The utility of cerebrospinal fluid (CSF) CXCL13 for diagnosis of acute Lyme neuroborreliosis (LNB) has been debated and the test is not yet routinely performed. This study's aim was to evaluate its ...overall diagnostic accuracy through meta-analysis.
Electronic searches in PubMed MEDLINE and Web of Science were performed to identify relevant articles published before January 2018. A summary receiver operating characteristic curve and an optimal cut-off were estimated modelling multiple cut-offs. Publication bias was evaluated using a funnel plot and the associated regression test.
A total of 18 studies involving 618 individuals with acute LNB and 2326 individuals with other neurological disorders meeting the eligibility criteria were identified. The pooled sensitivity for CSF CXCL13 was 89% (95% CI 85%–93%) and the pooled specificity was 96% (95% CI 92%–98%), using the identified optimal cut-off value of 162 pg/mL. There was marked heterogeneity between studies, caused by differences in the designs of the study populations and age distribution. The optimal cut-off in the seven studies with a cross-sectional design was 91 pg/mL (sensitivity 96%, 95% CI 92%–98%; specificity 94%, 95% CI 86%–97%) and in the 11 case–control studies it was 164 pg/mL (sensitivity 85%, 95% CI 78%–91%; specificity 95%, 95% CI 90%–98%). CSF CXCL13 values above the optimal cut-off level (determined in this meta-analysis) were also detectable in some other central nervous system disorders, namely neurosyphilis and central nervous system lymphoma.
Our meta-analysis shows that CSF CXCL13 has the potential to become a useful adjunct in the diagnosis of acute LNB.
Germ-line mutations in nonsyndromic pheochromocytoma Neumann, Hartmut P H; Bausch, Birke; McWhinney, Sarah R ...
New England journal of medicine/The New England journal of medicine,
05/2002, Volume:
346, Issue:
19
Journal Article
Peer reviewed
Open access
The group of susceptibility genes for pheochromocytoma that included the proto-oncogene RET (associated with multiple endocrine neoplasia type 2 MEN-2) and the tumor-suppressor gene VHL (associated ...with von Hippel-Lindau disease) now also encompasses the newly identified genes for succinate dehydrogenase subunit D (SDHD) and succinate dehydrogenase subunit B (SDHB), which predispose carriers to pheochromocytomas and glomus tumors. We used molecular tools to classify a large cohort of patients with pheochromocytoma with respect to the presence or absence of mutations of one of these four genes and to investigate the relevance of genetic analyses to clinical practice.
Peripheral blood from unrelated, consenting registry patients with pheochromocytoma was tested for mutations of RET, VHL, SDHD, and SDHB. Clinical data at first presentation and follow-up were evaluated.
Among 271 patients who presented with nonsyndromic pheochromocytoma and without a family history of the disease, 66 (24 percent) were found to have mutations (mean age, 25 years; 32 men and 34 women). Of these 66, 30 had mutations of VHL, 13 of RET, 11 of SDHD, and 12 of SDHB. Younger age, multifocal tumors, and extraadrenal tumors were significantly associated with the presence of a mutation. However, among the 66 patients who were positive for mutations, only 21 had multifocal pheochromocytoma. Twenty-three (35 percent) presented after the age of 30 years, and 17 (8 percent) after the age of 40. Sixty-one (92 percent) of the patients with mutations were identified solely by molecular testing of VHL, RET, SDHD, and SDHB; these patients had no associated signs and symptoms at presentation.
Almost one fourth of patients with apparently sporadic pheochromocytoma may be carriers of mutations; routine analysis for mutations of RET, VHL, SDHD, and SDHB is indicated to identify pheochromocytoma-associated syndromes that would otherwise be missed.
Objective: Preclinical and clinical findings suggest a substantial association of the endogenous opioid system in nicotine dependence. The present study investigates the possible dose-dependent ...influence of naloxone, an unspecific opioid-receptor-antagonist, combined with cue exposure on the physiological state, locomotor activity, craving and the hypothalamic-pituitary-adrenal axis in nicotine-dependent humans. Methods: Twenty nicotine-dependent, outpatient participants were deprived of nicotine for over 4 h, before receiving challenges with naloxone (1.6 mg or 3.2 mg q70 kg IV) or the placebo. Additionally, following drug administration, either smoking-related cues or neutral images were presented. Nicotine withdrawal was monitored by evaluating the following objective signs – skin conductance, heart rate, temperature, respiration, locomotor activity, cortisol, prolactin and ACTH levels as well as craving. Results: With respect to subjective effects, participants administered a higher dosage of naloxone and those who were shown smoking-related cues were significantly less pleased (p = 0.019), felt more depressed (p = 0.033) and thought smoking would make them feel better (p = 0.028) than participants given naloxone and shown neutral cues. Participants given no naloxone but with smoking-related cues felt a higher urge to smoke than participants given naloxone and shown neutral cues (p = 0.042). Naloxone – in both dosages – also decreased the desire and intention to smoke in comparison to placebo. Compared to the placebo group, significantly higher cortisol, prolactin and ACTH values were observed after administration of lower and higher dosage of naloxone followed by smoking-related cues. Conclusion: Naloxone influenced nicotine withdrawal and strengthened significantly by cue exposure, both on objective measurement and on craving scales. These findings suggest an involvement of the endogenous opioid system in the development and maintenance of nicotine dependence.
IntroductionChronic low back pain (CLBP) produces considerable direct costs as well as indirect burdens for society, industry and health systems. CLBP is characterised by heterogeneity, inclusion of ...several pain syndromes, different underlying molecular pathologies and interaction with psychosocial factors that leads to a range of clinical manifestations. There is still much to understand in the underlying pathological processes and the non-psychosocial factors which account for differences in outcomes. Biomarkers that may be objectively used for diagnosis and personalised, targeted and cost-effective treatment are still lacking. Therefore, any data that may be obtained at the ‘-omics’ level (glycomics, Activomics and genome-wide association studies—GWAS) may be helpful to use as dynamic biomarkers for elucidating CLBP pathogenesis and may ultimately provide prognostic information too. By means of a retrospective, observational, case-cohort, multicentre study, we aim to investigate new promising biomarkers potentially able to solve some of the issues related to CLBP.Methods and analysisThe study follows a two-phase, 1:2 case–control model. A total of 12 000 individuals (4000 cases and 8000 controls) will be enrolled; clinical data will be registered, with particular attention to pain characteristics and outcomes of pain treatments. Blood samples will be collected to perform -omics studies. The primary objective is to recognise genetic variants associated with CLBP; secondary objectives are to study glycomics and Activomics profiles associated with CLBP.Ethics and disseminationThe study is part of the PainOMICS project funded by European Community in the Seventh Framework Programme. The study has been approved from competent ethical bodies and copies of approvals were provided to the European Commission before starting the study. Results of the study will be reviewed by the Scientific Board and Ethical Committee of the PainOMICS Consortium. The scientific results will be disseminated through peer-reviewed journals.Trial registration numberNCT02037789; Pre-results.
Introduction
: Modulation of macrophages and microglia (tumor associated macrophages, TAMs) in glioblastoma (GBM) poses a strategy against the disease. But little is known about the composition of ...the TAM-pool and the role of GBM subtypes in shaping their microenvironment. Thus, we sought to decipher the contribution of peripheral macrophages and microglia to the GBM-TAM-pool and their response to myeloid modulation such as CD47-Sirpa disruption with CD47 blocking antibodies.
Methods:
We generated immunodeficient mice with genetically color-coded macrophages and microglia. B6
Ccr2
Rfp/+
Cx3cr1
Gfp/+
mice were crossed to
NSG (NOD.Cg-Prkdc
scid
Il2rg
tm1Wjl/SzJ
)-
mice, and termed
Ccr2
Rfp/+
Cx3cr1
Gfp/+
NSG-
mice. Further,
Ccr2
Rfp/Rfp
Cx3cr1
Gfp/+
NSG-
mice devoid of macrophage influx to the brain were generated. Mice were grafted with patient-derived GBM cell lines transduced with
EBFP2-luciferase
, and treated with anti-CD47 Mab. At endpoint, tumors were analyzed by flow cytometry to assess TAM composition, polarization and phagocytosis, and both microglial and macrophage TAMs sorted for RNAseq analysis. Plasma cytokines were assessed. Further, brain tumors were imaged through cranial windows using
in vivo
confocal and 2-photon microscopy to monitor macrophage and microglial phagocytosis and behavior upon anti-CD47 treatment in real time.
Results
: The composition of the TAM pool was highly variable depending on the xenografted cell line. While TAMs in diffuse, slow growing tumors almost exclusively consisted of microglia, high-passage mesenchymal and classical GBM lines induced significant peripheral macrophage influx. In contrast, TAMs of proneural tumors only had a minor macrophage component. Anti-CD47 treatment induced macrophage and microglial phagocytosis and a marked microglial morphology change assessed by intracranial
in vivo
imaging and flow-cytometry. Furthermore, anti-CD47 treatment led to modest peripheral macrophage recruitment to the tumor site in the absence of Ccr2. Anti-CD47 treatment in absence of Ccr2 was accompanied by a stronger proinflammatory cytokine profile compared to wildtype, and significantly improved survival of tumor burdened mice in presence or absence of Ccr2. RNAseq analysis of sorted macrophages and microglia after anti-CD47 treatment revealed a transcriptional change towards a proinflammatory and M1-polarized signature in macrophages, whereas microglia displayed a distinct loss of M2-related genes.
Conclusion:
The GBM TAM pool is dynamic and dependent on tumor- specific characteristics. Resident microglia by themselves are able to respond to anti-CD47 treatment and act as phagocytic effector cells that reduce GBM growth and improve survival. Additional recruitment and reprogramming of peripheral macrophages by CD47-blockade boosts the therapeutic response and points towards macrophage-microglial cooperativity.
Humanized hemato-lymphoid system mice Theocharides, Alexandre P A; Rongvaux, Anthony; Fritsch, Kristin ...
Haematologica
101, Issue:
1
Journal Article
Peer reviewed
Open access
Over the last decades, incrementally improved xenograft mouse models, supporting the engraftment and development of a human hemato-lymphoid system, have been developed and now represent an important ...research tool in the field. The most significant contributions made by means of humanized mice are the identification of normal and leukemic hematopoietic stem cells, the characterization of the human hematopoietic hierarchy, and their use as preclinical therapy models for malignant hematopoietic disorders. Successful xenotransplantation depends on three major factors: tolerance by the mouse host, correct spatial location, and appropriately cross-reactive support and interaction factors such as cytokines and major histocompatibility complex molecules. Each of these can be modified. Experimental approaches include the genetic modification of mice to faithfully express human support factors as non-cross-reactive cytokines, to create free niche space, the co-transplantation of human mesenchymal stem cells, the implantation of humanized ossicles or other stroma, and the implantation of human thymic tissue. Besides the source of hematopoietic cells, the conditioning regimen and the route of transplantation also significantly affect human hematopoietic development in vivo. We review here the achievements, most recent developments, and the remaining challenges in the generation of pre-clinically-predictive systems for human hematology and immunology, closely resembling the human situation in a xenogeneic mouse environment.
Background Several legacy and emerging per- and polyfluoroalkyl substances (PFAS) have been regulated around the world. There is growing concern over the proliferation of alternative PFAS, as well as ...PFAS precursors. Biomonitoring data for PFAS are critical for assessing exposure and human health risk. Methods We collected serum samples from 289 adult female participants in a 2018-2021 follow-up study of the Maternal-Infant Research on Environmental Chemicals (MIREC) Canadian pregnancy cohort. Samples were analyzed for 40 PFAS using ultra-performance liquid chromatography-tandem mass spectrometry. For those compounds with > 50% detection, as well as the sum of these compounds, we describe serum concentrations and patterns of exposure according to sociodemographic and obstetrical history characteristics. Results 17 out of 40 PFAS were detected in > 50% of samples with 7 of these detected in > 97% of samples. Median 95th percentile concentrations (microg/L) were highest for PFOS (1.62 4.56), PFOA (0.69 1.52), PFNA (0.38 0.81), and PFHxS (0.33 0.92). Geometric mean concentrations of PFOA and PFHxS were approximately 2-fold lower among those with more children (greater than or equal to 3 vs. 1), greater number of children breastfed (greater than or equal to 3 vs. less than or equal to 1), longer lifetime duration of breastfeeding (> 4 years vs. less than or equal to 9 months), and shorter time since last pregnancy (less than or equal to 4 years vs. > 8 years). We observed similar patterns for PFOS, PFHpS, and the sum of 17 PFAS, though the differences between groups were smaller. Concentrations of PFOA were higher among "White" participants, while concentrations of N-MeFOSE, N-EtFOSE, 7:3 FTCA, and 4:2 FTS were slightly higher among participants reporting a race or ethnicity other than "White". Concentrations of legacy, alternative, and precursor PFAS were generally similar across levels of age, education, household income, body mass index, and menopausal status. Conclusions We report the first Canadian biomonitoring data for several alternative and precursor PFAS. Our findings suggest that exposure to PFAS, including several emerging alternatives, may be widespread. Our results are consistent with previous studies showing that pregnancy and breastfeeding are excretion pathways for PFAS. Keywords: Biomonitoring, Perfluorinated substances, Polyfluoroalkyl substances, Environmental chemicals
The progression of chronic myelogenous leukemia (CML) to blast crisis is supported by self-renewing leukemic stem cells. In normal mouse hematopoietic stem cells, the process of self-renewal involves ...the beta-catenin-signaling pathway. We investigated whether leukemic stem cells in CML also use the beta-catenin pathway for self-renewal.
We used fluorescence-activated cell sorting to isolate hematopoietic stem cells, common myeloid progenitors, granulocyte-macrophage progenitors, and megakaryocyte-erythroid progenitors from marrow during several phases of CML and from normal marrow. BCR-ABL, beta-catenin, and LEF-1 transcripts were compared by means of a quantitative reverse-transcriptase-polymerase-chain-reaction assay in normal and CML hematopoietic stem cells and granulocyte-macrophage progenitors. Confocal fluorescence microscopy and a lymphoid enhancer factor/T-cell factor reporter assay were used to detect nuclear beta-catenin in these cells. In vitro replating assays were used to identify self-renewing cells as candidate leukemic stem cells, and the dependence of self-renewal on beta-catenin activation was tested by lentiviral transduction of hematopoietic progenitors with axin, an inhibitor of the beta-catenin pathway.
The granulocyte-macrophage progenitor pool from patients with CML in blast crisis and imatinib-resistant CML was expanded, expressed BCR-ABL, and had elevated levels of nuclear beta-catenin as compared with the levels in progenitors from normal marrow. Unlike normal granulocyte-macrophage progenitors, CML granulocyte-macrophage progenitors formed self-renewing, replatable myeloid colonies, and in vitro self-renewal capacity was reduced by enforced expression of axin.
Activation of beta-catenin in CML granulocyte-macrophage progenitors appears to enhance the self-renewal activity and leukemic potential of these cells.
Tumor-to-tumor metastasis is rare. The authors report a case of a 52-year-old man with a 1-year history of a right parasaggital meningioma, whose clinical signs were consistent with enlarging ...meningioma. In preparation for surgery, the routine preoperative chest radiograph revealed a lung mass. Fine-needle aspiration of the mass revealed adenocarcinoma. The patient underwent surgical excision of the intracranial mass, which was thought to be a meningioma. However, pathologic examination revealed a transitional meningioma extensively infiltrated with deposits of metastatic carcinoma from the patient's primary lung tumor. Metastasis to meningioma was therefore responsible for the rapid enlargement of the long-standing meningioma, and caused the first clinical manifestation of primary lung carcinoma. Recurrent metastasis developed at the surgical site 5 weeks later, requiring surgical excision and postoperative radiation to prevent further recurrence. This is a highly unusual presentation for lung carcinoma and, to the authors' best knowledge, is the first such case reported. A review of the published literature revealed 20 other cases of lung carcinoma metastatic to meningioma, which were incidentally discovered on surgery or autopsy.
PDF
