Cognitive Science, EarlyView.
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Τετάρτη 13 Ιουνίου 2018
The Recruitment of Shifting and Inhibition in On‐line Science and Mathematics Tasks
Selective targeting of 3 repeat Tau with brain penetrating single chain antibodies for the treatment of neurodegenerative disorders
Abstract
Alzheimer's disease (AD) is the most common form of dementia in the elderly affecting more than 5 million people in the U.S. AD is characterized by the accumulation of β-amyloid (Aβ) and Tau in the brain, and is manifested by severe impairments in memory and cognition. Therefore, removing tau pathology has become one of the main therapeutic goals for the treatment of AD. Tau (tubulin-associated unit) is a major neuronal cytoskeletal protein found in the CNS encoded by the gene MAPT. Alternative splicing generates two major isoforms of tau containing either 3 or 4 repeat (R) segments. These 3R or 4RTau species are differentially expressed in neurodegenerative diseases. Previous studies have been focused on reducing Tau accumulation with antibodies against total Tau, 4RTau or phosphorylated isoforms. Here, we developed a brain penetrating, single chain antibody that specifically recognizes a pathogenic 3RTau. This single chain antibody was modified by the addition of a fragment of the apoB protein to facilitate trafficking into the brain, once in the CNS these antibody fragments reduced the accumulation of 3RTau and related deficits in a transgenic mouse model of tauopathy. NMR studies showed that the single chain antibody recognized an epitope at aa 40–62 of 3RTau. This single chain antibody reduced 3RTau transmission and facilitated the clearance of Tau via the endosomal–lysosomal pathway. Together, these results suggest that targeting 3RTau with highly specific, brain penetrating, single chain antibodies might be of potential value for the treatment of tauopathies such as Pick's Disease.
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Pediatric low-grade gliomas can be molecularly stratified for risk
Abstract
Pediatric low-grade gliomas (PLGGs) consist of a number of entities with overlapping histological features. PLGGs have much better prognosis than the adult counterparts, but a significant proportion of PLGGs suffers from tumor progression and recurrence. It has been shown that pediatric and adult low-grade gliomas are molecularly distinct. Yet the clinical significance of some of newer biomarkers discovered by genomic studies has not been fully investigated. In this study, we evaluated in a large cohort of 289 PLGGs a list of biomarkers and examined their clinical relevance. TERT promoter (TERTp), H3F3A and BRAF V600E mutations were detected by direct sequencing. ATRX nuclear loss was examined by immunohistochemistry. CDKN2A deletion, KIAA1549-BRAF fusion, and MYB amplification were determined by fluorescence in situ hybridization (FISH). TERTp, H3F3A, and BRAF V600E mutations were identified in 2.5, 6.4, and 7.4% of PLGGs, respectively. ATRX loss was found in 4.9% of PLGGs. CDKN2A deletion, KIAA1549-BRAF fusion and MYB amplification were detected in 8.8, 32.0 and 10.6% of PLGGs, respectively. Survival analysis revealed that TERTp mutation, H3F3A mutation, and ATRX loss were significantly associated with poor PFS (p < 0.0001, p < 0.0001, and p = 0.0002) and OS (p < 0.0001, p < 0.0001, and p < 0.0001). BRAF V600E was associated with shorter PFS (p = 0.011) and OS (p = 0.032) in a subset of PLGGs. KIAA1549-BRAF fusion was a good prognostic marker for longer PFS (p = 0.0017) and OS (p = 0.0029). MYB amplification was also a favorable marker for a longer PFS (p = 0.040). Importantly, we showed that these molecular biomarkers can be used to stratify PLGGs into low- (KIAA1549-BRAF fusion or MYB amplification), intermediate-I (BRAF V600E and/or CDKN2A deletion), intermediate-II (no biomarker), and high-risk (TERTp or H3F3A mutation or ATRX loss) groups with distinct PFS (p < 0.0001) and OS (p < 0.0001). This scheme should aid in clinical decision-making.
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Relations between early maternal sensitivity and toddler self‐regulation: Exploring variation by oxytocin and dopamine D2 receptor genes
Developmental Psychobiology, EarlyView.
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Quercetin inhibits prostate cancer by attenuating cell survival and inhibiting anti-apoptotic pathways
Abstract
Background
Despite recent advances in diagnosis and treatment, prostate cancer (PCa) remains the leading cause of cancer-related deaths in men. Current treatments offered in the clinics are often toxic and have severe side effects. Hence, to treat and manage PCa, new agents with fewer side effects or having potential to reduce side effects of conventional therapy are needed. In this study, we show anti-cancer effects of quercetin, an abundant bioflavonoid commonly used to treat prostatitis, and defined quercetin-induced cellular and molecular changes leading to PCa cell death.
Methods
Cell viability was assessed using MTT. Cell death mode, mitochondrial outer membrane potential, and oxidative stress levels were determined by flow cytometry using Annexin V-7 AAD dual staining kit, JC-1 dye, and ROS detection kit, respectively. Antibody microarray and western blot were used to delineate the molecular changes induced by quercetin.
Results
PCa cells treated with various concentrations of quercetin showed time- and dose-dependent decrease in cell viability compared to controls, without affecting normal prostate epithelial cells. Quercetin led to apoptotic and necrotic cell death in PCa cells by affecting the mitochondrial integrity and disturbing the ROS homeostasis depending upon the genetic makeup and oxidative status of the cells. LNCaP and PC-3 cells that have an oxidative cellular environment showed ROS quenching after quercetin treatment while DU-145 showed rise in ROS levels despite having a highly reductive environment. Opposing effects of quercetin were also observed on the pro-survival pathways of PCa cells. PCa cells with mutated p53 (DU-145) and increased ROS showed significant reduction in the activation of pro-survival Akt pathway while Raf/MEK were activated in response to quercetin. PC-3 cells lacking p53 and PTEN with reduced ROS levels showed significant activation of Akt and NF-κB pathway. Although some of these changes are commonly associated with oncogenic response, the cumulative effect of these alterations is PCa cell death.
Conclusions
Our results demonstrated quercetin exerts its anti-cancer effects by modulating ROS, Akt, and NF-κB pathways. Quercetin could be used as a chemopreventive option as well as in combination with chemotherapeutic drugs to improve clinical outcomes of PCa patients.
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Effect of Dengue Serostatus on Dengue Vaccine Safety and Efficacy
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Trolleyology and the Dengue Vaccine Dilemma
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Histamine H 3 receptor density is negatively correlated with neural activity related to working memory in humans
Abstract
Background
The histamine H3 receptor is regarded as a drug target for cognitive impairments in psychiatric disorders. H3 receptors are expressed in neocortical areas, including the prefrontal cortex, the key region of cognitive functions such as working memory. However, the role of prefrontal H3 receptors in working memory has not yet been clarified. Therefore, using functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) techniques, we aimed to investigate the association between the neural activity of working memory and the density of H3 receptors in the prefrontal cortex.
Findings
Ten healthy volunteers underwent both fMRI and PET scans. The N-back task was used to assess the neural activities related to working memory. H3 receptor density was measured with the selective PET radioligand [11C] TASP457. The neural activity of the right dorsolateral prefrontal cortex during the performance of the N-back task was negatively correlated with the density of H3 receptors in this region.
Conclusions
Higher neural activity of working memory was associated with lower H3 receptor density in the right dorsolateral prefrontal cortex. This finding elucidates the role of H3 receptors in working memory and indicates the potential of H3 receptors as a therapeutic target for the cognitive impairments associated with neuropsychiatric disorders.
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Immunotherapy resistance by inflammation-induced dedifferentiation [Research Briefs]
A promising arsenal of targeted and immunotherapy treatments for metastatic melanoma has emerged over the last decade. With these therapies, we now face new mechanisms of tumor acquired resistance. We report here a patient whose metastatic melanoma underwent dedifferentiation as a resistance mechanism to adoptive T cell transfer therapy (ACT) to the MART-1 antigen, a phenomenon that had only been observed in mouse studies to date. After an initial period of tumor regression, the patient presented in relapse with tumors lacking melanocytic antigens (MART-1, gp100) and expressing an inflammation-induced neural crest marker (NGFR). We demonstrate using human melanoma cell lines that this resistance phenotype can be induced in vitro by treatment with MART-1 T-cell receptor expressing T cells or with TNFα, and that the phenotype is reversible with withdrawal of inflammatory stimuli. This supports the hypothesis that acquired resistance to cancer immunotherapy can be mediated by inflammation-induced cancer dedifferentiation.
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CDK6 antagonizes p53-induced responses during tumorigenesis [Research Articles]
Tumor formation is a multi-step process during which cells acquire genetic and epigenetic changes until they reach a fully transformed state. We show that CDK6 contributes to tumor formation by regulating transcriptional responses in a stage-specific manner. In early stages CDK6 kinase induces a complex transcriptional program to block p53 in hematopoietic cells. Cells lacking CDK6 kinase function are required to mutate p53 to achieve a fully transformed immortalized state. CDK6 binds to the promoters of genes including the p53-antagonists PRMT5, PPM1D and MDM4. The findings are relevant to human patients: tumors with low levels of CDK6 have mutations in p53 significantly more often than expected.
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EWS/ETS-driven Ewing Sarcoma requires BET bromodomain proteins
The EWS/ETS fusion transcription factors drive Ewing sarcoma (EWS) by orchestrating an oncogenic transcription program. Therapeutic targeting of EWS/ETS has been unsuccessful; however, identifying mediators of the EWS/ETS function could offer new therapeutic options. Here we describe the dependency of EWS/ETS-driven transcription upon chromatin reader BET bromdomain proteins and investigate the potential of BET inhibitors in treating EWS. EWS/FLI1 and EWS/ERG were found in a transcriptional complex with BRD4, and knockdown of BRD2/3/4 significantly impaired the oncogenic phenotype of EWS cells. RNA-seq analysis following knockdown or inhibition of BRD4 with JQ1 revealed an attenuated EWS/ETS transcriptional signature. In contrast to previous reports, JQ1 reduced proliferation and induced apoptosis through MYC-independent mechanisms without affecting EWS/ETS protein levels; this was confirmed by depleting BET proteins using PROTAC-BET degrader (BETd). Polycomb repressive complex 2 (PRC2)-associated factor PHF19 was downregulated by JQ1/BETd or BRD4 knockdown in multiple EWS lines. EWS/FLI1 bound a distal regulatory element of PHF19, and EWS/FLI1 knockdown resulted in downregulation of PHF19 expression. Deletion of PHF19 via CRISPR-Cas9 resulted in a decreased tumorigenic phenotype, a transcriptional signature that overlapped with JQ1 treatment, and increased sensitivity to JQ1. PHF19 expression was also associated with worse prognosis in Ewing sarcoma patients. In vivo, JQ1 demonstrated anti-tumor efficacy in multiple mouse xenograft models of EWS. Together these results indicate that EWS/ETS requires BET epigenetic reader proteins for its transcriptional program and can be mitigated by BET inhibitors. This study provides a clear rationale for the clinical utility of BET inhibitors in treating Ewing sarcoma.
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Flightless-I blocks p62-mediated recognition of LC3 to impede selective autophagy and promote breast cancer progression
p62 is a receptor that facilitates selective autophagy by interacting simultaneously with cargoes and LC3 protein on the autophagosome to maintain cellular homeostasis. However, the regulatory mechanism(s) behind this process and its association with breast cancer remain to be elucidated. Here we report that Flightless-I (FliI), a novel p62-interacting protein, promotes breast cancer progression by impeding selective autophagy. FliI was highly expressed in clinical breast cancer samples, and heterozygous deletion of FliI retarded development of mammary tumors in PyVT mice. FliI induced p62-recruited cargoes into Triton X-100 insoluble fractions (TI) to form aggregates, thereby blocking p62 recognition of LC3 and hindering p62-dependent selective autophagy. This function of Flil was reinforced by Akt-mediated phosphorylation at Ser436 and inhibited by phosphorylation of Ulk1 at Ser64. Obstruction of autophagic clearance of p62-recruited cargoes by FliI was associated with the accumulation of oxidative damage on proteins and DNA, which could contribute to the development of cancer. Heterozygous knockout of FliI facilitated selectively autophagic clearance of aggregates, abatement of ROS levels, and protein oxidative damage, ultimately retarding mammary cancer progression. In clinical breast cancer samples, Akt-mediated phosphorylation of FliI at Ser436 negatively correlated with long-term prognosis, while Ulk1-induced FliI phosphorylation at Ser64 positively correlation with clinical outcome. Together, this work demonstrates that FliI functions as a checkpoint protein for selective autophagy in the crosstalk between FliI and p62-recruited cargoes, and its phosphorylation may serve as a prognostic marker for breast cancer.
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Syntaphilin Ubiquitination Regulates Mitochondrial Dynamics And Tumor Cell Movements
Syntaphilin (SNPH) inhibits the movement of mitochondria in tumor cells, preventing their accumulation at the cortical cytoskeleton and limiting the bioenergetics of cell motility and invasion. Although this may suppress metastasis, the regulation of the SNPH pathway is not well understood. Using a global proteomics screen, we show that SNPH associates with multiple regulators of ubiquitin-dependent responses and is ubiquitinated by the E3 ligase CHIP (or STUB1) on Lys111 and Lys153 in the microtubule-binding domain. SNPH ubiquitination did not result in protein degradation, but instead anchored SNPH on tubulin to inhibit mitochondrial motility and cycles of organelle fusion and fission i.e. dynamics. Expression of ubiquitination-defective SNPH mutant Lys111→Arg or Lys153→Arg increased the speed and distance traveled by mitochondria, repositioned mitochondria to the cortical cytoskeleton, and supported heightened tumor chemotaxis, invasion, and metastasis in vivo. Interference with SNPH ubiquitination activated mitochondrial dynamics, resulting in increased recruitment of the fission regulator dynamin-related protein-1 (Drp1) to mitochondria, and Drp1-dependent tumor cell motility. These data uncover non-degradative ubiquitination of SNPH as a key regulator of mitochondrial trafficking and tumor cell motility and invasion. In this way, SNPH may function as a unique, ubiquitination-regulated suppressor of metastasis
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Elective nodal irradiation attenuates the combinatorial efficacy of stereotactic radiation therapy and immunotherapy
PURPOSE: In the proper context, radiation therapy (RT) can promote anti-tumor immunity. It is unknown if elective nodal irradiation (ENI), a strategy that irradiates tumor-associated draining lymph nodes (DLN), impacts adaptive immune responses and combinatorial efficacy of RT with immune checkpoint blockade (ICB). EXPERIMENTAL DESIGN: We developed a preclinical model to compare stereotactic RT (Tumor RT) with or without ENI to examine immunological differences between RT techniques that spare or irradiate the DLN. RESULTS: Tumor RT was associated with up-regulation of an intratumoral T-cell chemoattractant chemokine signature (CXCR3, CCR5-related) that resulted in robust infiltration of antigen-specific CD8+ effector T-cells as well as FoxP3+ regulatory T-cells (Tregs). The addition of ENI attenuated chemokine expression, restrained immune infiltration and adversely impacted survival when combined with ICB, especially with anti-CLTA4 therapy. The combination of stereotactic RT and ICB led to long-term survival in a subset of mice and was associated with favorable CD8 effector-to-Treg ratios and increased intratumoral density of antigen-specific CD8+ T-cells. While RT technique (Tumor RT vs. ENI) impacted initial tumor control and survival, the ability to reject tumor upon re-challenge was partially dependent upon the mechanism of action of ICB; as RT/anti-CTLA4 was superior to RT/anti-PD-1. CONCLUSIONS: Our results highlight that irradiation of the DLN restrains adaptive immune responses through altered chemokine expression and CD8+ T-cell trafficking. These data have implications for combining RT and ICB, long-term survival and induction of immunological memory. Clinically, the immunomodulatory effect of the RT strategy should be considered when combining stereotactic RT with immunotherapy.
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Disruption of a -35kb enhancer impairs CTCF binding and MLH1 expression in colorectal cells
Purpose: MLH1 is a major tumour suppressor gene involved in the pathogenesis of Lynch syndrome and various sporadic cancers. Despite their potential pathogenic importance, genomic regions capable of regulating MLH1 expression over long distances have yet to be identified. Experimental Design: Here we use chromosome conformation capture (3C) to screen a 650-kb region flanking the MLH1 locus to identify interactions between the MLH1 promoter and distal regions in MLH1 expressing and non-expressing cells. Putative enhancers were functionally validated using luciferase reporter assays, chromatin immunoprecipitation and CRISPR-Cas9 mediated deletion of endogenous regions. To evaluate whether germline variants in the enhancer might contribute to impaired MLH1 expression in patients with suspected Lynch syndrome, we also screened germline DNA from a cohort of 74 patients with no known coding mutations or epimutations at the MLH1 promoter. Results: A 1.8kb DNA fragment, 35kb upstream of the MLH1 transcription start site enhances MLH1 gene expression in colorectal cells. The enhancer was bound by CTCF and CRISPR-Cas9 mediated deletion of a core binding region impairs endogenous MLH1 expression. 5.4% of suspected Lynch syndrome patients have a rare single nucleotide variant (G>A; rs143969848; 2.5% in gnomAD European, non-Finnish) within a highly conserved CTCF binding motif, which disrupts enhancer activity in SW620 colorectal carcinoma cells. Conclusions: A CTCF bound region within the MLH1-35 enhancer regulates MLH1 expression in colorectal cells and is worthy of scrutiny in future genetic screening strategies for suspected Lynch syndrome associated with loss of MLH1 expression.
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MET-oncogenic and JAK2-inactivating alterations are independent factors that affect regulation of PD-L1 expression in lung cancer
Purpose:The blockade of immune checkpoints such as PD-L1 and PD-1 is being exploited therapeutically in several types of malignancies. Here, we aimed to understand the contribution of the genetics of lung cancer (LC) to the ability of tumor cells to escape immunosurveillance checkpoints. Experimental Design: Over 150 primary non-small cell lung cancers, including pulmonary sarcomatoid carcinomas, were tested for the levels of HLA-I complex, PD-L1, tumor-infiltrating CD8+ lymphocytes and alterations in main LC genes. Correlations were validated in cancer cell lines using appropriate treatments to activate or inhibit selected pathways. We also performed RNA sequencing to assess changes in gene expression after these treatments Results: MET-oncogenic activation tended to associate with positive PD-L1 immunostaining, whereas STK11 mutations were correlated with negative immunostaining. In MET-altered cancer cells, MET triggered a transcriptional increase of PD-L1 that was independent of the IFN-mediated JAK/STAT pathway. The activation of MET also up-regulated other immunosuppressive genes (PDCD1LG2 and SOCS1), and transcripts involved in angiogenesis (VEGFA and NRP1) and in cell proliferation. We also report recurrent inactivating mutations in JAK2 that co-occur with alterations in MET and STK11, which prevented the induction of immunoresponse-related genes following treatment with IFN. Conclusions: We show that MET activation promotes the expression of several negative checkpoint regulators of the immunoresponse, including PD-L1. In addition, we report inactivation of JAK2 in LC cells that prevented the response to IFN. These alterations are likely to facilitate tumor growth by enabling immune tolerance and may affect the response to immune checkpoint inhibitors.
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Impact of Emergent Circulating Tumor DNA RAS Mutation in Panitumumab-Treated Chemoresistant Metastatic Colorectal Cancer
Purpose: The accumulation of emergent RAS mutations during anti-epidermal growth factor receptor (EGFR) therapy is of interest as a mechanism for acquired resistance to anti-EGFR treatment. Plasma analysis of circulating tumor (ct) DNA is a minimally invasive and highly sensitive method to determine RAS mutational status. Experimental Design: This biomarker analysis of the global phase III ASPECCT study used next-generation sequencing to detect expanded RAS ctDNA mutations in panitumumab-treated patients. Plasma samples collected at baseline and posttreatment were analyzed categorically for the presence of RAS mutations by the PlasmaSelect-R™ 64-gene panel at 0.1% sensitivity. Results: Among panitumumab-treated patients with evaluable plasma samples at baseline (n = 238), 188 (79%) were wild-type (WT) RAS, and 50 (21%) were mutant RAS. Of the 188 patients with baseline ctDNA WT RAS status, 164 had evaluable posttreatment results with a 32% rate of emergent RAS mutations. The median overall survival (OS) for WT and RAS mutant status by ctDNA at baseline was 13.7 (95% confidence interval: 11.5-15.4) and 7.9 months (6.4-9.6), respectively (P < 0.0001). Clinical outcomes were not significantly different between patients with and without emergent ctDNA RAS mutations. Conclusions: Although patients with baseline ctDNA RAS mutations had worse outcomes than patients who were WT RAS before initiating treatment, emergent ctDNA RAS mutations were not associated with less favorable patient outcomes in panitumumab-treated patients. Further research is needed to determine a clinically relevant threshold for baseline and emergent ctDNA RAS mutations.
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Age Correlates with Response to Anti-PD1, Reflecting Age-Related Differences in Intratumoral Effector and Regulatory T-Cell Populations
Purpose: We have shown that the aged microenvironment increases melanoma metastasis, and decreases response to targeted therapy, and here we queried response to anti-PD1.
Experimental Design: We analyzed the relationship between age, response to anti-PD1, and prior therapy in 538 patients. We used mouse models of melanoma, to analyze the intratumoral immune microenvironment in young versus aged mice and confirmed our findings in human melanoma biopsies.
Results: Patients over the age of 60 responded more efficiently to anti-PD-1, and likelihood of response to anti-PD-1 increased with age, even when we controlled for prior MAPKi therapy. Placing genetically identical tumors in aged mice (52 weeks) significantly increased their response to anti-PD1 as compared with the same tumors in young mice (8 weeks). These data suggest that this increased response in aged patients occurs even in the absence of a more complex mutational landscape. Next, we found that young mice had a significantly higher population of regulatory T cells (Tregs), skewing the CD8+:Treg ratio. FOXP3 staining of human melanoma biopsies revealed similar increases in Tregs in young patients. Depletion of Tregs using anti-CD25 increased the response to anti-PD1 in young mice.
Conclusions: While there are obvious limitations to our study, including our inability to conduct a meta-analysis due to a lack of available data, and our inability to control for mutational burden, there is a remarkable consistency in these data from over 500 patients across 8 different institutes worldwide. These results stress the importance of considering age as a factor for immunotherapy response. Clin Cancer Res; 1–10. ©2018 AACR.
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Correction: Protein biomarkers predictive for response to anti-EGFR treatment in RAS wild-type metastatic colorectal carcinoma
Correction: Protein biomarkers predictive for response to anti-EGFR treatment in RAS wild-type metastatic colorectal carcinoma
Correction: Protein biomarkers predictive for response to anti-EGFR treatment in RAS wild-type metastatic colorectal carcinoma, Published online: 14 June 2018; doi:10.1038/s41416-018-0130-x
Correction: Protein biomarkers predictive for response to anti-EGFR treatment in RAS wild-type metastatic colorectal carcinoma
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G1P3 (IFI6), a mitochondrial localised antiapoptotic protein, promotes metastatic potential of breast cancer cells through mtROS
G1P3 (IFI6), a mitochondrial localised antiapoptotic protein, promotes metastatic potential of breast cancer cells through mtROS
G1P3 (IFI6), a mitochondrial localised antiapoptotic protein, promotes metastatic potential of breast cancer cells through mtROS, Published online: 14 June 2018; doi:10.1038/s41416-018-0137-3
G1P3 (IFI6), a mitochondrial localised antiapoptotic protein, promotes metastatic potential of breast cancer cells through mtROS
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TGFβ shuts the door on T cells
TGFβ shuts the door on T cells
TGFβ shuts the door on T cells, Published online: 14 June 2018; doi:10.1038/s41416-018-0122-x
TGFβ shuts the door on T cells
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Heterogeneous relationships of squamous and basal cell carcinomas of the skin with smoking: the UK Million Women Study and meta-analysis of prospective studies
Heterogeneous relationships of squamous and basal cell carcinomas of the skin with smoking: the UK Million Women Study and meta-analysis of prospective studies
Heterogeneous relationships of squamous and basal cell carcinomas of the skin with smoking: the UK Million Women Study and meta-analysis of prospective studies, Published online: 14 June 2018; doi:10.1038/s41416-018-0105-y
Heterogeneous relationships of squamous and basal cell carcinomas of the skin with smoking: the UK Million Women Study and meta-analysis of prospective studies
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Addition of intraperitoneal cisplatin and etoposide to first-line chemotherapy for advanced ovarian cancer: a randomised, phase 2 trial
Addition of intraperitoneal cisplatin and etoposide to first-line chemotherapy for advanced ovarian cancer: a randomised, phase 2 trial
Addition of intraperitoneal cisplatin and etoposide to first-line chemotherapy for advanced ovarian cancer: a randomised, phase 2 trial, Published online: 14 June 2018; doi:10.1038/s41416-018-0036-7
Addition of intraperitoneal cisplatin and etoposide to first-line chemotherapy for advanced ovarian cancer: a randomised, phase 2 trial
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Transcriptomic immune profiling of ovarian cancers in paraneoplastic cerebellar degeneration associated with anti-Yo antibodies
Transcriptomic immune profiling of ovarian cancers in paraneoplastic cerebellar degeneration associated with anti-Yo antibodies
Transcriptomic immune profiling of ovarian cancers in paraneoplastic cerebellar degeneration associated with anti-Yo antibodies, Published online: 14 June 2018; doi:10.1038/s41416-018-0125-7
Transcriptomic immune profiling of ovarian cancers in paraneoplastic cerebellar degeneration associated with anti-Yo antibodies
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APA: Suicide Prevention Should Be a Public Health Priority
WEDNESDAY, June 13, 2018 -- Suicide prevention needs to be a public health priority, according to the American Psychological Association (APA). The APA calls for a multifaceted approach that includes increasing access to mental health screenings and...
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Diabetes Meds Reconciliation May Reduce Risk of ER Visits
WEDNESDAY, June 13, 2018 -- Ambulatory medication reconciliation is associated with lower risk of a composite primary outcome of combined frequency of emergency department visits and hospitalizations over six months, according to a study published...
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IV Fluid Specs Do Not Influence Neuro Outcomes in Kids w/DKA
WEDNESDAY, June 13, 2018 -- Neurologic outcomes in children with diabetic ketoacidosis are similar regardless of the rate of administration or the sodium chloride content of intravenous fluids, according to a study published in the June 14 issue of...
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60 Sickened So Far in Salmonella-Tainted Melon Outbreak
WEDNESDAY, June 13, 2018 -- Federal, state, and local health officials are investigating a salmonella outbreak linked to fruit salad mixes that has sickened 60 people in five U.S. states. The fruit salad mixes included precut watermelon, honeydew...
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Strong Link Identified Between T2DM and Parkinson's Disease
WEDNESDAY, June 13, 2018 -- There is an increased rate of subsequent Parkinson's disease among individuals diagnosed with type 2 diabetes mellitus (T2DM), according to a study published online June 13 in Neurology. Eduardo De Pablo-Fernandez, M.D.,...
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Frequency and nature of potentially harmful preventable problems in primary care from the patients perspective with clinician review: a population-level survey in Great Britain
Objectives
To estimate the frequency of patient-perceived potentially harmful problems occurring in primary care. To describe the type of problem, patient predictors of perceiving a problem, the primary care service involved, how the problem was discussed and patient suggestions as to how the problem might have been prevented. To describe clinician/public opinions regarding the likelihood that the patient-described scenario is potentially harmful.
DesignPopulation-level survey.
SettingGreat Britain.
ParticipantsA nationally representative sample of 3975 members of the public aged ≥15 years interviewed during April 2016.
Main outcome measuresCounts of patient-perceived potentially harmful problems in the last 12 months, descriptions of patient-described scenarios and review by clinicians/members of the public.
Results3975 of 3996 participants in a nationally representative survey completed the relevant questions (99.5%). 300 (7.6%; 95% CI 6.7% to 8.4%) of respondents reported experiencing a potentially harmful preventable problem in primary care during the past 12 months and 145 (48%) discussed their concerns within primary care. This did not vary with age, gender or type of service used. A substantial minority (30%) of the patient-perceived problems occurred outside general practice, particularly the dental surgery, walk in clinic, out of hours care and pharmacy. Patients perceiving a potentially harmful preventable problem were eight times more likely to have 'no confidence and trust in primary care' compared with 'yes, definitely' (OR 7.9; 95% CI 5.9 to 10.7) but those who discussed their perceived-problem appeared to maintain higher trust and confidence. Generally, clinicians ranked the patient-described scenarios as unlikely to be potentially harmful.
ConclusionsThis study highlights the importance of actively soliciting patient's views about preventable harm in primary care as patients frequently perceive potentially harmful preventable problems and make useful suggestions for their prevention. Such engagement may also help to improve confidence and trust in primary care.
https://ift.tt/2LPOeVn
Diagnostic Value of Somatosensory Evoked Potential Changes During Carotid Endarterectomy for 30-Day Perioperative Stroke
Carotid Endarterectomy (CEA) is a standard surgical treatment in the secondary prevention of stroke performed in patients with both symptomatic and asymptomatic carotid stenosis (CS)(Malcharek et al. 2013), (Pennekamp et al. 2011), (Pulli et al. 2002), (Reinert et al. 2012). CEA is shown to benefit symptomatic and asymptomatic patients, when compared to medical management alone in the short term and long term due to decreased stroke. (Akhmedov et al. 2013), (Baton et al. 2007), (Floriani et al. 1989), (Hartmann et al.
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Prevention of haematoma progression by tranexamic acid in intracerebral haemorrhage patients with and without spot sign on admission scan: a statistical analysis plan of a pre-specified sub-study of the TICH-2 trial
We present the statistical analysis plan of a prespecified Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage (TICH)-2 sub-study aiming to investigate, if tranexamic acid has a different effect i...
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Role of temperature in reported chickenpox cases in northern European countries: Denmark and Finland
In this study, we sought to explore the temperature-dependent transition of patterns of reported chickenpox cases in the northern European countries of Denmark and Finland to help determine the potential relat...
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Magnitude of diabetes self-care practice and associated factors among type two adult diabetic patients following at public Hospitals in central zone, Tigray Region, Ethiopia, 2017
Self-care practice in type two diabetes is a critical factor to keep the disease under control. Despite the important role of self-care practices in management of diabetes were recognized to be useful and effe...
https://ift.tt/2MrlJy7
Liver transplant score for prediction of biliary atresia patients’ survival following Kasai procedure
Recently, a scoring system has been developed to predict which patients with biliary atresia (BA) who underwent a Kasai procedure should be considered for liver transplant. Here, we applied the scoring system ...
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Statin Therapy Does Not Reduce Liver Fat Scores in Patients Receiving Antiretroviral Therapy for HIV Infection
Therapies are needed to limit progression of fatty liver diseases in patients with HIV infection. We analyzed data from a prospective study of the effects of rosuvastatin (a statin) on hepatic steatosis in HIV-positive adults.
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Heterogeneity in Clinical, Endoscopic, and Histologic Outcome Measures and Placebo Response Rates in Clinical Trials of Eosinophilic Esophagitis: A Systematic Review
Agents are being developed for treatment of eosinophilic esophagitis (EoE). However, it is not clear what outcome measures would best determine the efficacy and safety of these agents in clinical trials. We performed a systematic review of outcomes used in randomized placebo-controlled trials of EoE and we estimate the placebo response and rates of remission.
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Magnetic Resonance vs Transient Elastography Analysis of Patients With Non-alcoholic Fatty Liver Disease: a Systematic Review and Pooled Analysis of Individual Participants
Magnetic resonance elastography (MRE) and transient elastography (TE) are noninvasive techniques for detection of liver fibrosis. Single-center studies have compared the diagnostic performance of MRE vs TE in patients with nonalcoholic fatty liver disease (NAFLD). We conducted a pooled analysis of individual participant data from published studies to compare the diagnostic performance of MRE vs TE for staging of liver fibrosis in patients with NAFLD, using liver biopsy as reference.
https://ift.tt/2JCCVmE
Non-alcoholic Steatohepatitis is the Fastest Growing Cause of Hepatocellular Carcinoma in Liver Transplant Candidates
While hepatitis B and C have been the main drivers of hepatocellular carcinoma (HCC), non-alcoholic steatohepatitis (NASH) has recently become an important cause of HCC. The aim of this study was to assess the causes of HCC among liver transplant (LT) candidates in the U.S.
https://ift.tt/2JJkVTG
Incidence of Upper and Lower Gastrointestinal Bleeding in New Users of Low-dose Aspirin
There are few data on the incidence of upper and lower gastrointestinal bleeding (UGIB and LGIB) from observational studies of low-dose aspirin users. We aimed to estimate incidence rates of UGIB and LGIB in a large cohort of new users of low-dose aspirin in the United Kingdom, with sub-analyses of hospitalization status and fatalities.
https://ift.tt/2JApBPK
An Automated Multiparametric MRI Quantitative Imaging Prostate Habitat Risk Scoring System for Defining External Beam Radiotherapy Boost Volumes
Prostate multiparamateric MRI has a high sensitivity and specificity for identifying tumor regions in the prostate; but, there is subjectivity in defining high risk 3D volumes that could be boosted, as opposed to entire prostate dose escalation. Registering to prostatectomy Gleason score, a habitat risk score based on pixel by pixel quantitative diffusion and perfusion was developed and then applied to guiding radiotherapy boost volumes in the background of a randomized Phase II clinical trial.
https://ift.tt/2JOpmjf
New-generation full-spectrum endoscopy versus standard forward-viewing colonoscopy: a multicenter, randomized, tandem colonoscopy trial (J-FUSE Study)
Although colonoscopy is the criterion standard for detection of colorectal adenomas, some adenomas are missed. Full-spectrum endoscopy (FUSE) allows for observation with a 330° angle of view, which is expected to decrease the miss rate. However, no consensus has been reached regarding the superiority of FUSE over standard forward-viewing colonoscopy (SFVC) for detection of adenomas; we therefore compared new-generation FUSE and SFVC regarding colorectal adenoma miss rate (AMR) in this, the first reported randomized control trial using new-generation FUSE.
https://ift.tt/2JVAzil
Young Patients with Sporadic Colorectal Adenomas: Current Endoscopic Surveillance Practices and Outcomes
For young individuals (<40) without strong family histories that would put them at risk for genetic colorectal cancer syndromes, it is unclear if national Multi-Society Task Force surveillance recommendations apply or if endoscopists follow these guideline recommendations when such patients are incidentally found to have adenoma(s) on colonoscopy.
https://ift.tt/2HN3a46
Su1439 EUS-GUIDED APPROACH AND THERAPY FOR BILE DUCT DISEASES WITH A RENDEZVOUS OR ANTEGRADE METHOD
Endoscopic ultrasonography (EUS)-guided procedures including an antegrade procedure (EUS-AG) /rendezvous method (EUS-RV) have been spreading as alternatives for conventional transpapillary or percutaneous biliary procedures. However, there have been few reports about clinical results of EUS-AG/EUS-RV. Thus, we aimed to clarify the clinical outcomes of EUS-AG and EUS-RV.
https://ift.tt/2LOEwTa
Tu1033 RISK FACTORS FOR INADEQUATE BOWEL PREPARATION IN PATIENTS WITH FUNCTIONAL CONSTIPATION
Constipation is a common reason of poor bowel preparation, which negatively influences the quality of colonoscopy. The risk factors associated with inadequate bowel preparation in constipated patients remains unclear. The aim of this study was to investigate the high-risk factors which might influence the quality of bowel preparation in patients with functional constipation.
https://ift.tt/2JMFstM
Arterial Stiffness in CKD: A Review
This narrative review summarizes a decade of experience examining the cross-sectional and longitudinal relationships of arterial stiffness, as assessed using carotid-femoral pulse wave velocity, with outcomes in patients with chronic kidney disease enrolled in the Chronic Renal Insufficiency Cohort. Our goal is to review the importance of the pulse wave contour and pulse wave velocity and present data on the reproducibility of pulse wave velocity measurements, determinants of pulse wave velocity, and the relationship that velocity measurements have with longitudinal kidney and cardiovascular outcomes.
https://ift.tt/2y9gfFr
Collapsing Glomerulopathy in Lambda Light Chain Amyloidosis: A Report of 2 Cases
Amyloid nephropathy is an uncommon disease that frequently presents with reduced kidney function and proteinuria and, in developed nations, is most often associated with underlying paraproteinemia. The histologic appearance of glomerular amyloid deposition includes mesangial and capillary wall infiltration by an amorphous eosinophilic material, and features of endo- or extracapillary proliferation are not typically seen. Rare cases of crescentic injury have been reported in a subset of patients with amyloid nephropathy, particularly those with amyloid derived from serum amyloid A protein.
https://ift.tt/2lbkKpn
Methods for the Study of Regeneration in Stentor
The giant ciliate, Stentor coeruleus, is an excellent system to study regeneration and wound healing. We present procedures for establishing Stentor cell cultures from single cells or cell fragments, inducing regeneration by cutting cells, chemically inducing the regeneration of membranellar band and oral apparatus, imaging, and analysis of cell regeneration.
https://ift.tt/2JNmp2r
Solvothermal Synthesis of MIL-96 and UiO-66-NH2 on Atomic Layer Deposited Metal Oxide Coatings on Fiber Mats
https://ift.tt/2LIP31W
Preparing Developing Peripheral Olfactory Tissue for Molecular and Immunohistochemical Analysis in Drosophila
Here, we present a protocol to stage and dissect developing olfactory tissue from Drosophila species. The dissected tissue can later be used for molecular analyses, such as quantitative RT-PCR (Reverse Transcription-Polymerase Chain Reaction) or RNA sequencing (RNAseq), as well as in vivo analyses such as immunohistochemistry or in situ hybridization.
https://ift.tt/2JMvrgj
Tracking the glossopharyngeal nerve pathway through anatomical references in cross-sectional imaging techniques: a pictorial review
Abstract
The glossopharyngeal nerve (GPN) is a rarely considered cranial nerve in imaging interpretation, mainly because clinical signs may remain unnoticed, but also due to its complex anatomy and inconspicuousness in conventional cross-sectional imaging. In this pictorial review, we aim to conduct a comprehensive review of the GPN anatomy from its origin in the central nervous system to peripheral target organs. Because the nerve cannot be visualised with conventional imaging examinations for most of its course, we will focus on the most relevant anatomical references along the entire GPN pathway, which will be divided into the brain stem, cisternal, cranial base (to which we will add the parasympathetic pathway leaving the main trunk of the GPN at the cranial base) and cervical segments. For that purpose, we will take advantage of cadaveric slices and dissections, our own developed drawings and schemes, and computed tomography (CT) and magnetic resonance imaging (MRI) cross-sectional images from our hospital's radiological information system and picture and archiving communication system.
Teaching Points
• The glossopharyngeal nerve is one of the most hidden cranial nerves.
• It conveys sensory, visceral, taste, parasympathetic and motor information.
• Radiologists' knowledge must go beyond the limitations of conventional imaging techniques.
• The nerve's pathway involves the brain stem, cisternal, skull base and cervical segments.
• Systematising anatomical references will help with nerve pathway tracking.
https://ift.tt/2y60e35
Suppression of AMPA Receptor Exocytosis Contributes to Hippocampal LTD
The decrease in number of AMPA-type glutamate receptor (AMPAR) at excitatory synapses causes LTD, a cellular basis of learning and memory. The number of postsynaptic AMPARs is regulated by the balance of exocytosis and endocytosis, and enhanced endocytosis of AMPAR has been suggested to underlie the LTD expression. However, it remains unclear how endocytosis and exocytosis of AMPAR change during LTD. In this study, we addressed this question by analyzing exocytosis and endocytosis of AMPAR by imaging super-ecliptic pHlorin (SEP)-tagged AMPAR around postsynaptic structure formed directly on the glass surface in the hippocampal culture prepared from rat embryos of both sexes. Contrary to a prevailing view on the LTD expression by endocytosis enhancement, the LTD induction by NMDA application only transiently enhanced endocytosis of SEP-tagged GluA1 subunits of AMPAR, which was counteracted by simultaneous augmentation of exocytosis. As a result, soon after the start of the LTD induction (~1 min), the surface AMPAR did not markedly decrease. Thereafter, the surface GluA1-SEP gradually decreased (2–5 min) and kept at a low level until the end of observation (>30 min). Surprisingly, this gradual and sustained decrease of surface AMPAR was accompanied not by the enhanced endocytic events of GluA1, but by the suppression of exocytosis. Together, our data highlight an unprecedented mechanism for the LTD expression by attenuation of exocytosis of AMPAR, but not by enhanced endocytosis, together with a reduction of postsynaptic AMPAR scaffolding protein PSD95.
SIGNIFICANCE STATEMENT It has been generally assumed that LTD is expressed by enhancement of AMPAR endocytosis. Previous studies reported that endocytosis-related protein was involved in LTD and that significant amount of cell-surface AMPAR moved into intracellular compartments during LTD. Here, we report changes of cell-surface amount of AMPAR, and where and when individual exocytosis and endocytosis occurred during LTD. Cell-surface AMPAR gradually decreased in synchrony with suppression of exocytosis but not with enhancement of endocytosis. These results suggest that the decrease of cell-surface AMPAR amount during LTD was caused not by enhancement of endocytosis but rather by suppression of exocytosis, which revises current understanding of the expression mechanism of LTD.
https://ift.tt/2y79eVl
The Frequency Response of Outer Hair Cell Voltage-Dependent Motility Is Limited by Kinetics of Prestin
The voltage-dependent protein SLC26a5 (prestin) underlies outer hair cell electromotility (eM), which is responsible for cochlear amplification in mammals. The electrical signature of eM is a bell-shaped nonlinear capacitance (NLC), deriving from prestin sensor-charge (Qp) movements, which peaks at the membrane voltage, Vh, where charge is distributed equally on either side of the membrane. Voltage dependencies of NLC and eM differ depending on interrogation frequency and intracellular chloride, revealing slow intermediate conformational transitions between anion binding and voltage-driven Qp movements. Consequently, NLC exhibits low-pass characteristics, substantially below prevailing estimates of eM frequency response. Here we study in guinea pig and mouse of either sex synchronous prestin electrical (NLC, Qp) and mechanical (eM) activity across frequencies under voltage clamp (whole cell and microchamber). We find that eM and Qp magnitude and phase correspond, indicating tight piezoelectric coupling. Electromechanical measures (both NLC and eM) show dual-Lorentzian, low-pass behavior, with a limiting (2) time constant at Vh of 32.6 and 24.8 μs, respectively. As expected for voltage-dependent kinetics, voltage excitation away from Vh has a faster, flatter frequency response, with our fastest measured 2 for eM of 18.2 μs. Previous observations of ultrafast eM ( 2 μs) were obtained at offsets far removed from Vh. We hypothesize that trade-offs in eM gain-bandwith arising from voltage excitation at membrane potentials offset from Vh influence the effectiveness of cochlear amplification across frequencies.
SIGNIFICANCE STATEMENT Of two types of hair cells within the organ of Corti, inner hair cells and outer hair cells, the latter evolved to boost sensitivity to sounds. Damage results in hearing loss of 40–60 dB, revealing amplification gains of 100–1000x that arise from voltage-dependent mechanical responses [electromotility (eM)]. eM, driven by the membrane protein prestin, may work beyond 70 kHz. However, this speed exceeds, by over an order of magnitude, kinetics of typical voltage-dependent membrane proteins. We find eM is actually low pass in nature, indicating that prestin bears kinetics typical of other membrane proteins. These observations highlight potential difficulties in providing sufficient amplification beyond a cutoff frequency near 20 kHz. Nevertheless, observed trade-offs in eM gain-bandwith may sustain cochlear amplification across frequency.
https://ift.tt/2JKPx7n
Neurotrophin Responsiveness of Sympathetic Neurons Is Regulated by Rapid Mobilization of the p75 Receptor to the Cell Surface through TrkA Activation of Arf6
The p75 neurotrophin receptor (p75NTR) plays an integral role in patterning the sympathetic nervous system during development. Initially, p75NTR is expressed at low levels as sympathetic axons project toward their targets, which enables neurotrophin-3 (NT3) to activate TrkA receptors and promote growth. Upon reaching nerve growth factor (NGF) producing tissues, p75NTR is upregulated, resulting in formation of TrkA-p75 complexes, which are high-affinity binding sites selective for NGF, thereby blunting NT3 signaling. The level of p75NTR expressed on the neuron surface is instrumental in regulating trophic factor response; however, the mechanisms by which p75NTR expression is regulated are poorly understood. Here, we demonstrate a rapid, translation independent increase in surface expression of p75NTR in response to NGF in rat sympathetic neurons. p75NTR was mobilized to the neuron surface from GGA3-postitive vesicles through activation of the GTPase Arf6, which was stimulated by NGF, but not NT3 binding to TrkA. Arf6 activation required PI3 kinase activity and was prevented by an inhibitor of the cytohesin family of Arf6 guanine nucleotide exchange factors. Overexpression of a constitutively active Arf6 mutant (Q67L) was sufficient to significantly increase surface expression of p75NTR even in the absence of NGF. Functionally, expression of active Arf6 markedly attenuated the ability of NT3 to promote neuronal survival and neurite outgrowth, whereas the NGF response was unaltered. These data suggest that NGF activation of Arf6 through TrkA is critical for the increase in p75NTR surface expression that enables the switch in neurotrophin responsiveness during development in the sympathetic nervous system.
SIGNIFICANCE STATEMENT p75NTR is instrumental in the regulation of neuronal survival and apoptosis during development and is also implicated as a contributor to aberrant neurodegeneration in numerous conditions. Therefore, a better understanding of the mechanisms that mediate p75NTR surface availability may provide insight into how and why neurodegenerative processes manifest and reveal new therapeutic targets. Results from this study indicate a novel mechanism by which p75NTR can be rapidly shuttled to the cell surface from existing intracellular pools and explores a unique pathway by which NGF regulates the sympathetic innervation of target tissues, which has profound consequences for the function of these organs.
https://ift.tt/2JI2Bdz
miR126-5p Downregulation Facilitates Axon Degeneration and NMJ Disruption via a Non-Cell-Autonomous Mechanism in ALS
Axon degeneration and disruption of neuromuscular junctions (NMJs) are key events in amyotrophic lateral sclerosis (ALS) pathology. Although the disease's etiology is not fully understood, it is thought to involve a non–cell-autonomous mechanism and alterations in RNA metabolism. Here, we identified reduced levels of miR126-5p in presymptomatic ALS male mice models, and an increase in its targets: axon destabilizing Type 3 Semaphorins and their coreceptor Neuropilins. Using compartmentalized in vitro cocultures, we demonstrated that myocytes expressing diverse ALS-causing mutations promote axon degeneration and NMJ dysfunction, which were inhibited by applying Neuropilin1 blocking antibody. Finally, overexpressing miR126-5p is sufficient to transiently rescue axon degeneration and NMJ disruption both in vitro and in vivo. Thus, we demonstrate a novel mechanism underlying ALS pathology, in which alterations in miR126-5p facilitate a non–cell-autonomous mechanism of motor neuron degeneration in ALS.
SIGNIFICANCE STATEMENT Despite some progress, currently no effective treatment is available for amyotrophic lateral sclerosis (ALS). We suggest a novel regulatory role for miR126-5p in ALS and demonstrate, for the first time, a mechanism by which alterations in miR126-5p contribute to axon degeneration and NMJ disruption observed in ALS. We show that miR126-5p is altered in ALS models and that it can modulate Sema3 and NRP protein expression. Furthermore, NRP1 elevations in motor neurons and muscle secretion of Sema3A contribute to axon degeneration and NMJ disruption in ALS. Finally, overexpressing miR126-5p is sufficient to transiently rescue NMJ disruption and axon degeneration both in vitro and in vivo.
https://ift.tt/2JyR0Sa
Modeling Osteosarcoma Using Li-Fraumeni Syndrome Patient-derived Induced Pluripotent Stem Cells
https://ift.tt/2JzWThN
“Late for testing, early for antiretroviral therapy, less likely to die”: results from a large HIV cohort study in China, 2006–2014
Timely HIV testing and initiation of antiretroviral therapy are two major determinants of survival for HIV-infected individuals. Our study aimed to explore the trend of late HIV/AIDS diagnoses and to assess th...
https://ift.tt/2MoCI4c
Light-sheet Microscopy for Three-dimensional Visualization of Human Immune Cells
Here, we present a protocol to visualize immune cells embedded in a three-dimensional (3D) collagen matrix using light-sheet microscopy. This protocol also elaborates how to track cell migration in 3D. This protocol can be employed for other types of suspension cells in the 3D matrix.
https://ift.tt/2HLenlE
Deep Dermal Injection As a Model of Candida albicans Skin Infection for Histological Analyses
https://ift.tt/2JB3VmD
Evaluation of D-isomers of 4-borono-2- 18 F-fluoro-phenylalanine and O - 11 C-methyl-tyrosine as brain tumor imaging agents: a comparative PET study with their L-isomers in rat brain glioma
Abstract
Background
The potential of the D-isomerization of 4-borono-2-18F-fluoro-phenylalanine (18F-FBPA) to improve its target tumor to non-target normal brain tissue ratio (TBR) was evaluated in rat brain glioma and compared with those of L- and D-11C-methyl-tyrosine (11C-CMT).
The L- or D-isomer of 18F-FBPA was injected into rats through the tail vein, and their whole body kinetics and distributions were assessed using the tissue dissection method up to 90 min after the injection. The kinetics of L- and D-18F-FBPA or L- and D-11C-CMT in the C-6 glioma-inoculated rat brain were measured for 90 or 60 min, respectively, using high-resolution animal PET, and their TBRs were assessed.
Results
Tissue dissection analyses showed that D-18F-FBPA uptake was significantly lower than that of L-18F-FBPA in the brain and abdominal organs, except for the kidney and bladder, reflecting the faster elimination rate of D-18F-FBPA than L-18F-FBPA from the blood to the urinary tract. PET imaging using 18F-FBPA revealed that although the brain uptake of D-18F-FBPA was significantly lower than that of L-18F-FBPA, the TBR of the D-isomer improved to 6.93 from 1.45 for the L-isomer. Similar results were obtained with PET imaging using 11C-CMT with a smaller improvement in TBR to 1.75 for D-11C-CMT from 1.33 for L-11C-CMT.
Conclusions
The present results indicate that D-18F-FBPA is a better brain tumor imaging agent with higher TBR than its original L-isomer and previously reported tyrosine-based PET imaging agents. This improved TBR of D-18F-FBPA without any pre-treatments, such as tentative blood-brain barrier disruption using hyperosmotic agents or sonication, suggests that the D-isomerization of BPA results in the more selective accumulation of 10B in tumor cells that is more effective and less toxic than conventional L-BPA.
https://ift.tt/2HJ9fyl
Mir-98 reduces the expression of HMGA2 and promotes osteogenic differentiation of mesenchymal stem cells
OBJECTIVE: To study effects of microRNA-98 (miR-98) on osteogenic differentiation of mesenchymal stem cells (MSCs).
PATIENTS AND METHODS: We predicted target gene of miR-98 with software test, and detected expression changes of miR-98, as well as its target gene HMGA2, in the process of osteogenic differentiation of mesenchymal stem cells. After transfection of miR-98 mimic and HMGA2 siRNA, we induced osteogenic differentiation and detected expression changes of osteogenic differentiation markers (RUNX2, ALP, OCN, and BSP).
RESULTS: MiR-98 combined directly with target gene HMGA2 and inhibited its expression. During the process of osteogenic differentiation, expression of miR-98 was up-regulated, while HMGA2 expression was down-regulated. In addition, the expression of osteogenesis maker genes increased in cells being transfected with miR-98 mimics and HMGA2 siRNA.
CONCLUSIONS: MiR-98 can promote osteogenic differentiation of mesenchymal stem cells by targeting gene HMGA2.
L'articolo Mir-98 reduces the expression of HMGA2 and promotes osteogenic differentiation of mesenchymal stem cells sembra essere il primo su European Review.
https://ift.tt/2JRhtJX
MiR-29a promotes osteogenic differentiation of mesenchymal stem cells via targeting HDAC4
OBJECTIVE: To investigate the role of miR-29a in regulating the differentiation mesenchymal stem cells into osteoblasts.
MATERIALS AND METHODS: For the first step, the changes of expression of miR-29a during the process of mesenchymal stem cells (MSCs) differentiation into osteoblast were detected. Then, we infected the MSCs with mimics or inhibitors of miR-29a to explore the roles of miR-29a in the differentiation. Further, the prediction and verification of the possible target genes of miR-29a were achieved by bioinformatics analysis and luciferase reporter assay.
RESULTS: MiR-29a was up-regulated during the process of MSCs differentiation into osteoblasts. Overexpression or inhibition of miR-29a using mimics or inhibitors had no significant effect on cell proliferation. Furthermore, the differentiation was enhanced when miR-29a was artificially overexpressed in vitro, whereas silencing of miR-29a attenuated this process. It was evidenced by alkaline phosphatase (ALP) staining, matrix mineralization, and increased expression of osteoblast-specific genes. Furthermore, we determined that the gene HDAC4 might be a direct target of miR-29a.
CONCLUSIONS: In the current study, miR-29a promotes osteogenesis via suppressing HDAC4, indicating that targeting miR-29a may be feasible in the management of osteoporosis.
L'articolo MiR-29a promotes osteogenic differentiation of mesenchymal stem cells via targeting HDAC4 sembra essere il primo su European Review.
https://ift.tt/2LKLF6W
Work Stress May Increase Risk of Developing Atrial Fibrillation
WEDNESDAY, June 13, 2018 -- Job strain is associated with an increased risk of incident atrial fibrillation, according to a study published online May 30 in the European Journal of Preventive Cardiology. Eleonor I. Fransson, Ph.D., from Stockholm...
https://ift.tt/2Jz0AEy
Addition of Bezafibrate Beneficial in Primary Biliary Cholangitis
WEDNESDAY, June 13, 2018 -- Nearly one-third of patients with primary biliary cholangitis who had had an inadequate response to ursodeoxycholic acid alone achieved a complete biochemical response with the addition of bezafibrate to treatment,...
https://ift.tt/2HKWjIo
Negative Pressure Wound Tx No Benefit for Lower Limb Open Fx
WEDNESDAY, June 13, 2018 -- Use of a negative pressure wound therapy (NPWT) for severe open fracture of the lower limb is not associated with improved self-rated disability at 12 months, compared with standard wound dressing, according to a study...
https://ift.tt/2JBiczK
CDC: Preterm Births Increased in United States During 2014-2016
WEDNESDAY, June 13, 2018 -- During 2014 to 2016, the rate of preterm births in the United States increased, according to a June data brief published by the U.S. Centers for Disease Control and Prevention's National Center for Health Statistics...
https://ift.tt/2HM7Jvw
Exposure to Maternal HTN May Up Risk of ASD, ADHD in Child
WEDNESDAY, June 13, 2018 -- Exposure to hypertensive disorders of pregnancy (HDP) may be associated with an increase in the risk of autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD) in offspring, according to a...
https://ift.tt/2JBc4Yj
Higher Blood Pressure at Mid-Life Increases Dementia Risk
WEDNESDAY, June 13, 2018 -- The risk of dementia is increased in 50-year-olds with blood pressure ≥130 mm Hg, which is below the current threshold for hypertension, according to a study published online June 13 in the European Heart...
https://ift.tt/2HKWhjK
Dexmedetomidine Cuts γ-Aminobutyric Acid Receptor Function
WEDNESDAY, June 13, 2018 -- Dexmedetomidine prevents excessive γ-aminobutyric acid type A receptor function after anesthesia, according to a study published online June 7 in Anesthesiology. Dian-Shi Wang, M.D., Ph.D., from the University of...
https://ift.tt/2sUhpzo
Sun Defenses Up in Transplant Patients After Skin Cancer Study
WEDNESDAY, June 13, 2018 -- For organ transplant recipients, participation in a skin cancer research study is associated with increased use of multiple sun protection behaviors, according to a research letter published online June 6 in JAMA...
https://ift.tt/2LJ7OT5
Older Adults Increasingly Have HPV+ Oropharyngeal Cancers
WEDNESDAY, June 13, 2018 -- Human papillomavirus (HPV)-positive oropharyngeal cancers are increasing among older adults, according to a study published online April 30 in Cancer. Melina J. Windon, M.D., from Johns Hopkins University in Baltimore,...
https://ift.tt/2sT2W6L
Pre-Op Psychiatric Dx Not Tied to Bariatric Sx Outcomes in Teens
WEDNESDAY, June 13, 2018 -- Preoperative psychiatric diagnoses are not associated with weight loss outcomes in severely obese adolescents receiving bariatric surgery, according to a study published online June 1 in Pediatrics. Eleanor R. Mackey,...
https://ift.tt/2HMbh0C
The prevalence, antibiotic resistance and mecA characterization of coagulase negative staphylococci recovered from non-healthcare settings in London, UK
Coagulase negative staphylococci (CoNS) are important reservoirs of antibiotic resistance genes and associated mobile genetic elements and are believed to contribute to the emergence of successful methicillin ...
https://ift.tt/2MiMDIJ
Neural Signatures of the Processing of Temporal Patterns in Sound
The ability to detect regularities in sound (i.e., recurring structure) is critical for effective perception, enabling, for example, change detection and prediction. Two seemingly unconnected lines of research concern the neural operations involved in processing regularities: one investigates how neural activity synchronizes with temporal regularities (e.g., frequency modulation; FM) in sounds, whereas the other focuses on increases in sustained activity during stimulation with repeating tone-frequency patterns. In three electroencephalography studies with male and female human participants, we investigated whether neural synchronization and sustained neural activity are dissociable, or whether they are functionally interdependent. Experiment I demonstrated that neural activity synchronizes with temporal regularity (FM) in sounds, and that sustained activity increases concomitantly. In Experiment II, phase coherence of FM in sounds was parametrically varied. Although neural synchronization was more sensitive to changes in FM coherence, such changes led to a systematic modulation of both neural synchronization and sustained activity, with magnitude increasing as coherence increased. In Experiment III, participants either performed a duration categorization task on the sounds, or a visual object tracking task to distract attention. Neural synchronization was observed regardless of task, whereas the sustained response was observed only when attention was on the auditory task, not under (visual) distraction. The results suggest that neural synchronization and sustained activity levels are functionally linked: both are sensitive to regularities in sounds. However, neural synchronization might reflect a more sensory-driven response to regularity, compared with sustained activity which may be influenced by attentional, contextual, or other experiential factors.
SIGNIFICANCE STATEMENT Optimal perception requires that the auditory system detects regularities in sounds. Synchronized neural activity and increases in sustained neural activity both appear to index the detection of a regularity, but the functional interrelation of these two neural signatures is unknown. In three electroencephalography experiments, we measured both signatures concomitantly while listeners were presented with sounds containing frequency modulations that differed in their regularity. We observed that both neural signatures are sensitive to temporal regularity in sounds, although they functionally decouple when a listener is distracted by a demanding visual task. Our data suggest that neural synchronization reflects a more automatic response to regularity compared with sustained activity, which may be influenced by attentional, contextual, or other experiential factors.
https://ift.tt/2JKPVml
Identification of a Rhythmic Firing Pattern in the Enteric Nervous System That Generates Rhythmic Electrical Activity in Smooth Muscle
The enteric nervous system (ENS) contains millions of neurons essential for organization of motor behavior of the intestine. It is well established that the large intestine requires ENS activity to drive propulsive motor behaviors. However, the firing pattern of the ENS underlying propagating neurogenic contractions of the large intestine remains unknown. To identify this, we used high-resolution neuronal imaging with electrophysiology from neighboring smooth muscle. Myoelectric activity underlying propagating neurogenic contractions along murine large intestine [also referred to as colonic migrating motor complexes, (CMMCs)] consisted of prolonged bursts of rhythmic depolarizations at a frequency of ~2 Hz. Temporal coordination of this activity in the smooth muscle over large spatial fields (~7 mm, longitudinally) was dependent on the ENS. During quiescent periods between neurogenic contractions, recordings from large populations of enteric neurons, in mice of either sex, revealed ongoing activity. The onset of neurogenic contractions was characterized by the emergence of temporally synchronized activity across large populations of excitatory and inhibitory neurons. This neuronal firing pattern was rhythmic and temporally synchronized across large numbers of ganglia at ~2 Hz. ENS activation preceded smooth muscle depolarization, indicating rhythmic depolarizations in smooth muscle were controlled by firing of enteric neurons. The cyclical emergence of temporally coordinated firing of large populations of enteric neurons represents a unique neural motor pattern outside the CNS. This is the first direct observation of rhythmic firing in the ENS underlying rhythmic electrical depolarizations in smooth muscle. The pattern of neuronal activity we identified underlies the generation of CMMCs.
SIGNIFICANCE STATEMENT How the enteric nervous system (ENS) generates neurogenic contractions of smooth muscle in the gastrointestinal (GI) tract has been a long-standing mystery in vertebrates. It is well known that myogenic pacemaker cells exist in the GI tract [called interstitial cells of Cajal (ICCs)] that generate rhythmic myogenic contractions. However, the mechanisms underlying the generation of rhythmic neurogenic contractions of smooth muscle in the GI tract remains unknown. We developed a high-resolution neuronal imaging method with electrophysiology to address this issue. This technique revealed a novel pattern of rhythmic coordinated neuronal firing in the ENS that has never been identified. Rhythmic neuronal firing in the ENS was found to generate rhythmic neurogenic depolarizations in smooth muscle that underlie contraction of the GI tract.
https://ift.tt/2JzU0Oj
Statistics of Natural Communication Signals Observed in the Wild Identify Important Yet Neglected Stimulus Regimes in Weakly Electric Fish
Sensory systems evolve in the ecological niches that each species is occupying. Accordingly, encoding of natural stimuli by sensory neurons is expected to be adapted to the statistics of these stimuli. For a direct quantification of sensory scenes, we tracked natural communication behavior of male and female weakly electric fish, Apteronotus rostratus, in their Neotropical rainforest habitat with high spatiotemporal resolution over several days. In the context of courtship, we observed large quantities of electrocommunication signals. Echo responses, acknowledgment signals, and their synchronizing role in spawning demonstrated the behavioral relevance of these signals. In both courtship and aggressive contexts, we observed robust behavioral responses in stimulus regimes that have so far been neglected in electrophysiological studies of this well characterized sensory system and that are well beyond the range of known best frequency and amplitude tuning of the electroreceptor afferents' firing rate modulation. Our results emphasize the importance of quantifying sensory scenes derived from freely behaving animals in their natural habitats for understanding the function and evolution of neural systems.
SIGNIFICANCE STATEMENT The processing mechanisms of sensory systems have evolved in the context of the natural lives of organisms. To understand the functioning of sensory systems therefore requires probing them in the stimulus regimes in which they evolved. We took advantage of the continuously generated electric fields of weakly electric fish to explore electrosensory stimulus statistics in their natural Neotropical habitat. Unexpectedly, many of the electrocommunication signals recorded during courtship, spawning, and aggression had much smaller amplitudes or higher frequencies than stimuli used so far in neurophysiological characterizations of the electrosensory system. Our results demonstrate that quantifying sensory scenes derived from freely behaving animals in their natural habitats is essential to avoid biases in the choice of stimuli used to probe brain function.
https://ift.tt/2MqpYtV
Major microbiota dysbiosis in severe obesity: fate after bariatric surgery
Objectives
Decreased gut microbial gene richness (MGR) and compositional changes are associated with adverse metabolism in overweight or moderate obesity, but lack characterisation in severe obesity. Bariatric surgery (BS) improves metabolism and inflammation in severe obesity and is associated with gut microbiota modifications. Here, we characterised severe obesity-associated dysbiosis (ie, MGR, microbiota composition and functional characteristics) and assessed whether BS would rescue these changes.
DesignSixty-one severely obese subjects, candidates for adjustable gastric banding (AGB, n=20) or Roux-en-Y-gastric bypass (RYGB, n=41), were enrolled. Twenty-four subjects were followed at 1, 3 and 12 months post-BS. Gut microbiota and serum metabolome were analysed using shotgun metagenomics and liquid chromatography mass spectrometry (LC-MS). Confirmation groups were included.
ResultsLow gene richness (LGC) was present in 75% of patients and correlated with increased trunk-fat mass and comorbidities (type 2 diabetes, hypertension and severity). Seventy-eight metagenomic species were altered with LGC, among which 50% were associated with adverse body composition and metabolic phenotypes. Nine serum metabolites (including glutarate, 3-methoxyphenylacetic acid and L-histidine) and functional modules containing protein families involved in their metabolism were strongly associated with low MGR. BS increased MGR 1 year postsurgery, but most RYGB patients remained with low MGR 1 year post-BS, despite greater metabolic improvement than AGB patients.
ConclusionsWe identified major gut microbiota alterations in severe obesity, which include decreased MGR and related functional pathways linked with metabolic deteriorations. The lack of full rescue post-BS calls for additional strategies to improve the gut microbiota ecosystem and microbiome–host interactions in severe obesity.
Trial registration numberhttps://ift.tt/2HPkwNW
Culturing Mammalian Cells in Three-dimensional Peptide Scaffolds
Here, we present a protocol to obtain 3D-culture systems in self-assembling peptide scaffolds to promote the differentiation of dedifferentiated human articular chondrocytes into cartilage-like tissue.
https://ift.tt/2JBlAKY
Stent-induced compression necrosis for the endoscopic removal of a partially eroded Lap-Band
Endoscopic removal of eroded Lap-Bands is a minimally invasive alternative to surgical removal that prerequires sufficient erosion through the gastric wall, that is, ≥180° of the gastro-oesophageal wall circumference. A 69-year-old woman presented with dysphagia due to a long-standing Lap-Band erosion, currently of a 60° circumference. Adhesions due to her extensive surgical history rendered surgical treatment undesirable, so a self-expanding stent was placed endoscopically to induce sufficient erosion for subsequent endoscopic removal. During therapy, the patient complained of ructus and dysphagia, probably related to an overly proximally (oesophageal) positioned stent. After a total of 12 weeks, far longer than the described stenting duration in the literature, the Lap-Band was found free in the gastric lumen and was successfully removed using an endoscopic loop. Stent-induced compression necrosis should be considered as a minimally invasive treatment option for Lap-Bands eroded for <180°, with caution in the context of extensive fibrosis.
https://ift.tt/2JGbRPl
Phlegmasia cerulea dolens presenting with acute compartment syndrome and pulmonary embolism
Description
A 50-year-old woman, a known diabetic and hypertensive with poor compliance to treatment, presented with fever, dyspnoea and left-sided pleuritic chest pain for 15 days and left lower limb swelling worsening over the past 1 week. On examination, her vitals were stable, and she had significant left lower limb oedema extending up to the upper thigh with livedo reticularis (figure 1). The left lower limb pulses were not palpable. There was excruciating pain on light touch and passive flexion of the toes and ankle. Urgent arterial and venous Doppler sonography of the lower limbs revealed a left-sided iliofemoral venous thrombus. With the clinical diagnosis of acute compartment syndrome, urgent single incision four compartment fasciotomy was performed.
Figure 1
(A) Clinical examination at the time of admission showing lower limb oedema with livedo reticularis, (B) left lower leg livedo reticularis with superficial blistering (white arrow) and (C)...
https://ift.tt/2Mmz4YR
Spontaneous tumour lysis syndrome in small cell lung cancer: a rare phenomenon
Tumour lysis syndrome (TLS) is an oncological emergency. It is caused by cellular death occurring secondary to cancer therapy or spontaneously in rapidly dividing tumours. More common in haematological malignancies, it has also been reported in solid tumours. Out of 14 cases of small cell lung cancer (SCLC) with TLS, only three cases of spontaneous TLS have been reported in literature to date. Here we report a case of SCLC presenting as a spontaneous TLS.
https://ift.tt/2y7nwpc
Fulminant pulmonary embolism with fatal outcome in a patient with low clinical prediction scores
We present a case of a 72-year-old man with submassive acute pulmonary thromboembolism. Pulmonary embolism severity index Score and common clinical risk stratification recommended systemic anticoagulation and a clinical course without complications was expected. A primary reperfusion strategy was not indicated by the current guidelines. Under established anticoagulation, the patient was found in cardiac arrest immediately after mobilisation from the bed the next morning. Right heart catheterisation under ongoing resuscitation revealed a complete obstruction of the right pulmonary artery by a big thrombus. Catheter-directed intervention trying to bypass the thrombus with interventional guidewires failed. Ultimately, the patient died from acute right heart failure. The current case raises concern that the prediction scores available for pulmonary embolism may insufficiently predict short-term outcome in isolated patients.
https://ift.tt/2MiGbBv
Giant choledochal cyst presenting during third trimester of pregnancy
Biliary cystic disease is a rare entity. Twenty-five per cent of cases are diagnosed during adulthood and only a few reports have described this condition during pregnancy, where it represents a therapeutic challenge for both obstetricians and surgeons with regard to the risks it entails for the patient and the fetus.
Definitive management is surgical resection, as cysts may progress to malignancy if untreated. During pregnancy, resection is generally deferred to after delivery, especially in the context of suspected cholangitis.
A 19-year-old young woman with no previous prenatal control, presented to the emergency department on her 32nd week of gestation with abdominal pain and jaundice. A giant Todani I biliary cyst was observed on imaging along with dilation of the proximal biliary tree suggesting acute cholangitis. Fetal compromise prompted immediate delivery after which percutaneous biliary drainage was performed. Following recovery, the cyst was surgically resected.
https://ift.tt/2JLufql
Circumcaval ureter/retrocaval ureter
Description
A 33-year-old non-diabetic married woman from rural background presented with complaints of dull intermittent right flank pain since 1 year. She had no history of fever, dysuria, haematuria or weight loss. Clinical examination of the abdomen was within normal limits. Complete laboratory evaluation including urinalysis, complete blood picture, urea, creatinine and electrolytes were within normal limits. Ultrasonography (USG) of kidney, ureters and bladder showed moderate hydroureteronephrosis (HDUN) until right midureter. Intravenous pyelography (IVP) revealed dilated right renal pelvicalyceal system and upper ureter with abrupt S-shaped turn of ureter at the level of L4 vertebrae.
The appearance on IVP was strongly suspicious of retrocaval ureter and hence a contrast-enhanced CT urography was performed to confirm the diagnosis, which showed dilated right proximal ureter (figure 1) coursing medially and lying posterior to inferior vena cava (IVC). Three-dimensional reconstruction from CT urography showed proximal HDUN and classical S-shaped loop of the ureter behind the IVC...
https://ift.tt/2MiG88N
Aortopulmonary window with pumonary atresia with ventricular septal defect with D-transposition of great arteries: extremely rare anomaly
Aortopulmonary window (APW) is rare a congenital heart disease accounting for 0.1%–0.2% of all congenital heart defects. The 35% of the APW has been associated with wide variety of other structural heart diseases such as ventricular septal defect, persistent ductus arteriosus, arch anomalies and coronary artery anomalies. To the best of our knowledge, only six cases of APW with pulmonary atresia with ventricular septal defect has been described in the literature. It resembles the type 1 truncus arteriosus, and differentiation from this condition is important prior to surgical correction. We present a case of 14-year-old girl child; she was diagnosed with APW with pulmonary atresia with ventricular septal defect and D transposition of great arteries with the help of echocardiography, cardiac catheterisation and cardiac CT.
https://ift.tt/2JGbHrd
The absolute lymphocyte count can predict the overall survival of patients with non-small cell lung cancer on nivolumab: a clinical study
Abstract
Introduction
The neutrophil-to-lymphocyte (ANC/ALC) ratio is associated with worse prognosis in patients with NSCLC on immunotherapies, but the role of ALC remains unclear. The previous radiation therapy causes lymphopenia, and given approaches of combining radiation with immunotherapies, it is critical to better understand the impact of peripheral lymphocytes.
Patients and methods
We evaluated retrospectively 22 patients with advanced NSCLC treated with nivolumab at Boston Medical Center from January 2014 to September 2016 and correlated the peripheral blood counts with the overall survival (OS) and overall time on treatment. We assessed the effect of the previous radiation on peripheral blood counts and clinical outcomes.
Results
Baseline ALC and ANC/ALC ratios are positively and negatively correlated, respectively, with the OS on nivolumab. The ALC and ALC/WBC ratios at 6 weeks on treatment are positively associated with the OS. Kaplan–Meier analysis at baseline and at 6 weeks showed significantly increased OS in the group of patients with the highest ALC. The previous radiation therapy was positively correlated with the ANC and negatively correlated with the ALC/WBC ratio at 8 weeks after the initiation of nivolumab.
Conclusion
Our finding that ALC at baseline and at 6 weeks on treatment is positively correlated with the OS provides an easily obtained predictive marker. Our result that the previous radiation is associated with higher ANC and lower ALC during treatment supports that the combination of radiation therapy with immunotherapy should be carefully applied and potentially peripheral blood counts can be utilized to stratify patients for this approach.
https://ift.tt/2JBpT8S
Noninvasive Assessment of Hemodynamic Stress Distribution after Indirect Revascularization for Pediatric Moyamoya Vasculopathy [PEDIATRICS]
BACKGROUND AND PURPOSE:
Indirect revascularization surgery is an effective treatment in children with Moyamoya vasculopathy. In the present study, we hypothesized that DSC-PWI may reliably assess the evolution of CBF-related parameters after revascularization surgery, monitoring the outcome of surgical pediatric patients with Moyamoya vasculopathy. Thus, we aimed to evaluate differences in DSC-PWI parameters, including the hemodynamic stress distribution, in surgical and nonsurgical children with Moyamoya vasculopathy and to correlate them with long-term postoperative outcome.
MATERIALS AND METHODS:Pre- and postoperative DSC parameters of 28 patients (16 females; mean age, 5.5 ± 4.8 years) treated with indirect revascularization were compared with those obtained at 2 time points in 10 nonsurgical patients (6 females; mean age, 6.9 ± 4.7 years). We calculated 4 normalized CBF-related parameters and their percentage variance: mean normalized CBF of the MCA territory, mean normalized CBF of the proximal MCA territory, mean normalized CBF of cortical the MCA territory, and hemodynamic stress distribution. The relationship between perfusion parameters and postoperative outcomes (poor, fair, good, excellent) was explored using 1-way analysis of covariance (P < .05).
RESULTS:A significant decrease of the mean normalized CBF of the proximal MCA territory and hemodynamic stress distribution and an increase of the mean normalized CBF of the cortical MCA territory were observed after revascularization surgery (P < .001). No variations were observed in nonsurgical children. Postoperative hemodynamic stress distribution and its percentage change were significantly different in outcome groups (P < .001).
CONCLUSIONS:DSC-PWI indices show postoperative hemodynamic changes that correlate with clinical outcome after revascularization surgery in children with Moyamoya disease.
https://ift.tt/2sRUkO0
Surpass Streamline Flow-Diverter Embolization Device for Treatment of Iatrogenic and Traumatic Internal Carotid Artery Injuries [INTERVENTIONAL]
SUMMARY:
Iatrogenic and traumatic cerebral internal carotid artery injuries are uncommon but potentially lethal complications. Direct surgical repair of ICA injuries may be difficult in an acute setting. However, endovascular treatment with a flow-diverter embolization device is a feasible alternative technique that we experienced. In this clinical report, we describe demographic data, radiographic images, lesion characteristics, endovascular procedure notes, postprocedural hospital course, and follow-up digital subtraction angiography of 5 patients. At least 6-month follow-up was available in all patients without occurrence of rebleeding and other complications.
https://ift.tt/2sUNN4S
Clinical Outcomes of Endovascular Treatment within 24 Hours in Patients with Mild Ischemic Stroke and Perfusion Imaging Selection [INTERVENTIONAL]
BACKGROUND AND PURPOSE:
Endovascular thrombectomy has been accepted as the standard of care for patients with acute ischemic stroke. Our aim was to investigate the clinical outcomes of patients with mild ischemic stroke with acute proximal large-vessel occlusion after endovascular treatment within 24 hours of symptom onset.
MATERIALS AND METHODS:Between January 2014 and August 2017, ninety-three Chinese patients with mild ischemic stroke (NIHSS scores, 0–8) and large-vessel occlusion with endovascular treatment were retrospectively enrolled from 7 comprehensive stroke centers. They were divided into 2 groups: ≤6 hours and 6–24 hours from symptom onset to groin puncture. We analyzed their modified Rankin Scale scores at 90 days, symptomatic intracranial hemorrhage at 48 hours, and mortality during 90 days. Multivariable linear regression analysis was used to identify predictors for NIHSS shift after discharge.
RESULTS:Twenty-nine patients received endovascular treatment within 6–24 hours after symptom onset and had an imaging mismatch based on perfusion CT or diffusion-weighted MR imaging. There were no substantial differences between the 2 groups in 90-day functional independence (P = .54) and the risks of the combination of symptomatic intracranial hemorrhage and death (P = .72). Two significant indicators of NIHSS shift were 48-hour symptomatic intracranial hemorrhage (unstandardized β = 7.28; 95% CI, 3.48–11.1; P < .001) and baseline systolic blood pressure (unstandardized β = 0.08; 95% CI, 0.03–0.14; P = .005).
CONCLUSIONS:Patients with mild ischemic stroke and large-vessel occlusion in the anterior circulation, an imaging mismatch, and endovascular treatment within 6–24 hours of initial symptoms showed no heterogeneity in the efficacy and safety outcome compared with those treated ≤6 hours from symptom onset.
https://ift.tt/2MmtF41
Cavitary Plaques in Otospongiosis: CT Findings and Clinical Implications [HEAD & NECK]
BACKGROUND AND PURPOSE:
Cavitary plaques have been reported as a manifestation of otospongiosis. They have been related to third window manifestations, complications during cochlear implantation, and sensorineural hearing loss. However, their etiology and clinical implications are not entirely understood. Our purpose was to determine the prevalence, imaging findings, and clinical implications of cavitary plaques in otospongiosis.
MATERIALS AND METHODS:We identified patients with otospongiosis at a tertiary care academic medical center from January 2012 to April 2017. Cross-sectional CT images and clinical records of 47 patients (89 temporal bones) were evaluated for the presence, location, and imaging features of cavitary and noncavitary otospongiotic plaques, as well as clinical symptoms and complications in those who underwent cochlear implantation.
RESULTS:Noncavitary otospongiotic plaques were present in 86 (97%) temporal bones and cavitary plaques in 30 (35%). Cavitary plaques predominated with increasing age (mean age, 59 years; P = .058), mostly involving the anteroinferior wall of the internal auditory canal (P = .003), and their presence was not associated with a higher grade of otospongiosis by imaging (P = .664) or with a specific type of hearing loss (P = .365). No patients with cavitary plaques had third window manifestations, and those with a history of cochlear implantation (n = 6) did not have complications during the procedure.
CONCLUSIONS:Cavitary plaques occurred in one-third of patients with otospongiosis. Typically, they occurred in the anteroinferior wall of the internal auditory canal. There was no correlation with the degree of otospongiosis, type of hearing loss, or surgical complications. Cavitary plaques tended to present in older patients.
https://ift.tt/2MnypGw
CSF Pressure Change in Relation to Opening Pressure and CSF Volume Removed [SPINE]
BACKGROUND AND PURPOSE:
Idiopathic intracranial hypertension is a complex neurologic disorder resulting from increased intracranial pressure. Our aim was to determine whether a correlation exists between the CSF pressure-volume relationship, specifically the craniospinal elastance and pressure-volume index, in patients with idiopathic intracranial hypertension and whether opening pressure affects this relationship.
MATERIALS AND METHODS:Lumbar punctures performed for suspected idiopathic intracranial hypertension from 2006 to 2017 were identified. Opening and closing pressures, CSF volume removed, and clinical diagnosis of idiopathic intracranial hypertension were obtained from the medical records. The craniospinal elastance (pressure change per milliliter of CSF removed) and pressure-volume index were calculated, and the Pearson correlation coefficients between both the craniospinal elastance and pressure-volume index and opening pressure were determined. Linear regression models of craniospinal elastance and the pressure-volume index and interaction terms with opening pressure were assessed for covariate influence on this association.
RESULTS:One hundred sixteen patients were included in the final analysis. The mean craniospinal elastance according to opening pressure group was 0.52 ± 0.18 for <20 cm H2O, 0.57 ± 0.20 for 20–29 cm H2O, 0.91 ± 0.28 for 30–39 cm H2O, and 1.20 ± 0.25 for ≥40 cm H2O. There was a positive linear association between opening pressure and craniospinal elastance with a 0.28 cm H2O/mL increase in craniospinal elastance (standard error = 0.03, P < .001) for every 10 cm H2O increase in opening pressure. Of the covariables analyzed, only age older than 50 years and total volume of CSF removed affected this association.
CONCLUSIONS:As opening pressure increases, the craniospinal elastance increases in a linear fashion while the pressure-volume index decreases. Further studies are needed to determine whether these changes relate to the underlying pathophysiology of idiopathic intracranial hypertension or simply represent established CSF volume pressure dynamics.
https://ift.tt/2sT4qhu
Multicentric Experience in Distal-to-Proximal Revascularization of Tandem Occlusion Stroke Related to Internal Carotid Artery Dissection [INTERVENTIONAL]
BACKGROUND AND PURPOSE:
Internal carotid dissection is a frequent cause of ischemic stroke in young adults. It may cause tandem occlusions in which cervical carotid obstruction is associated with intracranial proximal vessel occlusion. To date, no consensus has emerged concerning endovascular treatment strategy. Our aim was to evaluate our endovascular "distal-to-proximal" strategy in the treatment of this stroke subtype in the first large multicentric cohort.
MATERIALS AND METHODS:Prospectively managed stroke data bases from 2 separate centers were retrospectively studied between 2009 and 2014 for records of tandem occlusions related to internal carotid dissection. Atheromatous tandem occlusions were excluded. The first step in the revascularization procedure was intracranial thrombectomy. Then, cervical carotid stent placement was performed depending on the functionality of the circle of Willis and the persistence of residual cervical ICA occlusion, severe stenosis, or thrombus apposition. Efficiency, complications, and radiologic and clinical outcomes were recorded.
RESULTS:Thirty-four patients presenting with tandem occlusion stroke secondary to internal carotid dissection were treated during the study period. The mean age was 52.5 years, the mean initial NIHSS score was 17.29 ± 6.23, and the mean delay between onset and groin puncture was 3.58 ± 1.1 hours. Recanalization TICI 2b/3 was obtained in 21 cases (62%). Fifteen patients underwent cervical carotid stent placement. There was no recurrence of ipsilateral stroke in the nonstented subgroup. Twenty-one patients (67.65%) had a favorable clinical outcome after 3 months.
CONCLUSIONS:Endovascular treatment of internal carotid dissection–related tandem occlusion stroke using the distal-to-proximal recanalization strategy appears to be feasible, with low complication rates and considerable rates of successful recanalization.
https://ift.tt/2sU5mSS
What Have We Learned from Perfusion MRI in Multiple Sclerosis? [ADULT BRAIN]
SUMMARY:
Using MR imaging, perfusion can be assessed either by dynamic susceptibility contrast MR imaging or arterial spin-labeling. Alterations of cerebral perfusion have repeatedly been described in multiple sclerosis compared with healthy controls. Acute lesions exhibit relative hyperperfusion in comparison with normal-appearing white matter, a finding mostly attributed to inflammation in this stage of lesion development. In contrast, normal-appearing white and gray matter of patients with MS has been mostly found to be hypoperfused compared with controls, and correlations with cognitive impairment as well as fatigue in multiple sclerosis have been described. Mitochondrial failure, axonal degeneration, and vascular dysfunction have been hypothesized to underlie the perfusion MR imaging findings. Clinically, perfusion MR imaging could allow earlier detection of the acute focal inflammatory changes underlying relapses and new lesions, and could constitute a marker for cognitive dysfunction in MS. Nevertheless, the clinical relevance and pathogenesis of the brain perfusion changes in MS remain to be clarified.
https://ift.tt/2JNN3s9
Anatomic and Angiographic Analyses of Ophthalmic Artery Collaterals in Moyamoya Disease [EXTRACRANIAL VASCULAR]
BACKGROUND AND PURPOSE:
Moyamoya disease is a progressive neurovascular pathology defined by steno-occlusive disease of the distal internal carotid artery and associated with the development of compensatory vascular collaterals. The etiology and exact anatomy of vascular collaterals have not been extensively studied. The aim of this study was to describe the anatomy of collaterals developed between the ophthalmic artery and the anterior cerebral artery in a Moyamoya population.
MATERIALS AND METHODS:All patients treated for Moyamoya disease from 2004 to 2016 in 4 neurosurgical centers with available cerebral digital subtraction angiography were included. Sixty-three cases were evaluated, and only 38 met the inclusion criteria. Two patients had a unilateral cervical internal carotid occlusion that limited analysis of ophthalmic artery collaterals to one hemisphere. This study is consequently based on the analysis of 74 cerebral hemispheres.
RESULTS:Thirty-eight patients fulfilled the inclusion criteria. The most frequently encountered anastomosis between the ophthalmic artery and cerebral artery was a branch of the anterior ethmoidal artery (31.1%, 23 hemispheres). In case of proximal stenosis of the anterior cerebral artery, a collateral from the posterior ethmoidal artery could be visualized (16 hemispheres, 21.6%). One case (1.4%) of anastomosis between the lacrimal artery and the middle meningeal artery that permitted the vascularization of a middle cerebral artery territory was also noted.
CONCLUSIONS:Collaterals from the ophthalmic artery are frequent in Moyamoya disease. Their development depends on the perfusion needs of the anterior cerebral artery territories. Three other systems of compensation could be present (callosal circle, leptomeningeal anastomosis, and duro-pial anastomoses).
https://ift.tt/2Mpl3JV
Who's Contributing Most to American Neuroscience Journals: American or Foreign Authors? [research-article]
BACKGROUND AND PURPOSE:
With globalization, the contributions of authors from abroad to the American published literature has increased. We sought to determine the changes with time in the proportional contributions of American and non-American authors in the American neurosciences literature. We hypothesized the following: 1) During the past 21 years, manuscript contributions of American institutions have proportionally decreased in neuroradiology, more than in neurosurgery or neurology; 2) contributions of Asian institutions have affected neuroradiology more than neurosurgery and neurology; and 3) American articles garner more citations.
MATERIALS AND METHODS:We reviewed the May issues of 2 of the highest impact American-based neurology, neurosurgery, and neuroradiology journals published from 1997 to 2017. We counted the number of articles published by nation based on the institution of origin. We looked at trends across time and compared neurology, neurosurgery, and neuroradiology journals. We also gathered data on the number of citations of each article by nationality.
RESULTS:We reviewed 3025 articles. There was a significantly lower ratio of American to non-American authorship in neuroradiology versus neurology/neurosurgery journals (odds ratio = 0.70; 95% confidence interval, 0.60–0.82). There was a significantly decreasing trend in American authorship across the 21 years in neuroradiology. Of the countries outside the United States, Japan contributed most for neuroradiology and neurosurgery journals, and the UK, for neurology. American-authored articles were cited, on average, 1.25 times more frequently than non-American-authored articles.
CONCLUSIONS:Non-American contributions have impacted neuroradiology more than other clinical neuroscience fields with Asian authorship showing the greatest impact. That impact is growing, and the causes are manifold. Nonetheless American-authored articles are cited more.
https://ift.tt/2LMoUzD
Characteristic MR Imaging Findings of the Neonatal Brain in RASopathies [PEDIATRICS]
BACKGROUND AND PURPOSE:
Neuroimaging features in neonates with RASopathies are rarely reported, and to date, there are no neuroimaging studies conducted in this population. Our aim was to investigate the occurrence of supratentorial and posterior fossa abnormalities on brain MRIs of neonates with a RASopathy.
MATERIALS AND METHODS:An observational case-control study of neonates with a confirmed RASopathy was conducted. The presence of an intraventricular and/or parenchymal hemorrhage and punctate white matter lesions and assessments of the splenium of the corpus callosum, gyrification of the cortical gray matter, and enlargement of the extracerebral space were noted. The vermis height, transverse cerebellar diameter, cranial base angle, tentorial angle, and infratentorial angle were measured.
RESULTS:We reviewed 48 brain MR studies performed at 3 academic centers in 3 countries between 2009 and 2017. Sixteen of these infants had a genetically confirmed RASopathy (group 1), and 32 healthy infants were enrolled as the control group (group 2). An increased rate of white matter lesions, extracerebral space enlargement, simplification of the cortical gyrification, and white matter abnormalities were seen in group 1 (P < .001, for each). The vermis height of patients was significantly lower, and tentorial and infratentorial angles were significantly higher in group 1 (P = .01, P < .001, and P = .001, respectively).
CONCLUSIONS:Neonates with a RASopathy had characteristic structural and acquired abnormalities in the cortical gray matter, white matter, corpus callosum, cerebellum, and posterior fossa. This study provides novel neuroimaging findings on supratentorial and posterior fossa abnormalities in neonates with a RASopathy.
https://ift.tt/2sUpwMx
Multisite Concordance of DSC-MRI Analysis for Brain Tumors: Results of a National Cancer Institute Quantitative Imaging Network Collaborative Project [ADULT BRAIN]
BACKGROUND AND PURPOSE:
Standard assessment criteria for brain tumors that only include anatomic imaging continue to be insufficient. While numerous studies have demonstrated the value of DSC-MR imaging perfusion metrics for this purpose, they have not been incorporated due to a lack of confidence in the consistency of DSC-MR imaging metrics across sites and platforms. This study addresses this limitation with a comparison of multisite/multiplatform analyses of shared DSC-MR imaging datasets of patients with brain tumors.
MATERIALS AND METHODS:DSC-MR imaging data were collected after a preload and during a bolus injection of gadolinium contrast agent using a gradient recalled-echo–EPI sequence (TE/TR = 30/1200 ms; flip angle = 72°). Forty-nine low-grade (n = 13) and high-grade (n = 36) glioma datasets were uploaded to The Cancer Imaging Archive. Datasets included a predetermined arterial input function, enhancing tumor ROIs, and ROIs necessary to create normalized relative CBV and CBF maps. Seven sites computed 20 different perfusion metrics. Pair-wise agreement among sites was assessed with the Lin concordance correlation coefficient. Distinction of low- from high-grade tumors was evaluated with the Wilcoxon rank sum test followed by receiver operating characteristic analysis to identify the optimal thresholds based on sensitivity and specificity.
RESULTS:For normalized relative CBV and normalized CBF, 93% and 94% of entries showed good or excellent cross-site agreement (0.8 ≤ Lin concordance correlation coefficient ≤ 1.0). All metrics could distinguish low- from high-grade tumors. Optimum thresholds were determined for pooled data (normalized relative CBV = 1.4, sensitivity/specificity = 90%:77%; normalized CBF = 1.58, sensitivity/specificity = 86%:77%).
CONCLUSIONS:By means of DSC-MR imaging data obtained after a preload of contrast agent, substantial consistency resulted across sites for brain tumor perfusion metrics with a common threshold discoverable for distinguishing low- from high-grade tumors.
https://ift.tt/2JQ1LP7
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
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