry in Carolyn Forché’s anthology, Against Forgetting, and novels from Rwanda, the United States, and Bosnia, I focus on the mode of lament, the literature of mourning. Lament is a social and ritualized form, the purposes of which are congruent with the aims of transitional justice institutions. Both laments and truth commissions employ grieving narratives to help survivors of human rights trauma bequeath to the ghosts of the past the justice of a monument while renewing the survivors’ capacity for rebuilding civil society in the future. Human rights scholars need a broader, extra-juridical meaning for “transitional justice” if we hope to capture its power

Co-ordinated Gene Expression in the Liver and Spleen during Schistosoma japonicum Infection Regulates Cell Migration

Determining the molecular events induced in the spleen during schistosome infection is an essential step in better understanding the immunopathogenesis of schistosomiasis and the mechanisms by which schistosomes modulate the host immune response. The present study defines the transcriptional and cellular events occurring in the murine spleen during the progression of Schistosoma japonicum infection. Additionally, we compared and contrasted these results with those we have previously reported for the liver. Microarray analysis combined with flow cytometry and histochemistry demonstrated that transcriptional changes occurring in the spleen were closely related to changes in cellular composition. Additionally, the presence of alternatively activated macrophages, as indicated by up-regulation of Chi3l3 and Chi3l4 and expansion of F4/80+ macrophages, together with enhanced expression of the immunoregulatory genes ANXA1 and CAMP suggests the spleen may be an important site for the control of S. japonicum-induced immune responses. The most striking difference between the transcriptional profiles of the infected liver and spleen was the contrasting expression of chemokines and cell adhesion molecules. Lymphocyte chemokines, including the homeostatic chemokines CXCL13, CCL19 and CCL21, were significantly down-regulated in the spleen but up-regulated in the liver. Eosinophil (CCL11, CCL24), neutrophil (CXCL1) and monocyte (CXCL14, CCL12) chemokines and the cell adhesion molecules VCAM1, NCAM1, PECAM1 were up-regulated in the liver but unchanged in the spleen. Chemokines up-regulated in both organs were expressed at significantly higher levels in the liver. Co-ordinated expression of these genes probably contributes to the development of a chemotactic signalling gradient that promotes recruitment of effector cells to the liver, thereby facilitating the development of hepatic granulomas and fibrosis. Together these data provide, for the first time, a comprehensive overview of the molecular events occurring in the spleen during schistosomiasis and will substantially further our understanding of the local and systemic mechanisms driving the immunopathogenesis of this disease