Τρίτη 7 Απριλίου 2020

Pediatric septal dysembryoplastic neuroepithelial tumor (sDNT): case-based update.

Pediatric septal dysembryoplastic neuroepithelial tumor (sDNT): case-based update.:

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Pediatric septal dysembryoplastic neuroepithelial tumor (sDNT): case-based update.

Childs Nerv Syst. 2020 Apr 05;:

Authors: Ahluwalia R, Miles L, Hayes L, Scherer A

Abstract

PURPOSE: The purpose of this study was to review a case of a septal dysembryoplastic neuroepithelial tumor (sDNT) and compare it to cases reported in the current literature.

METHODS: We review a case of sDNT and compare with 7 other previously noted cases in the literature.

RESULTS: The mainstay treatment is gross total resection, and most patients achieve full clinical resolution. Septal dysembryoplastic neuroepithelial tumor (sDNT) is a rare pediatric disease most commonly presenting as intractable epilepsy or headache. sDNT has been recognized as a genotypically distinct entity from DNT. A high frequency (~ 80%) of mutations of platelet-derived growth factor receptor A (PDGFRA) has been isolated in sDNT and could form the basis for future therapy. MRI is most commonly used to radiographically diagnose the disease and usually demonstrates a lobular interventricular mass involving the septum, potentially extending to the third ventricle.

CONCLUSIONS: Our case and literature review validates endoscopic biopsy as a diagnostic and therapeutic intervention.

PMID: 32249358 [PubMed - as supplied by publisher]

Pathogenesis of peritumoral hyperexcitability in an immunocompetent CRISPR-based glioblastoma model.

Pathogenesis of peritumoral hyperexcitability in an immunocompetent CRISPR-based glioblastoma model.:

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Pathogenesis of peritumoral hyperexcitability in an immunocompetent CRISPR-based glioblastoma model.

J Clin Invest. 2020 Apr 06;:

Authors: Hatcher A, Yu K, Meyer J, Aiba I, Deneen B, Noebels JL

Abstract

Seizures often herald the clinical appearance of gliomas or appear at later stages. Dissecting their precise evolution and cellular pathogenesis in brain malignancies could inform the development of staged therapies for these highly pharmaco-resistant epilepsies. Studies in immunodeficient xenograft models have identified local interneuron loss and excess glial glutamate release as chief contributors to network disinhibition, but how hyperexcitability in the peritumoral microenvironment evolves in an immunocompetent brain is unclear. We generated gliomas in WT mice via in utero deletion of key tumor suppressor genes and serially monitored cortical epileptogenesis during tumor infiltration with in vivo electrophysiology and GCAMP7 calcium imaging, revealing a reproducible progression from hyperexcitability to convulsive seizures. Long before seizures, coincident with loss of inhibitory cells and their protective scaffolding, gain of glial glutamate antiporter xCT expression, and reactive astrocytosis, we detected local Iba1+ microglial inflammation that intensified and later extended far beyond tumor boundaries. Hitherto unrecognized episodes of cortical spreading depolarization that arose frequently from the peritumoral region may provide a mechanism for transient neurological deficits. Early blockade of glial xCT activity inhibited later seizures, and genomic reduction of host brain excitability by deleting MapT suppressed molecular markers of epileptogenesis and seizures. Our studies confirmed xenograft tumor-driven pathobiology and revealed early and late components of tumor-related epileptogenesis in a genetically tractable, immunocompetent mouse model of glioma, allowing the complex dissection of tumor versus host pathogenic seizure mechanisms.

PMID: 32250339 [PubMed - as supplied by publisher]

Malignant transformation rate of oral leukoplakia-systematic review.

Malignant transformation rate of oral leukoplakia-systematic review.:

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Malignant transformation rate of oral leukoplakia-systematic review.

Oral Surg Oral Med Oral Pathol Oral Radiol. 2020 Apr 02;:

Authors: Pinto AC, Caramês J, Francisco H, Chen A, Azul AM, Marques D

Abstract

OBJECTIVE: The aim of this study was to perform a systematic review of prevalence studies to determine the rate of malignant transformation of oral leukoplakia and assess the influence of demographic factors (age, gender, and geographic region) on the overall transformation rate.

STUDY DESIGN: A search was conducted for publications until July 2019 in 4 electronic databases and peer-reviewed journals. A manual search was performed on the bibliographies of the collected articles, and the authors were contacted for additional information. This study was previously registered with the trial number CRD42019126909 and study quality assessed through established methods. The results were expressed by means of proportions or odds ratios with a 95% confidence interval. Meta-regression was undertaken to evaluate possible sources of heterogeneity, and funnel plot visual analysis was performed to assess publication bias.

RESULTS: The 34 observational epidemiologic studies included reported data on 26,209 patients with oral leukoplakia from 18 different countries. Meta-analysis of 32 studies (23,489 patients) presented an estimated overall mean proportion of malignant transformation rate of 9.70% (7.80-11.70) (I2 = 98.66%; τ2 < 0.001; χ2 = 23.18; degrees of freedom [df] = 31). When comparing genders, the odds ratio favored males with 0.622 (0.468-0.826) (I2 = 29.77%; τ2 = 0.089; χ2 = 22.78; df = 16).

CONCLUSIONS: Within the limitations of the included studies in this systematic review, the results suggest that the malignant transformation rate was dependent on demographic factors and follow-up time. Future studies should include the development of guidelines to standardize the methodology for long-term follow-up assessment, thus reducing the risk of bias.

PMID: 32249069 [PubMed - as supplied by publisher]

Olaparib for advanced breast cancer.

Olaparib for advanced breast cancer.:

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Olaparib for advanced breast cancer.

Future Oncol. 2020 Apr 06;:

Authors: Griguolo G, Dieci MV, Miglietta F, Guarneri V, Conte P

Abstract

Olaparib, an oral PARP-inhibitor, has shown clinical benefit for HER2-negative advanced breast cancer patients carrying a germinal BRCA1/2 mutation. In a randomized Phase III trial, olaparib significantly prolonged progression-free survival as compared with chemotherapy of physician choice. Moreover, in the same trial, a prespecified subgroup analysis reported an overall survival benefit for patients not previously pretreated with chemotherapy for metastatic disease. This review focuses on available preclinical, pharmacokinetic and pharmacodynamic data regarding olaparib and clinical evidence of its antitumor efficacy (both as monotherapy and in combination) and tolerability in breast cancer patients. Open questions, such as use of appropriate biomarkers for patient selection and combination/sequencing with other anticancer drugs, are also addressed.

PMID: 32249603 [PubMed - as supplied by publisher]

lncRNA and mRNA signature for prognosis prediction of glioblastoma.

lncRNA and mRNA signature for prognosis prediction of glioblastoma.:

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lncRNA and mRNA signature for prognosis prediction of glioblastoma.

Future Oncol. 2020 Apr 06;:

Authors: Liu G, Pan Y, Li Y, Xu H

Abstract

Aims: We aimed to find out potential novel biomarkers for prognosis of glioblastoma (GBM). Materials & methods: We downloaded mRNA and lncRNA expression profiles of 169 GBM and five normal samples from The Cancer Genome Atlas and 129 normal brain samples from genotype-tissue expression. We use R language to perform the following analyses: differential RNA expression analysis of GBM samples using 'edgeR' package, survival analysis taking count of single or multiple gene expression level using 'survival' package, univariate and multivariate Cox regression analysis using Cox function plugged in 'survival' package. Gene ontology and Kyoto encyclopedia of genes and genomes pathway analysis were performed using FunRich tool online. Results and conclusion: We obtained differentially DEmRNAs and DElncRNAs in GBM samples. Most prognostically relevant mRNAs and lncRNAs were filtered out. 'GPCR ligand binding' and 'Class A/1' are found to be of great significance. In short, our study provides novel biomarkers for prognosis of GBM.

PMID: 32250161 [PubMed - as supplied by publisher]

DHRS12 inhibits the proliferation and metastasis of osteosarcoma via Wnt3a/β-catenin pathway.

DHRS12 inhibits the proliferation and metastasis of osteosarcoma via Wnt3a/β-catenin pathway.:

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DHRS12 inhibits the proliferation and metastasis of osteosarcoma via Wnt3a/β-catenin pathway.

Future Oncol. 2020 Apr 06;:

Authors: Xu Z, He W, Ke T, Zhang Y, Zhang G

Abstract

Aim: This experimental design was based on DHRS12 to explore its biological effects on osteosarcoma (OS). Materials & methods: The expression level of endogenous DHRS12 was analyzed by immunohistochemical analysis. DHRS12 was overexpressed in MG-63 and HOS cells by plasmid transfection. Cell proliferation, invasion, migration, apoptosis and western blot were used in the experiment. Results: The expression of DHRS12 was significantly reduced in OS. Overexpression of DHRS12 inhibited the proliferation, migration and invasion of MG-63 and HOS cells and induced apoptosis of OS cells. Overexpression of DHRS12 upregulated Bax, Caspase 9 and Caspase 3. Overexpression of DHRS12 resulted in inactivation of the Wnt3a/β-catenin signaling pathway. Conclusion: Overexpression of DHRS12 inhibited the progression of OS via the Wnt3a/β-catenin pathway.

PMID: 32250163 [PubMed - as supplied by publisher]

Whole lung irradiation for completely responding pulmonary metastases in pediatric Ewing sarcoma.

Whole lung irradiation for completely responding pulmonary metastases in pediatric Ewing sarcoma.:

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Whole lung irradiation for completely responding pulmonary metastases in pediatric Ewing sarcoma.

Future Oncol. 2020 Apr 06;:

Authors: Elghazawy H, Nasr A, Zaky I, Zamzam M, Elgammal A, Farid N, Zaghloul MS

Abstract

Aim: Scarce data assessing the real value of whole lung irradiation (WLI) in Ewing's sarcoma (ES) with lung-only metastasis, with published conflicting results. We studied the impact of WLI in a homogenous pediatric population. Materials & methods: Retrospective study evaluating the survival outcomes of WLI in these patients. Results: Out of 163 metastatic ES; 41 patients were eligible for WLI. 30 patients (73.1%) received WLI (+ve) while 11 patients (26.8%) did not receive WLI (-ve). Five-year event-free survival was statistically significant in WLI (+ve). Five-year pulmonary relapse-free survival showed trend for improvement with WLI (+ve), while 5-year overall survival was not statistically significant between the two arms. Conclusion: WLI added significantly to the long term clinical outcome of metastatic ES patients, with no irreversible toxicity.

PMID: 32250164 [PubMed - as supplied by publisher]

ENGINE: a Phase III randomized placebo controlled study of enzastaurin/R-CHOP as frontline therapy in high-risk diffuse large B-cell lymphoma patients with the genomic biomarker DGM1.

ENGINE: a Phase III randomized placebo controlled study of enzastaurin/R-CHOP as frontline therapy in high-risk diffuse large B-cell lymphoma patients with the genomic biomarker DGM1.:

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ENGINE: a Phase III randomized placebo controlled study of enzastaurin/R-CHOP as frontline therapy in high-risk diffuse large B-cell lymphoma patients with the genomic biomarker DGM1.

Future Oncol. 2020 Apr 06;:

Authors: Nowakowski GS, Zhu J, Zhang Q, Brody J, Sun X, Maly J, Song Y, Rizvi S, Song Y, Lansigan F, Jing H, Cao J, Lue JK, Luo W, Zhang L, Li L, Han I, Sun J, Jivani M, Liu Y, Heineman T, Smith SD

Abstract

While combination of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) cures most patients with diffuse large B-cell lymphoma (DLBCL), those with high-risk international prognostic index disease have inferior survival. Enzastaurin as a potent inhibitor of PKC-β and PI3K/AKT pathway suppressor has been tested in many clinical trials including two key studies in DLBCL: Phase III maintenance study (Preventing Relapse in Lymphoma Using Daily Enzastaurin [PRELUDE]) and a first-line Phase II study (S028). DNA extracted from PRELUDE patients' blood samples was retrospectively genotyped identifying a novel genetic biomarker, DGM1 that showed high correlation with response to enzastaurin. A similar finding observed in the S028 study suggested that addition of enzastaurin to R-CHOP may significantly improve outcomes as frontline therapy for high-risk DGM1 positive DLBCL patients. ENGINE is a global, multicenter, placebo-controlled and randomized study to compare the effect of R-CHOP/enzastaurin as frontline treatment in high-risk DLBCL patients. The primary end point for this study is overall survival in patients who are DGM1 positive. Clinical Trial Registration Identifier: NCT03263026.

PMID: 32250167 [PubMed - as supplied by publisher]

Quantification of heterogeneity to classify benign parotid tumors: a feasibility study on most frequent histotypes.

Quantification of heterogeneity to classify benign parotid tumors: a feasibility study on most frequent histotypes.:

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Quantification of heterogeneity to classify benign parotid tumors: a feasibility study on most frequent histotypes.

Future Oncol. 2020 Apr 06;:

Authors: Patella F, Sansone M, Franceschelli G, Tofanelli L, Petrillo M, Fusco M, Nicolino GM, Buccimazza G, Fusco R, Gopalakrishnan V, Pesapane F, Biglioli F, Cariati M

Abstract

Aim: To differentiate Warthin tumors (WTs) and pleomorphic adenomas (PAs) measuring heterogeneity of intravoxel incoherent motion (IVIM) and dynamic-contrast enhanced-magnetic resonance imaging biomarkers. Methods: Volumes of interest were traced on 18 WT and 18 PA in 25 patients. For each IVIM and dynamic-contrast enhanced biomarker, histogram parameters were calculated and then compared using the Wilcoxon-signed-rank test. Receiver operating characteristic curves and multivariate analysis were employed to identify the parameters and their pairs with the best accuracy. Results: Most of the biomarkers exhibited significant difference (p < 0.05) between PA and WT for histogram parameters. Time to peak median and skewness, and D* median and entropy showed the highest area under the curve. No meaningful improvement of accuracy was obtained using two features. Conclusion: IVIM and dynamic-contrast enhanced histogram descriptors may help in the classification of WT and PA.

PMID: 32250169 [PubMed - as supplied by publisher]

Kappa opioids modulate hedgehog signaling to attenuate osteoarthritis.

Kappa opioids modulate hedgehog signaling to attenuate osteoarthritis.:

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Kappa opioids modulate hedgehog signaling to attenuate osteoarthritis.

Arthritis Rheumatol. 2020 Apr 05;:

Authors: Weber AE, Jalali O, Limfat S, Shkhyan R, Van Der Horst R, Lee S, Lin Y, Li L, Mayer EN, Wang L, Liu NQ, Petrigliano FA, Lieberman JR, Evseenko D

Abstract

OBJECTIVE: Inhibition of Hedgehog (Hh) signaling prevents cartilage degeneration and promotes repair in animal models of osteoarthritis (OA). Current study was designed to explore if modulation of kappa opioid receptor (KOR) signaling may have therapeutic potential for achieving disease-modifying activity in OA models through Hh modulation.

METHODS: Normal human primary tissues were obtained from the NDRI. Human OA samples were collected from patients with osteoarthritis undergoing total joint replacements. For in vivo studies, a partial medial meniscectomy (PMM) rat model was used. A novel automated 3D indentation tester (Mach-1) was used to quantify articular cartilage thickness and stiffness properties.

RESULTS: We have demonstrated that activation of KOR by a selective peptide agonist JT09 inhibits Hh signaling (p=0.002) in normal and osteoarthritic human articular chondrocytes via cAMP/CREB pathway. JT09 markedly decreased matrix degeneration in articular chondrocytes and cartilage explants induced by a Hh agonist, SAG (p=0.026). Moreover, in vivo application of JT09 via intra-articular injection significantly (60% improvement, p=0.021 for the tibial plateau) attenuated articular cartilage degeneration after PMM. In JT09 treated rats, cartilage content, structure and functional properties were largely maintained, and osteophyte formation was reduced (by 70%, p=0.005).

CONCLUSION: Current study defines a novel mechanism for the role of the KOR in articular cartilage homeostasis and disease, providing a potential unifying mechanistic basis for the overlap in processes and pathologies shown to involve opioid and Hh signaling. Moreover, this study identifies a potential novel therapeutic strategy in which KOR modulation can improve outcomes in patients with arthritis.

PMID: 32249508 [PubMed - as supplied by publisher]

Nobiletin Attenuates DSS-Induced Intestinal Barrier Damage through HNF4α-claudin-7 Signaling Pathway.

Nobiletin Attenuates DSS-Induced Intestinal Barrier Damage through HNF4α-claudin-7 Signaling Pathway.:

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Nobiletin Attenuates DSS-Induced Intestinal Barrier Damage through HNF4α-claudin-7 Signaling Pathway.

J Agric Food Chem. 2020 Apr 05;:

Authors: Zhao H, Wen X, Li S, Wang M, Cao X, Ho C, Guan W, Liu J, DU G, Wang L, Wang L, Tian J, Jiang X

Abstract

The intestinal epithelium barrier functions to protect human bodies from damages such as harmful microorganisms, antigens, and toxins. In this study, we evaluated the protective effect and molecular mechanism of a dominant polymethoxyflavone nobiletin (NOB) from tangerine peels on intestinal epithelial integrity. The results from transepithelial electrical resistance (TEER) suggested that NOB pretreatment counteracts epithelial injury induced by inflammatory cytokines (TEER Value in 48 hours: Vehicle, 135.6±3.9 Ω/cm2; TNF-α+IL-1β, 90.7±0.5 Ω/cm2; 10 μM NOB+TNF-α+IL-1β, 126.1±0.8 Ω/cm2; 100 μM NOB+TNF-α+IL-1β, 125.3±0.5 Ω/cm2. p<0.001). Clinical and pathological test results suggested that administration of NOB effectively alleviates intestinal barrier injury induced by dextran sulfate sodium (DSS) as evidenced by the length of colon villi on day 7 (Control, 253.7±4.8 μm, DSS 131.6±4.6 μm, NOB+DSS, 234.5±5.1 μm. p<0.001). Interestingly, when screening tight junction molecules for intestinal barrier integrity, we observed that independent treatment with NOB sharply increased claudin-7 levels (Ratio of claudin-7 over GAPDH: Control, 1.0±0.06; DSS, 0.02±0.001; NOB+DSS, 0.3±0.07. p<0.001), which was previously suppressed upon DSS stimulation. Furthermore, hepatocyte nuclear factor 4α (HNF-4α) transcriptional regulation of claudin-7 contributed to intestinal barrier homeostasis. Therefore, our study suggests potential intestinal protective strategies based on polymethoxyflavones of aged tangerine peels.

PMID: 32249565 [PubMed - as supplied by publisher]

Small molecules, big effects- microbial metabolites in intestinal immunity.

Small molecules, big effects- microbial metabolites in intestinal immunity.:

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Small molecules, big effects- microbial metabolites in intestinal immunity.

Am J Physiol Gastrointest Liver Physiol. 2020 Apr 06;:

Authors: Glotfelty LG, Wong AC, Levy M

Abstract

The mammalian intestine is host to a vast number of microbial organisms. The immune system must balance tolerance with innate and adaptive defense mechanisms to maintain homeostasis with the microbial community. Interestingly, microbial metabolites have been shown to play a role in shaping the host immune response, thus assisting with adaptations that have significant implications for human health and disease. New investigations have uncovered roles for metabolites in modulating almost every aspect of the immune system. In this mini review, we survey these recent findings, which taken together, reveal nuanced interactions that we are just beginning to understand.

PMID: 32249590 [PubMed - as supplied by publisher]

Network-based metabolic characterization of renal cell carcinoma.

Network-based metabolic characterization of renal cell carcinoma.:

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Network-based metabolic characterization of renal cell carcinoma.

Sci Rep. 2020 Apr 06;10(1):5955

Authors: Pandey N, Lanke V, Vinod PK

Abstract

An emerging hallmark of cancer is metabolic reprogramming, which presents opportunities for cancer diagnosis and treatment based on metabolism. We performed a comprehensive metabolic network analysis of major renal cell carcinoma (RCC) subtypes including clear cell, papillary and chromophobe by integrating transcriptomic data with the human genome-scale metabolic model to understand the coordination of metabolic pathways in cancer cells. We identified metabolic alterations of each subtype with respect to tumor-adjacent normal samples and compared them to understand the differences between subtypes. We found that genes of amino acid metabolism and redox homeostasis are significantly altered in RCC subtypes. Chromophobe showed metabolic divergence compared to other subtypes with upregulation of genes involved in glutamine anaplerosis and aspartate biosynthesis. A difference in transcriptional regulation involving HIF1A is observed between subtypes. We identified E2F1 and FOXM1 as other major transcriptional activators of metabolic genes in RCC. Further, the co-expression pattern of metabolic genes in each patient showed the variations in metabolism within RCC subtypes. We also found that co-expression modules of each subtype have tumor stage-specific behavior, which may have clinical implications.

PMID: 32249812 [PubMed - in process]

Aggregates of RNA Binding Proteins and ER Chaperones Linked to Exosomes in Granulovacuolar Degeneration of the Alzheimer's Disease Brain.

Aggregates of RNA Binding Proteins and ER Chaperones Linked to Exosomes in Granulovacuolar Degeneration of the Alzheimer's Disease Brain.:

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Aggregates of RNA Binding Proteins and ER Chaperones Linked to Exosomes in Granulovacuolar Degeneration of the Alzheimer's Disease Brain.

J Alzheimers Dis. 2020 Apr 02;:

Authors: Yamoah A, Tripathi P, Sechi A, Köhler C, Guo H, Chandrasekar A, Nolte KW, Wruck CJ, Katona I, Anink J, Troost D, Aronica E, Steinbusch H, Weis J, Goswami A

Abstract

Granulovacuolar degeneration (GVD) occurs in Alzheimer's disease (AD) brain due to compromised autophagy. Endoplasmic reticulum (ER) function and RNA binding protein (RBP) homeostasis regulate autophagy. We observed that the ER chaperones GRP78/BiP, Sigma receptor 1 (SigR1), and VAPB were elevated in many AD patients' subicular neurons. However, those neurons which were affected by GVD showed lower chaperone levels, and there was only minor co-localization of chaperones with GVD bodies (GVBs), suggesting that neurons lacking sufficient chaperone-mediated proteostasis enter the GVD pathway. Consistent with this notion, granular, incipient pTau aggregates in human AD and pR5 tau transgenic mouse neurons were regularly co-localized with increased chaperone immunoreactivity, whereas neurons with mature neurofibrillary tangles lacked both the chaperone buildup and significant GVD. On the other hand, APP/PS1 (APPswe/PSEN1dE9) transgenic mouse hippocampal neurons that are devoid of pTau accumulation displayed only few GVBs-like vesicles, which were still accompanied by prominent chaperone buildup. Identifying a potential trigger for GVD, we found cytoplasmic accumulations of RBPs including Matrin 3 and FUS as well as stress granules in GVBs of AD patient and pR5 mouse neurons. Interestingly, we observed that GVBs containing aggregated pTau and pTDP-43 were consistently co-localized with the exosomal marker Flotillin 1 in both AD and pR5 mice. In contrast, intraneuronal 82E1-immunoreactive amyloid-β in human AD and APP/PS1 mice only rarely co-localized with Flotillin 1-positive exosomal vesicles. We conclude that altered chaperone-mediated ER protein homeostasis and impaired autophagy manifesting in GVD are linked to both pTau and RBP accumulation and that some GVBs might be targeted to exocytosis.

PMID: 32250292 [PubMed - as supplied by publisher]

HIV-1 infection and latency-reversing agents bryostatin-1 and JQ1 disrupt amyloid beta homeostasis in human astrocytes.

HIV-1 infection and latency-reversing agents bryostatin-1 and JQ1 disrupt amyloid beta homeostasis in human astrocytes.:

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HIV-1 infection and latency-reversing agents bryostatin-1 and JQ1 disrupt amyloid beta homeostasis in human astrocytes.

Glia. 2020 Apr 06;:

Authors: Proust A, Barat C, Leboeuf M, Drouin J, Gagnon MT, Vanasse F, Tremblay MJ

Abstract

Since the introduction of the combined antiretroviral therapy, HIV-1 infection has become a manageable chronic disease in which patients display a life expectancy almost identical to the general population. Nevertheless, various age-related pathologies such as neurocognitive disorders have emerged as serious complications. A "shock and kill" strategy using latency-reversing agents (LRA) to reactivate HIV-1 has been proposed to eliminate the viral reservoir in such chronically infected patients. However, the impact of LRA on the central nervous system remains elusive. Given that an increased amyloid beta (Aβ) deposition is a feature of HIV-1-infected brains, we investigated the consequences of HIV-1 infection and treatment with two LRA (bryostatin-1 and JQ1) on the capacity of human astrocytes to engulf and clear Aβ. We show here that HIV-1-infected astrocytes accumulate a very high amount of Aβ compared to uninfected cells, but the engulfed peptide in degraded very slowly. The LRA bryostatin-1 induces a reduction in Aβ endocytosis, whereas JQ1 treatment results in a very slow degradation of the ingested material associated with a reduced expression of the endopeptidase neprilysin. An exposure to JQ1 also induces a sustained release of Aβ-loaded microvesicles. Thus, both HIV-1 infection and treatment with some LRA could contribute to the reported Aβ accumulation in the brain of HIV-1-infected persons.

PMID: 32250524 [PubMed - as supplied by publisher]

Comparison of the effects of polynucleotide and hyaluronic acid fillers on periocular rejuvenation: a randomized, double-blind, split-face trial.

Comparison of the effects of polynucleotide and hyaluronic acid fillers on periocular rejuvenation: a randomized, double-blind, split-face trial.:

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Comparison of the effects of polynucleotide and hyaluronic acid fillers on periocular rejuvenation: a randomized, double-blind, split-face trial.

J Dermatolog Treat. 2020 Apr 06;:1-7

Authors: Lee YJ, Kim HT, Lee YJ, Paik SH, Moon YS, Lee WJ, Chang SE, Lee MW, Choi JH, Jung JM, Won CH

Abstract

Background: Filler injection has become an extremely popular method for facial skin rejuvenation, including the periorbital area. In the recent years, new polynucleotide (PN)-containing filler products have been used for esthetic purposes.Aim: We aimed to investigate the efficacy and safety of PN filler injection in the periorbital area.Patients/methods: A total of 27 subjects were enrolled in this randomized, pair-matched, and active-controlled study. Each subject received filler injections thrice with two-week intervals, with a PN filler injection on one side and a non-crosslinked hyaluronic acid (HA) filler injection on the contralateral side of the periorbital area.Results: Improvements in the visual analog scale and global esthetic improvement scale scores were not significantly different between the PN and HA groups. The improvement rates of skin elasticity and hydration decreased over time in both groups, with the PN group showing a higher improvement rate. The improvement rates of roughness and pore volume were higher in the PN group than in the HA group. The improvement rate of dermal density was not significantly different between the groups. No serious adverse events were reported.Conclusion: The PN filler injection is effective and safe for periorbital rejuvenation.

PMID: 32248707 [PubMed - as supplied by publisher]

Therapeutic outcome of diphencyprone and its correlation with serum cytokine profile in alopecia areata.

Therapeutic outcome of diphencyprone and its correlation with serum cytokine profile in alopecia areata.:

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Therapeutic outcome of diphencyprone and its correlation with serum cytokine profile in alopecia areata.

J Dermatolog Treat. 2020 Apr 06;:1-20

Authors: Pm R, R S, Rajappa M, Chandrashekar L

Abstract

INTRODUCTION: Diphencyprone (DPCP) is considered as the first line of management in severe and extensive alopecia areata. The present study aims to evaluate the effectiveness of DPCP in alopecia areata and identify various prognostic factors and biomarkers associated with clinical response.

MATERIALS AND METHODS: The study included participants with extensive alopecia areata (>30% scalp hair loss) treated with DPCP. Participants with Macdonald Hull and Norris grade 3 and 4 at the end of 6 months were considered as responders. We performed cytokine analysis prior and post-therapy. The protocol was registered with CTRI(REF/2017/09/015424)Results: The response rate was 54.5%. Longer disease duration, nail involvement, high severity of alopecia tool (SALT) scores were associated with non-response. There was no significant difference in the cytokine levels among responders and non-responders before therapy. Among the responders, we found a significant decrease in IFN-γ, IL-17A, IL-9, TGF-β and IL-13 except for IL-4, which significantly increased whereas, among the non-responders, only IL-17A and IL-13 levels have reduced considerably.

DISCUSSION: Diphencyprone reduced the level of Th1, Th17 and Th9 cytokines and increased the level of Th2 cytokines (IL-4) in the present study, which induced remission and promoted hair regrowth.

PMID: 32249656 [PubMed - as supplied by publisher]

Efficacy of non-surgical treatments for androgenetic alopecia in men and women: a systematic review with network meta-analyses, and an assessment of evidence quality.

Efficacy of non-surgical treatments for androgenetic alopecia in men and women: a systematic review with network meta-analyses, and an assessment of evidence quality.:

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Efficacy of non-surgical treatments for androgenetic alopecia in men and women: a systematic review with network meta-analyses, and an assessment of evidence quality.

J Dermatolog Treat. 2020 Apr 06;:1-34

Authors: Gupta AK, Bamimore MA, Foley KA

Abstract

Background and objective: Various treatments exist for androgenetic alopecia (AGA); we determined the relative efficacies of non-surgical AGA monotherapies separately for men and women.Methods: Randomized controlled trials (RCTs) were systematically searched in PubMed, EMBASE, Scopus and clinicaltrials.gov. Separate networks were used for men and women; for each network, a Bayesian network meta-analysis (NMA) of mean change in hair count from baseline (in units of hairs per squared centimetre) was performed using a random effects model.Results: The networks for male and female AGA included 30 and 10 RCTs, respectively. We identified the following treatments for male AGA in decreasing rank of efficacy: platelet-rich plasma (PRP), low-level laser therapy (LLLT), 0.5mg dutasteride, 1mg finasteride, 5% minoxidil, 2% minoxidil, and bimatoprost. For female AGA the following were identified in decreasing rank of efficacy: LLLT, 5% minoxidil, and 2% minoxidil. The evidence quality of the highest ranked therapies, for male and female AGA, was judged to be low.Conclusions: While newer treatments like LLLT may be more efficacious than more traditional therapies like 5% minoxidil, the efficacy of the more recent treatment modalities needs to be further validated by future RCTs.

PMID: 32250713 [PubMed - as supplied by publisher]

Efficacy of brodalumab in the treatment of scalp and nail psoriasis: results from three phase 3 trials.

Efficacy of brodalumab in the treatment of scalp and nail psoriasis: results from three phase 3 trials.:

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Efficacy of brodalumab in the treatment of scalp and nail psoriasis: results from three phase 3 trials.

J Dermatolog Treat. 2020 Apr 06;:1-21

Authors: Elewski B, Rich P, Lain E, Soung J, Lewitt GM, Jacobson A

Abstract

Introduction: We evaluated the efficacy of brodalumab in patients with nail or scalp psoriasis in three phase 3 studies (AMAGINE-1/-2/-3).Methods: In AMAGINE-1, scalp clearance, measured by the psoriasis scalp severity index (PSSI), was reported for patients who received brodalumab 210 mg every 2 weeks (Q2W) or placebo through 12 weeks. In AMAGINE-2/-3, nail clearance, measured by the nail psoriasis severity index (NAPSI), was reported for patients receiving either brodalumab 210 mg Q2W or ustekinumab continuously through 52 weeks.Results: At week 12, significantly more patients receiving brodalumab achieved 75% and 100% improvement rates from baseline PSSI and had lower mean PSSI across 12 weeks compared with placebo, with significant improvement in PSSI evident with brodalumab 210 mg Q2W vs placebo by week 2. Across 52 weeks, patients receiving brodalumab achieved significantly greater complete clearance of nail psoriasis (NAPSI 0), lower mean NAPSI, and higher mean percent improvement rates from baseline NAPSI than patients receiving ustekinumab. At week 52, 63.8% of patients receiving brodalumab achieved NAPSI 0 vs 39.1% of patients receiving ustekinumab.Conclusions: Brodalumab was associated with clearance of scalp psoriasis through 12 weeks and improvements in nail psoriasis, including complete nail clearance, through 52 weeks.

PMID: 32250714 [PubMed - as supplied by publisher]

Development of the Japanese version of the Other As Shamer Scale using item response theory.

Development of the Japanese version of the Other As Shamer Scale using item response theory.:

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Development of the Japanese version of the Other As Shamer Scale using item response theory.

BMC Res Notes. 2020 Apr 05;13(1):200

Authors: Hiramatsu Y, Asano K, Kotera Y, Sensui T, Endo A, Shimizu E, Basran J, Goss K

Abstract

OBJECTIVE: External shame reflects a person's anxiety that he or she might be rejected by others. The Other as Shamer Scale (OAS) is a scale for assessing external shame. The Japanese version of the OAS was developed, and its reliability and validity were examined using Item Response Theory (IRT).

RESULTS: A survey was conducted with university students (N = 199). Exploratory factor analysis of the results indicated a significantly high factor loading on the first factor, which was identical to the original version of the scale as well as high internal consistency. Moreover, the results confirmed that each item had adequate discrimination and information levels, suggesting that external shame could be discriminated against with high accuracy for a wide range of relatively low and relatively high external shame groups. These results suggest that the OAS could be used to screen external shame as a stress factor and to assess intervention effects.

PMID: 32248832 [PubMed - in process]

Systematic characterization of non-coding RNAs in triple-negative breast cancer.

Systematic characterization of non-coding RNAs in triple-negative breast cancer.:

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Systematic characterization of non-coding RNAs in triple-negative breast cancer.

Cell Prolif. 2020 Apr 06;:e12801

Authors: Mei J, Hao L, Wang H, Xu R, Liu Y, Zhu Y, Liu C

Abstract

Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer with negativity for oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER2). Non-coding RNAs (ncRNAs) make up most of the transcriptome and are widely present in eukaryotic cells. In recent years, emerging evidence suggests that ncRNAs, mainly microRNAs (miRNAs), long ncRNAs (lncRNAs) and circular RNAs (circRNAs), play prominent roles in the tumorigenesis and development of TNBC, but the functions of most ncRNAs have not been fully described. In this review, we systematically elucidate the general characteristics and biogenesis of miRNAs, lncRNAs and circRNAs, discuss the emerging functions of these ncRNAs in TNBC and present future perspectives in clinical practice.

PMID: 32249490 [PubMed - as supplied by publisher]

Generation of an Enteric Smooth Muscle Cell Line from the Pig Ileum.

Generation of an Enteric Smooth Muscle Cell Line from the Pig Ileum.:

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Generation of an Enteric Smooth Muscle Cell Line from the Pig Ileum.

J Anim Sci. 2020 Apr 03;:

Authors: Ji X, Lyu P, Hu R, Yao W, Jiang H

Abstract

Smooth muscle cells play an important role in physiology and production in farm animals such as pigs. Here, we report the generation of a pig smooth muscle cell line. Our original objective was to establish an enteroendocrine cell line from the pig ileum epithelium through lentiviral transduction of the Simian Virus (SV) 40 large T antigen. However, an initial expression analysis of marker genes in nine cell clones revealed that none of them were enteroendocrine cells or absorptive enterocytes, goblet cells, or Paneth cells, major cell types existing in the ileum epithelium. A more detailed characterization of one clone named PIC7 by RNA-seq showed that these cells expressed many of the known smooth muscle-specific or -enriched genes, including smooth muscle actin alpha 2, calponin 1, calponin 3, myosin heavy chain 11, myosin light chain kinase, smoothelin, tenascin C, transgelin, tropomyosin 1, and tropomyosin 2. Both qPCR and RNA-seq analyses showed that the PIC7 cells had high expression of mRNA for smooth muscle actin gamma 2, also known as enteric smooth muscle actin. A western blot analysis confirmed the expression of SV40 T antigen in the PIC7 cells. An immunohistochemical analysis demonstrated the expression of smooth muscle actin alpha 2 filaments in the PIC7 cells. A collagen gel contraction assay showed that the PIC7 cells were capable of both spontaneous contraction and contraction in response to serotonin stimulation. We conclude that the PIC7 cells are derived from an enteric smooth muscle cell from the pig ileum. These cells may be a useful model for studying the cellular and molecular physiology of pig enteric smooth muscle cells. Because pigs are similar to humans in anatomy and physiology, the PIC7 cells may be also used as a model for human intestinal smooth muscle cells.

PMID: 32249920 [PubMed - as supplied by publisher]

Amyloid-β Causes Mitochondrial Dysfunction via a Ca2+-Driven Upregulation of Oxidative Phosphorylation and Superoxide Production in Cerebrovascular Endothelial Cells.

Amyloid-β Causes Mitochondrial Dysfunction via a Ca2+-Driven Upregulation of Oxidative Phosphorylation and Superoxide Production in Cerebrovascular Endothelial Cells.:

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Amyloid-β Causes Mitochondrial Dysfunction via a Ca2+-Driven Upregulation of Oxidative Phosphorylation and Superoxide Production in Cerebrovascular Endothelial Cells.

J Alzheimers Dis. 2020 Apr 02;:

Authors: Quintana DD, Garcia JA, Anantula Y, Rellick SL, Engler-Chiurazzi EB, Sarkar SN, Brown CM, Simpkins JW

Abstract

Cerebrovascular pathology is pervasive in Alzheimer's disease (AD), yet it is unknown whether cerebrovascular dysfunction contributes to the progression or etiology of AD. In human subjects and in animal models of AD, cerebral hypoperfusion and hypometabolism are reported to manifest during the early stages of the disease and persist for its duration. Amyloid-β is known to cause cellular injury in both neurons and endothelial cells by inducing the production of reactive oxygen species and disrupting intracellular Ca2+ homeostasis. We present a mechanism for mitochondrial degeneration caused by the production of mitochondrial superoxide, which is driven by increased mitochondrial Ca2+ uptake. We found that persistent superoxide production injures mitochondria and disrupts electron transport in cerebrovascular endothelial cells. These observations provide a mechanism for the mitochondrial deficits that contribute to cerebrovascular dysfunction in patients with AD.

PMID: 32250296 [PubMed - as supplied by publisher]

Parental metabolic syndrome epigenetically reprograms offspring hepatic lipid metabolism in mice.

Parental metabolic syndrome epigenetically reprograms offspring hepatic lipid metabolism in mice.:

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Parental metabolic syndrome epigenetically reprograms offspring hepatic lipid metabolism in mice.

J Clin Invest. 2020 Apr 06;:

Authors: De Jesus DF, Orime K, Kaminska D, Kimura T, Basile G, Wang CH, Haertle L, Riemens R, Brown NK, Hu J, Männistö V, Silva AM, Dirice E, Tseng YH, Haaf T, Pihlajamäki J, Kulkarni RN

Abstract

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. Although gene-environment interactions have been implicated in the etiology of several disorders, the impact of paternal and/or maternal metabolic syndrome on the clinical phenotypes of offspring and the underlying genetic and epigenetic contributors of NAFLD have not been fully explored. To this end, we used the liver-specific insulin receptor knockout (LIRKO) mouse, a unique nondietary model manifesting 3 hallmarks that confer high risk for the development of NAFLD: hyperglycemia, insulin resistance, and dyslipidemia. We report that parental metabolic syndrome epigenetically reprograms members of the TGF-β family, including neuronal regeneration-related protein (NREP) and growth differentiation factor 15 (GDF15). NREP and GDF15 modulate the expression of several genes involved in the regulation of hepatic lipid metabolism. In particular, NREP downregulation increases the protein abundance of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and ATP-citrate lyase (ACLY) in a TGF-β receptor/PI3K/protein kinase B-dependent manner, to regulate hepatic acetyl-CoA and cholesterol synthesis. Reduced hepatic expression of NREP in patients with NAFLD and substantial correlations between low serum NREP levels and the presence of steatosis and nonalcoholic steatohepatitis highlight the clinical translational relevance of our findings in the context of recent preclinical trials implicating ACLY in NAFLD progression.

PMID: 32250344 [PubMed - as supplied by publisher]

Comparison of Methods To Collect Fecal Samples for Microbiome Studies Using Whole-Genome Shotgun Metagenomic Sequencing.

Comparison of Methods To Collect Fecal Samples for Microbiome Studies Using Whole-Genome Shotgun Metagenomic Sequencing.:

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Comparison of Methods To Collect Fecal Samples for Microbiome Studies Using Whole-Genome Shotgun Metagenomic Sequencing.

mSphere. 2020 Feb 26;5(1):

Authors: Byrd DA, Sinha R, Hoffman KL, Chen J, Hua X, Shi J, Chia N, Petrosino J, Vogtmann E

Abstract

Few previous studies have assessed stability and "gold-standard" concordance of fecal sample collection methods for whole-genome shotgun metagenomic sequencing (WGSS), an increasingly popular method for studying the gut microbiome. We used WGSS data to investigate ambient temperature stability and putative gold-standard concordance of microbial profiles in fecal samples collected and stored using fecal occult blood test (FOBT) cards, fecal immunochemical test (FIT) tubes, 95% ethanol, or RNAlater. Among 15 Mayo Clinic employees, for each collection method, we calculated intraclass correlation coefficients (ICCs) to estimate stability of fecal microbial profiles after storage for 4 days at ambient temperature and concordance with immediately frozen, no-solution samples (i.e., the putative gold standard). ICCs were estimated for multiple metrics, including relative abundances of select phyla, species, KEGG k-genes (representing any coding sequence that had >70% identity and >70% query coverage with respect to a known KEGG ortholog), KEGG modules, and KEGG pathways; species and k-gene alpha diversity; and Bray-Curtis and Jaccard species beta diversity. ICCs for microbial profile stability were excellent (≥90%) for fecal samples collected via most of the collection methods, except those preserved in 95% ethanol. Concordance with the immediately frozen, no-solution samples varied for all collection methods, but the number of observed species and the beta diversity metrics tended to have higher concordance than other metrics. Our findings, taken together with previous studies and feasibility considerations, indicated that FOBT cards, FIT tubes, and RNAlater are acceptable choices for fecal sample collection methods in future WGSS studies.IMPORTANCE A major direction for future microbiome research is implementation of fecal sample collections in large-scale, prospective epidemiologic studies. Studying microbiome-disease associations likely requires microbial data to be pooled from multiple studies. Our findings suggest collection methods that are most optimal to be used standardly across future WGSS microbiome studies.

PMID: 32250964 [PubMed - as supplied by publisher]

Prevention of Decompression Sickness by Novel Artificial Oxygen Carriers.

Prevention of Decompression Sickness by Novel Artificial Oxygen Carriers.:

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Prevention of Decompression Sickness by Novel Artificial Oxygen Carriers.

Med Sci Sports Exerc. 2020 Apr 01;:

Authors: Mayer D, Guerrero F, Goanvec C, Hetzel L, Linders J, Ljubkovic M, Kreczy A, Mayer C, Kirsch M, Ferenz KB

Abstract

For three decades, studies have demonstrated the therapeutic efficacy of perfluorocarbons (PFCs) in reducing the onset of decompression trauma. However, none of these emulsion-based preparations are accepted for therapeutic use in the western world, mainly because of severe side-effects and a long organ retention time. A new development to guarantee a stable dispersion without these disadvantages is the encapsulation of PFCs in nanocapsules with an albumin shell.

PURPOSE: Newly designed albumin-derived perfluorocarbon-based artificial oxygen carriers (A-AOCs) are used in a rodent in-vivo model as a preventive therapy for decompression sickness (DCS).

METHODS: Thirty-seven rats were treated with either A-AOCs (n=12), albumin nanocapsules filled with neutral oil (A-O-N, n=12) or 5% human serum albumin solution (A-0-0, n=13) before a simulated dive. Eleven rats, injected with A-AOCs, stayed at normal pressure (A-AOCs-surface). Clinical, laboratory and histological evaluations were performed.

RESULTS: The occurrence of DCS depended on the treatment group. A-AOCs significantly reduced DCS-appearance and mortality. Furthermore, a significant improvement of survival time was found (A-AOCs compared with A-0-0). Histological assessment of A-AOCs-dive compared with A-0-0-dive animals revealed significantly higher accumulation of macrophages, but less blood congestion in the spleen and significantly less hepatic circulatory disturbance, vacuolisation and cell damage. Compared to non-diving controls lactate and myoglobin showed a significant increase in the A-0-0- but not in the A-AOCs-dive group.

CONCLUSION: Intravenous application of A-AOCs was well tolerated and effective in reducing the occurrence of DCS, animals showed significantly higher survival rates and less symptoms compared to the albumin group (A-0-0). Analysis of histological results and fast reacting plasma parameters confirmed the preventive properties of A-AOCs.

PMID: 32251255 [PubMed - as supplied by publisher]

Leptin receptor-expressing neuron Sh2b1 supports sympathetic nervous system and protects against obesity and metabolic disease.

Leptin receptor-expressing neuron Sh2b1 supports sympathetic nervous system and protects against obesity and metabolic disease.:

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Leptin receptor-expressing neuron Sh2b1 supports sympathetic nervous system and protects against obesity and metabolic disease.

Nat Commun. 2020 Mar 23;11(1):1517

Authors: Jiang L, Su H, Wu X, Shen H, Kim MH, Li Y, Myers MG, Owyang C, Rui L

Abstract

Leptin stimulates the sympathetic nervous system (SNS), energy expenditure, and weight loss; however, the underlying molecular mechanism remains elusive. Here, we uncover Sh2b1 in leptin receptor (LepR) neurons as a critical component of a SNS/brown adipose tissue (BAT)/thermogenesis axis. LepR neuron-specific deletion of Sh2b1 abrogates leptin-stimulated sympathetic nerve activation and impairs BAT thermogenic programs, leading to reduced core body temperature and cold intolerance. The adipose SNS degenerates progressively in mutant mice after 8 weeks of age. Adult-onset ablation of Sh2b1 in the mediobasal hypothalamus also impairs the SNS/BAT/thermogenesis axis; conversely, hypothalamic overexpression of human SH2B1 has the opposite effects. Mice with either LepR neuron-specific or adult-onset, hypothalamus-specific ablation of Sh2b1 develop obesity, insulin resistance, and liver steatosis. In contrast, hypothalamic overexpression of SH2B1 protects against high fat diet-induced obesity and metabolic syndromes. Our results unravel an unrecognized LepR neuron Sh2b1/SNS/BAT/thermogenesis axis that combats obesity and metabolic disease.

PMID: 32251290 [PubMed - as supplied by publisher]

Biomarkers for Alzheimer's disease-preparing for a new era of disease-modifying therapies.

Biomarkers for Alzheimer's disease-preparing for a new era of disease-modifying therapies.:

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Biomarkers for Alzheimer's disease-preparing for a new era of disease-modifying therapies.

Mol Psychiatry. 2020 Apr 06;:

Authors: Zetterberg H, Bendlin BB

Abstract

Clinical trial results presented in 2019 suggest that antibody-based removal of cerebral amyloid β (Aβ) plaques may possibly clear tau tangles and modestly slow cognitive decline in symptomatic Alzheimer's disease (AD). Although regulatory approval of this approach is still pending, preparing the healthcare system for the advent of disease-modifying therapies against AD is imperative. In particular, it will be necessary to identify the most suitable biomarkers to facilitate appropriate treatment of AD. Here, we give an update on recent developments in fluid and imaging biomarkers for AD-related pathologies and discuss potential approaches that could be adopted to screen for and clarify the underlying pathology in people seeking medical advice because of cognitive symptoms. We succinctly review recent data regarding biomarkers for Aβ and tau pathology, neurodegeneration, synaptic dysfunction, and inflammation, highlight the need for further research into common copathologies, and suggest how different biomarkers could be used (most likely in combination) to facilitate the development and clinical implementation of novel drug candidates against AD.

PMID: 32251378 [PubMed - as supplied by publisher]

Network mechanisms and dysfunction within an integrated computational model of progression through mitosis in the human cell cycle.

Network mechanisms and dysfunction within an integrated computational model of progression through mitosis in the human cell cycle.:

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Network mechanisms and dysfunction within an integrated computational model of progression through mitosis in the human cell cycle.

PLoS Comput Biol. 2020 Apr 06;16(4):e1007733

Authors: Terhune SS, Jung Y, Cataldo KM, Dash RK

Abstract

The cellular protein-protein interaction network that governs cellular proliferation (cell cycle) is highly complex. Here, we have developed a novel computational model of human mitotic cell cycle, integrating diverse cellular mechanisms, for the purpose of generating new hypotheses and predicting new experiments designed to help understand complex diseases. The pathogenic state investigated is infection by a human herpesvirus. The model starts at mitotic entry initiated by the activities of Cyclin-dependent kinase 1 (CDK1) and Polo-like kinase 1 (PLK1), transitions through Anaphase-promoting complex (APC/C) bound to Cell division cycle protein 20 (CDC20), and ends upon mitotic exit mediated by APC/C bound to CDC20 homolog 1 (CDH1). It includes syntheses and multiple mechanisms of degradations of the mitotic proteins. Prior to this work, no such comprehensive model of the human mitotic cell cycle existed. The new model is based on a hybrid framework combining Michaelis-Menten and mass action kinetics for the mitotic interacting reactions. It simulates temporal changes in 12 different mitotic proteins and associated protein complexes in multiple states using 15 interacting reactions and 26 ordinary differential equations. We have defined model parameter values using both quantitative and qualitative data and using parameter values from relevant published models, and we have tested the model to reproduce the cardinal features of human mitosis determined experimentally by numerous laboratories. Like cancer, viruses create dysfunction to support infection. By simulating infection of the human herpesvirus, cytomegalovirus, we hypothesize that virus-mediated disruption of APC/C is necessary to establish a unique mitotic collapse with sustained CDK1 activity, consistent with known mechanisms of virus egress. With the rapid discovery of cellular protein-protein interaction networks and regulatory mechanisms, we anticipate that this model will be highly valuable in helping us to understand the network dynamics and identify potential points of therapeutic interventions.

PMID: 32251461 [PubMed - as supplied by publisher]

Comparative physiology and efficacy of atropine and scopolamine in sarin nerve agent poisoning.

Comparative physiology and efficacy of atropine and scopolamine in sarin nerve agent poisoning.:

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Comparative physiology and efficacy of atropine and scopolamine in sarin nerve agent poisoning.

Toxicol Appl Pharmacol. 2020 Apr 03;:114994

Authors: Cornelissen AS, Klaassen SD, van Groningen T, Bohnert S, Joosen MJA

Abstract

Anticholinergic treatment is key for effective medical treatment of nerve agent exposure. Atropine is included at a 2 mg intramuscular dose in so-called autoinjectors designed for self- and buddy-aid. As patient cohorts are not available, predicting and evaluating the efficacy of medical countermeasures relies on animal models. The use of atropine as a muscarinic antagonist is based on efficacy achieved in studies in a variety of species. The dose of atropine administered varies considerably across these studies. This is a complicating factor in the prediction of efficacy in the human situation, largely because atropine dosing also influences therapeutic efficacy of oximes and anticonvulsants generally part of the treatment administered. To improve translation of efficacy of dosing regimens, including pharmacokinetics and physiology provide a promising approach. In the current study, pharmacokinetics and physiological parameters obtained using EEG and ECG were assessed in naïve rats and in sarin-exposed rats for two anticholinergic drugs, atropine and scopolamine. The aim was to find a predictive parameter for therapeutic efficacy. Scopolamine and atropine showed a similar bioavailability, but brain levels reached were much higher for scopolamine. Scopolamine exhibited a dose-dependent loss of beta power in naïve animals, whereas atropine did not show any such central effect. This effect was correlated with an enhanced anticonvulsant effect of scopolamine compared to atropine. These findings show that an approach including pharmacokinetics and physiology could contribute to improved dose scaling across species and assessing the therapeutic potential of similar anticholinergic and anticonvulsant drugs against nerve agent poisoning.

PMID: 32251685 [PubMed - as supplied by publisher]

Biomonitoring of Bis(2-ethylhexyl)phthalate (DEHP) in Italian children and adolescents: Data from LIFE PERSUADED project.

Biomonitoring of Bis(2-ethylhexyl)phthalate (DEHP) in Italian children and adolescents: Data from LIFE PERSUADED project.:

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Biomonitoring of Bis(2-ethylhexyl)phthalate (DEHP) in Italian children and adolescents: Data from LIFE PERSUADED project.

Environ Res. 2020 Mar 30;185:109428

Authors: Tait S, Carli F, Busani L, Buzzigoli E, Della Latta V, Deodati A, Fabbrizi E, Gaggini M, Maranghi F, Tassinari R, Toffol G, Cianfarani S, Gastaldelli A, La Rocca C, LIFE PERSUADED Project Group

Abstract

The Bis(2-ethylhexyl)phthalate (DEHP), a widespread plasticizer, is considered an endocrine disrupting chemical with main toxicological effects on reproductive and metabolic systems. Human biomonitoring (HBM) studies are promoted to evaluate the background exposure levels. In the frame of LIFE PERSUADED project, the HBM study measured DEHP main metabolites (mono-(2-ethylhexyl) phthalate, MEHP; 2-ethyl-5-hydroxy-hexylphthalate, MEHHP; 2-ethyl-5-oxo-hexylphthalate, MEOHP) in Italian children and adolescent (4-14 years old) according to geographical macro-areas and areas, age and sex. Children from the South and the Centre of Italy showed higher median levels of DEHP, as a sum of its metabolites (48.14 and 47.80 μg/L), than those from the North (39.47 μg/L; p = 0.0090 and 0.0004, respectively). Considering the total population, boys are more exposed than girls (only as urinary volume), and children aged 4-6 years have higher median levels than those 7-10 and 11-14 years old. The derived reference values (RV95) for DEHP in children is 168 μg/L. The relative metabolic rates of DEHP, the background levels and, thus, the RV95, vary with the geographical area, age and sex, indicating that all these parameters should be considered in the risk assessment.

PMID: 32251910 [PubMed - as supplied by publisher]

Definition of locally recurrent head and neck squamous cell carcinoma: a systematic review and proposal for the Odense–Birmingham definition

Definition of locally recurrent head and neck squamous cell carcinoma: a systematic review and proposal for the Odense–Birmingham definition:

Abstract



Purpose

The objectives of this study were (1) to systematically review current definitions of head and neck squamous cell carcinoma (HNSCC) recurrence and (2) to propose a definition of locally recurrent HNSCC.




Methods

A systematic literature review was performed according to the ‘Preferred Reporting Items for Systematic Reviews and Meta-Analyses’ statement in Medline, Embase, and Cochrane databases guided by the study question “What is the definition of local recurrence for patients with HN:SCC?”. All retrieved studies were reviewed and qualitatively analyzed.




Results

The systematic literature search resulted in 3467 publications after removal of duplicates. Forty studies were examined as full text, and a total of five were found suitable for inclusion. All five included studies dealt with definitions of second primary HNSCC and were based on the Warren and Gates Criteria; (1) each of the tumors are malignant, (2) each must be distinct, and (3) the probability of one being a metastasis of the other must be excluded. Each of the included studies added specific anatomical and/or temporal separation measures to the criteria of second primary HNSCC. We propose the definition of locally recurrent HNSCC to be: (1) Same anatomical subsite or adjacent subsite within 3 cm of the primary lesion, (2) time-interval no more than 3 years (from completed treatment of the primary lesion), and (3) same p16-status for oropharyngeal carcinomas.




Conclusions

No uniform definition of locally recurrent HNSCC currently exists. We propose the Odense–Birmingham definition based on the anatomical subsite combined with a specific measurable distance and a temporal separation of three years.

Long-term electrophysiological assessment after hypoglossal-facial anastomosis

Long-term electrophysiological assessment after hypoglossal-facial anastomosis:

Abstract



Purpose

To investigate and provide objective documentation of the possible differences in the axonal reinnervation process of facial muscles after hypoglossal-facial nerve anastomosis. Then, to search for the presence of the trigemino-hypoglossal reflex and determine whether it indicates better peripheral recovery.




Methods

Electrophysiological examination performed on 20 patients who had undergone VII–XII anastomosis, with follow-up periods of more than 2 years.




Results

The mean follow-up time after surgery was 4.1 ± 1.3 years (range 2–8 years). The degrees of axonal reinnervation for the orbicularis oculi (OOc) and orbicularis oris (OOr) were 46.91 ± 19.77 and 32.65 ± 14.85, respectively. And the difference between these muscles was statistically significant (p = 0.018) in favor of the OOc. In addition, R1 blink reflexes that were not followed by R2 components were observed in 30% of the patients. However, these 6 patients with short-latency potential did not differ from the others in terms of latency, the amplitude of compound muscle action potential (CMAP), and degree of axonal reinnervation (p > 0.05) at both muscles (OOc and OOr).




Conclusion

The recoveries of the lower face and upper face are different after VII–XII anastomosis, and in our patients the OOc healed better. In addition, R1 blink reflexes that were not followed by R2 components were observed in 30% of the patients. However, the patients with these blink reflexes did not have better peripheral healing in their neuromuscular units, which suggests that the blink reflex is not an indicator for peripheral recovery.

Tension pneumocephalus after skull base surgery. A case report and review of literature.

Tension pneumocephalus after skull base surgery. A case report and review of literature.:

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Tension pneumocephalus after skull base surgery. A case report and review of literature.

J Clin Neurosci. 2020 Apr 02;:

Authors: Biju RD, Wu J, Hussain Z

Abstract

Pneumocephalus describes the presence of air within the cranial cavity and is often self-limiting. Tension pneumocephalus is a neurosurgical emergency manifested by headaches, seizures, reduced consciousness and even death resulting from raised intracranial pressure. Differentiating both entities clinically is often challenging but crucial. We present a case involving a sixty-year-old male who was transferred to our unit after he collapsed while undergoing rehabilitation. The patient had undergone a combined bifrontal craniotomy and transnasal endoscopic resection of recurrent sinonasal adenocarcinoma with anterior skull base involvement eight days prior. Imaging demonstrated the classic Mt. Fuji sign and a diagnosis of tension pneumocephalus was formed. The patient proceeded for definitive management which included a multi-layered repair of the anterior skull base. The three mechanisms that propose the development of tension pneumocephalus include the ball-valve mechanism, the inverted soda-bottle effect and rarely, infection from gas forming organisms. A review of current literature on PubMed/MEDLINE revealed tension pneumocephalus after skull base surgery to be a rare entity with only eleven cases reported. Most patients achieved complete recovery of symptoms post-treatment. Clinicians should recognise tension pneumocephalus as a potential complication after skull base surgery. Accurate diagnosis requires appreciation of imaging features and a high index of suspicion. Prompt management is imperative to prevent possible devastating outcomes.

PMID: 32249175 [PubMed - as supplied by publisher]

Antioxidant Micronutrients and Essential Fatty Acids Supplementation on Cystic Fibrosis Outcomes: A Systematic Review.

Antioxidant Micronutrients and Essential Fatty Acids Supplementation on Cystic Fibrosis Outcomes: A Systematic Review.:

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Antioxidant Micronutrients and Essential Fatty Acids Supplementation on Cystic Fibrosis Outcomes: A Systematic Review.

J Acad Nutr Diet. 2020 Apr 02;:

Authors: Simon MISDS, Dalle Molle R, Silva FM, Rodrigues TW, Feldmann M, Forte GC, Marostica PJC

Abstract

Antioxidant micronutrients and essential fatty acids supplementation intake appears to have a protective effect in some diseases such as cardiovascular disease, cancer, and asthma. The aim of this study was to perform a systematic review to evaluate the effects of these nutrients on nutritional and clinical outcomes of patients with cystic fibrosis (CF). This is a systematic review of randomized clinical trials (RCTs) in CF. MEDLINE (via PubMed), Embase, and Scopus databases were searched for RCTs published from 1948 through February 2019. Two investigators independently reviewed the titles and abstracts and then extracted the data from the included studies using a standardized predesigned form. Two reviewers independently performed the quality assessment of the RCTs according to the Cochrane risk of bias tools. A total of 4,792 studies were identified, and 23 were eligible (8 antioxidant micronutrient and 15 essential fatty acids). The interventions found were beta-carotene, zinc, magnesium, multivitamin, docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), linoleic acid and lipid matrix with choline supplementation. A significant improvement was observed in: (a) pulmonary function with magnesium (n=1) and essential fatty acids (n=2) supplementation; (b) less pulmonary exacerbations with beta-carotene (n=1), zinc (n=1), antioxidant-enriched multivitamin (n=1) and essential fatty acids (n=2) supplementation. One study with antioxidant-enriched multivitamin and four studies with EPA/DHA supplementation reported significant reductions in inflammatory markers. Nutritional status was not modified by antioxidants supplementation in any of the studies, while in five studies there was an improvement with fatty acids supplementation. The risk of bias of the majority of the parallel studies was high. The benefits of antioxidants or DHA/EPA supplementation for CF, although observed in some studies, are not consistent enough to recommend routine use of these supplements. The mechanisms of action of these nutrients, dose levels and timing should be further explored in future studies.

PMID: 32249071 [PubMed - as supplied by publisher]

Critically ill patients with COVID-19 in Hong Kong: a multicentre retrospective observational cohort study

Critically ill patients with COVID-19 in Hong Kong: a multicentre retrospective observational cohort study:

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Critically ill patients with COVID-19 in Hong Kong: a multicentre retrospective observational cohort study

Crit Care Resusc. 2020 Apr 06;

Authors: Ling L, So C, Shum HP, Chan PKS, Lai CKC, Kandamby DH, Ho E, So D, Yan WW, Lui G, Leung WS, Chan MC, Gomersall CD

Abstract

Objective: To report the first eight cases of critically ill patients with coronavirus disease 2019 (COVID-19) in Hong Kong, describing the treatments and supportive care they received and their 28-day outcomes.

Design: Multicentre retrospective observational cohort study.

Setting: Three multidisciplinary intensive care units (ICUs) in Hong Kong.

Participants: All adult critically ill patients with confirmed COVID-19 admitted to ICUs in Hong Kong between 22 January and 11 February 2020.

Main outcome measure: 28-day mortality.

Results: Eight out of 49 patients with COVID-19 (16%) were admitted to Hong Kong ICUs during the study period. The median age was 64.5 years (range, 42–70) with a median admission Sequential Organ Failure Assessment (SOFA) score of 6 (IQR, 4–7). Six patients (75%) required mechanical ventilation, six patients (75%) required vasopressors and two (25%) required renal replacement therapy. None of the patients required prone ventilation, nitric oxide or extracorporeal membrane oxygenation. The median times to shock reversal and extubation were 9 and 11 days respectively. At 28 days, one patient (12%) had died and the remaining seven (88%) all survived to ICU discharge. Only one of the survivors (14%) still required oxygen at 28 days.

Conclusion: Critically ill patients with COVID-19 often require a moderate duration of mechanical ventilation and vasopressor support. Most of these patients recover and survive to ICU discharge with supportive care using lung protective ventilation strategies, avoiding excess fluids, screening and treating bacterial co-infection, and timely intubation. Lower rather than upper respiratory tract viral burden correlates with clinical severity of illness.

PMID: 32248675 [PubMed - as supplied by publisher]

The role of the paediatrician in caring for children with tracheobronchomalacia.

The role of the paediatrician in caring for children with tracheobronchomalacia.:

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The role of the paediatrician in caring for children with tracheobronchomalacia.

Expert Rev Respir Med. 2020 Apr 06;:

Authors: Ramphul M, Bush A, Chang A, Prifits KN, Wallis C, Bhatt JM

Abstract

Introduction: Children with tracheobronchomalacia (TBM) experience excessive dynamic collapse of the central airway(s) (1). TBM remains an under-diagnosed condition (2), and there is on ongoing need to raise awareness amongst paediatricians.Areas covered: The literature from PubMed, MEDLINE, EMBASE and Cochrane Controlled Trials Register electronic databases was searched from 1 January 1980 to 14 January 2020. Eligible studies relating to the diagnosis, investigation and management of tracheobronchomalacia in children were included. In this review, we highlight the clinical symptoms of TBM (3) such as the typical barking cough, wheezing, recurrent lower respiratory tract infections or acute life-threatening events. These symptoms worsen when the child is making increased respiratory efforts (4), such as during crying, coughing and during intercurrent infective illness. This article focuses on the role of the paediatrician in recognising the condition, the investigative process, and the medical management based on the clinical severity. The principle of management should be holistic, tackling the medical issues of TBM and associated comorbidities, as providing support to families.Expert opinion: There remains a need to devise objective and reproducible bronchoscopic and radiological definitions of severity of TBM. Further studies looking at long-term outcomes of medical therapies used in TBM are required.

PMID: 32249702 [PubMed - as supplied by publisher]

Urban Particles Elevated Streptococcus pneumoniae Biofilms, Colonization of the Human Middle Ear Epithelial Cells, Mouse Nasopharynx and Transit to the Middle Ear and Lungs.

Urban Particles Elevated Streptococcus pneumoniae Biofilms, Colonization of the Human Middle Ear Epithelial Cells, Mouse Nasopharynx and Transit to the Middle Ear and Lungs.:

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Urban Particles Elevated Streptococcus pneumoniae Biofilms, Colonization of the Human Middle Ear Epithelial Cells, Mouse Nasopharynx and Transit to the Middle Ear and Lungs.

Sci Rep. 2020 Apr 06;10(1):5969

Authors: Yadav MK, Go YY, Jun I, Chae SW, Song JJ

Abstract

Air-pollutants containing toxic particulate matters (PM) deposit in the respiratory tract and increases microbial infections. However, the mechanism by which this occurs is not well understood. This study evaluated the effect of urban particles (UP) on Streptococcus pneumoniae (pneumococcus) in vitro biofilm formation, colonization of human middle ear epithelium cells (HMEECs) as well as mouse nasal cavity and its transition to the middle ear and lungs. The in vitro biofilms and planktonic growth of S. pneumoniae were evaluated in metal ion free medium in the presence of UP. Biofilms were quantified by crystal violet (CV) microplate assay, colony forming unit (cfu) counts and resazurin staining. Biofilm structures were analyzed using a scanning electron microscope (SEM) and confocal microscopy (CM). Gene expressions of biofilms were evaluated using real time RT-PCR. Effects of UP exposure on S. pneumoniae colonization to HMEECs were evaluated using fluorescent in-situ hybridization (FISH), cell viability was detected using the Ezcyto kit, apoptosis in HMEECs were evaluated using Annexin-V/PI based cytometry analysis and reactive oxygen species (ROS) production were evaluated using the Oxiselect kit. Alteration of HMEECs gene expressions on UP exposure or pneumococci colonization was evaluated using microarray. In vivo colonization of pneumococci in the presence of UP and transition to middle ear and lungs were evaluated using an intranasal mice colonization model. The UP exposure significantly increased (*p < 0.05) pneumococcal in vitro biofilms and planktonic growth. In the presence of UP, pneumococci formed organized biofilms with a matrix, while in absence of UP bacteria were unable to form biofilms. The luxS, ply, lytA, comA, comB and ciaR genes involved in bacterial pathogenesis, biofilm formation and quorum sensing were up-regulated in pneumococci biofilms grown in the presence of UP. The HMEECs viability was significantly decreased (p < 0.05) and bacteria colonization was significantly elevated (p < 0.05) in co-treatment (UP + S. pneumoniae) when compared to single treatment. Similarly, increased apoptosis and ROS production were detected in HMEECs treated with UP + pneumococci. The microarray analysis of HMEECs revealed that the genes involve in apoptosis and cell death, inflammation, and immune response, were up-regulated in co-treatment and were unchanged or expressed in less fold in single treatments of UP or S. pneumoniae. The in vivo study showed an increased pneumococcal colonization of the nasopharynx in the presence of UP and a higher transition of bacteria to the middle ear and lungs in the presence of UP. The UP exposure elevated S. pneumoniae in vitro biofilm and colonization of HMEECs, and in vivo mouse nasopharyngeal colonization, and increased dissemination to mouse middle ear and lungs.

PMID: 32249803 [PubMed - in process]

Point of care testing of Influenza A/B and RSV in an adult respiratory assessment unit is associated with improvement in isolation practices and reduction in hospital length of stay.

Point of care testing of Influenza A/B and RSV in an adult respiratory assessment unit is associated with improvement in isolation practices and reduction in hospital length of stay.:

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Point of care testing of Influenza A/B and RSV in an adult respiratory assessment unit is associated with improvement in isolation practices and reduction in hospital length of stay.

J Med Microbiol. 2020 Apr 06;:

Authors: Berry L, Lansbury L, Gale L, Carroll AM, Lim WS

Abstract

Introduction. Every winter seasonal influenza and other viral respiratory infections increase pressure on the health services and are associated with nosocomial infection and morbidity.Aim. To compare provision of point-of-care (POC) testing with laboratory-based testing for influenza and RSV detection on an adult respiratory assessment unit to assess the impact on isolation practices and length of stay (LOS).Methodology. Prospective interrupted 'on-off' study in adults admitted to the respiratory unit between December 2018 and April 2019 with a suspected respiratory tract infection. Nasopharyngeal samples were tested using either the GeneXpert rapid POC test for influenza and RSV (on-period), or were sent to the laboratory for multiplex PCR testing against a panel of 12 respiratory viruses (off-period). Outcome measures were time to patient isolation for infection control, LOS and turnaround time from admission to test results.Results. Of 1145 patients evaluated, 755 were tested with POC and 390 with laboratory multiplex; a respiratory virus was identified in 164 (21.7 %) and 138 (35.4 %) patients respectively. A positive POC test was associated with a shorter time to isolation (mean difference 16.9 h, P<0.001), shorter LOS (mean difference 15.5 h, P=0.05,) and shorter turnaround time (mean difference 28.3 h, P<0.001), compared to laboratory testing.Conclusion. Use of GeneXpert POC testing for Flu/RSV is associated with rapid reporting of results with significant improvements in isolation practices and reductions in LOS.

PMID: 32250239 [PubMed - as supplied by publisher]

Immunoactive preparations and regulatory responses in the respiratory tract: potential for clinical application in chronic inflammatory airway diseases.

Immunoactive preparations and regulatory responses in the respiratory tract: potential for clinical application in chronic inflammatory airway diseases.:

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Immunoactive preparations and regulatory responses in the respiratory tract: potential for clinical application in chronic inflammatory airway diseases.

Expert Rev Respir Med. 2020 Apr 06;:

Authors: Feleszko W, Rossi GA, Krenke R, Canonica GW, van Gerven L, Kalyuzhin O

Abstract

Introduction: The prevalence of chronic inflammatory airway diseases is rising. Their treatment with corticosteroids increases infection risk, while overuse of antimicrobial agents may increase morbidity and antimicrobial resistance. Non-specific immunomodulatory compounds alter immune responses to both infectious and atopic challenges. These compounds may offer an alternative approach for symptom reduction and prophylaxis against both infections and exacerbations in chronic inflammatory airway disease.Areas covered: We assessed the available data on the efficacy of non-specific immunomodulators including bacterial lysates, synthetic compounds, and vaccines in chronic rhinosinusitis (CRS); allergic and non-allergic rhinitis; chronic obstructive pulmonary disease (COPD), and asthma. A search of PubMed was carried out using the 'Clinical Trials' filter for each condition and immunomodulatory product detailed below, where available, data from meta-analyses were reported.Expert opinion: Pre-clinical data has revealed a coherent mechanistic path of action for oral immunomodulators on the respiratory immune system, principally via the gut-lung immune axis. In patients with asthma, allergic rhinitis, CRS, and COPD immunomodulatory therapy reduces symptoms, exacerbations, hospitalizations, and drug consumption. However, data are heterogeneous, and study quality remains limited. A lack of high-quality recent trials remains the major unmet research need in the field.

PMID: 32250709 [PubMed - as supplied by publisher]

Anesthesia timing for children undergoing therapeutic cardiac catheterization after upper respiratory infection: a prospective observational study.

Anesthesia timing for children undergoing therapeutic cardiac catheterization after upper respiratory infection: a prospective observational study.:

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Anesthesia timing for children undergoing therapeutic cardiac catheterization after upper respiratory infection: a prospective observational study.

Minerva Anestesiol. 2020 Apr 06;:

Authors: Kan Z, Siyuan W, Mengqi L, Chi W, Liping S, Sen Z, Jie B, Mazhong Z, Jijian Z

Abstract

BACKGROUND: We aimed to analyze anesthesia timing and perioperative respiratory adverse event (PRAE) risk factors in children undergoing therapeutic cardiac catheterization after upper respiratory tract infection (URI).

METHODS: We prospectively included children for elective therapeutic cardiac catheterization. Parents or legal guardians were asked to complete a questionnaire on the child's demographics, tobacco exposure, and URI symptoms. PRAEs (laryngospasm, bronchospasm, coughing, airway secretion, airway obstruction, and oxygen desaturation) as well as details of anesthesia management were recorded.

RESULTS: Of 332 children, 201 had a history of URI in the preceding eight weeks. The occurrence rate of PRAEs in children with URI ≤two weeks reached the highest proportion, which was higher than that in children without URI (66.3% vs 46.6%, P = 0.007). The overall incidence of PRAEs in children with URI in 3-8 weeks was significantly lower than that in children with URI in the recent ≤two weeks (49.0% vs. 66.3%, P = 0.007), and similar to that in the control group (49.0% vs. 46.6%). Multivariate analysis showed association between PRAEs and type of congenital heart disease (CHD) (P < 0.001), anesthesia timing (P = 0.007), and age (P = 0.021). Delayed schedule (two weeks after URI) minimized the risk of PRAEs to the level comparable to that observed in children without URI (OR, 1.11; 95% CI, 0.64-1.91; P = 0.707).

CONCLUSIONS: If treatment is not urgent, a pediatric patient at a high risk of PRAEs will be benefit from the postponement of an interventional operation by at least two weeks after URI.

PMID: 32251574 [PubMed - as supplied by publisher]

Safety and immunogenicity of a parenteral trivalent P2-VP8 subunit rotavirus vaccine: a multisite, randomised, double-blind, placebo-controlled trial.

Safety and immunogenicity of a parenteral trivalent P2-VP8 subunit rotavirus vaccine: a multisite, randomised, double-blind, placebo-controlled trial.:

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Safety and immunogenicity of a parenteral trivalent P2-VP8 subunit rotavirus vaccine: a multisite, randomised, double-blind, placebo-controlled trial.

Lancet Infect Dis. 2020 Apr 03;:

Authors: Groome MJ, Fairlie L, Morrison J, Fix A, Koen A, Masenya M, Jose L, Madhi SA, Page N, McNeal M, Dally L, Cho I, Power M, Flores J, Cryz S

Abstract

BACKGROUND: A monovalent, parenteral, subunit rotavirus vaccine was well tolerated and immunogenic in adults in the USA and in toddlers and infants in South Africa, but elicited poor responses against heterotypic rotavirus strains. We aimed to evaluate safety and immunogenicity of a trivalent vaccine formulation (P2-VP8-P[4],[6],[8]).

METHODS: A double-blind, randomised, placebo-controlled, dose-escalation, phase 1/2 study was done at three South African research sites. Healthy adults (aged 18-45 years), toddlers (aged 2-3 years), and infants (aged 6-8 weeks, ≥37 weeks' gestation, and without previous receipt of rotavirus vaccination), all without HIV infection, were eligible for enrolment. In the dose-escalation phase, adults and toddlers were randomly assigned in blocks (block size of five) to receive 30 μg or 90 μg of vaccine, or placebo, and infants were randomly assigned in blocks (block size of four) to receive 15 μg, 30 μg, or 90 μg of vaccine, or placebo. In the expanded phase, infants were randomly assigned in a 1:1:1:1 ratio to receive 15 μg, 30 μg, or 90 μg of vaccine, or placebo, in block sizes of four. Participants, parents of participants, and clinical, data, and laboratory staff were masked to treatment assignment. Adults received an intramuscular injection of vaccine or placebo in the deltoid muscle on the day of randomisation (day 0), day 28, and day 56; toddlers received a single injection of vaccine or placebo in the anterolateral thigh on day 0. Infants in both phases received an injection of vaccine or placebo in the anterolateral thigh on days 0, 28, and 56, at approximately 6, 10, and 14 weeks of age. Primary safety endpoints were local and systemic reactions (grade 2 or worse) within 7 days and adverse events and serious adverse events within 28 days after each injection in all participants who received at least one injection. Primary immunogenicity endpoints were analysed in infants in either phase who received all planned injections, had blood samples analysed at the relevant timepoints, and presented no major protocol violations considered to have an effect on the immunogenicity results of the study, and included serum anti-P2-VP8 IgA, IgG, and neutralising antibody geometric mean titres and responses measured 4 weeks after the final injection in vaccine compared with placebo groups. This trial is registered with ClinicalTrials.gov, NCT02646891.

FINDINGS: Between Feb 15, 2016, and Dec 22, 2017, 30 adults (12 each in the 30 μg and 90 μg groups and six in the placebo group), 30 toddlers (12 each in the 30 μg and 90 μg groups and six in the placebo group), and 557 infants (139 in the 15 μg group, 140 in the 30 μg group, 139 in the 90 μg group, and 139 in the placebo group) were randomly assigned, received at least one dose, and were assessed for safety. There were no significant differences in local or systemic adverse events, or unsolicited adverse events, between vaccine and placebo groups. There were no serious adverse events within 28 days of injection in adults, whereas one serious adverse event occurred in a toddler (febrile convulsion in the 30 μg group) and 23 serious adverse events (four in placebo, ten in 15 μg, four in 30 μg, and five in 90 μg groups) occurred among 20 infants, most commonly respiratory tract infections. One death occurred in an infant within 28 days of injection due to pneumococcal meningitis. In 528 infants (130 in placebo, 132 in 15 μg, 132 in 30 μg, and 134 in 90 μg groups), adjusted anti-P2-VP8 IgG seroresponses (≥4-fold increase from baseline) to P[4], P[6], and P[8] antigens were significantly higher in the 15 μg, 30 μg, and 90 μg groups (99-100%) than in the placebo group (10-29%; p<0·0001). Although significantly higher than in placebo recipients (9-10%), anti-P2-VP8 IgA seroresponses (≥4-fold increase from baseline) to each individual antigen were modest (20-34%) across the 15 μg, 30 μg, and 90 μg groups. Adjusted neutralising antibody seroresponses in infants (≥2·7-fold increase from baseline) to DS-1 (P[4]), 1076 (P[6]), and Wa (P[8]) were higher in vaccine recipients than in placebo recipients: p<0·0001 for all comparisons.

INTERPRETATION: The trivalent P2-VP8 vaccine was well tolerated, with promising anti-P2-VP8 IgG and neutralising antibody responses across the three vaccine P types. Our findings support advancing the vaccine to efficacy testing.

FUNDING: Bill & Melinda Gates Foundation.

PMID: 32251641 [PubMed - as supplied by publisher]

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