Publications by authors named "Sarah Schmidt"

64 Publications

Azacitidine maintenance therapy post-allogeneic stem cell transplantation in poor-risk acute myeloid leukemia.

Hematol Oncol Stem Cell Ther 2021 Mar 19. Epub 2021 Mar 19.

University of Oklahoma Health Sciences Center, Stephenson Cancer Center, Oklahoma City, OK 73104, USA. Electronic address:

Objective/background: Allogeneic hematopoietic stem cell transplant (HSCT) is the potential curative modality for poor-risk acute myeloid leukemia (AML), relapse remains the main reason for transplant failure. Early-phase studies showed azacitidine is safe for post-transplant maintenance therapy in AML.

Methods: We performed a single institutional prospective cohort study to evaluate the benefit of azacitidine maintenance therapy following allogeneic HSCT in poor-risk AML. The main objective of this study is to generate a hypothesis aiming to optimize post-transplantation outcomes in poor-risk AML. Forty-nine adults with poor-risk AML who underwent allogeneic HSCT were evaluated in a nonrandomized prospective cohort fashion. Thirty-one participants received post-transplant azacitidine (32 mg/m) on Days 1-5 for a 28-day treatment cycle beginning approximately 40 days after transplantation. The study was controlled using 18 matched individuals who were on a noninterventional surveillance protocol.

Results: The relapse rate was significantly higher in the control cohort (66.67%) versus (25.81%) in the azacitidine maintenance cohort (p < .005). Time to relapse was significantly prolonged by azacitidine maintenance, not reached versus 4.1 months in the control arm (p < .0001). In addition, median overall survival was lower in the control cohort at 7.6 versus 27.4 months in the interventional cohort (p < .0001). At a median follow-up of 24 months, incidence of graft-versus-host disease (GVHD) did not differ between study groups (p = .325). In both cohorts, minimal residual disease was correlated with higher hazard of relapse (95% confidence interval, 2.31-13.74; p < .001).

Conclusion: We conclude that low dose azacitidine maintenance following allogeneic HSCT in poor-risk AML, decreased relapse rate, and increased both the time to relapse and overall survival without increased risk of GVHD.
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http://dx.doi.org/10.1016/j.hemonc.2021.03.001DOI Listing
March 2021

Heterologous arenavirus vector prime-boost overrules self-tolerance for efficient tumor-specific CD8 T cell attack.

Cell Rep Med 2021 Mar 3;2(3):100209. Epub 2021 Mar 3.

University of Basel, Department of Biomedicine, Basel, Switzerland.

Therapeutic vaccination regimens inducing clinically effective tumor-specific CD8 T lymphocyte (CTL) responses are an unmet medical need. We engineer two distantly related arenaviruses, Pichinde virus and lymphocytic choriomeningitis virus, for therapeutic cancer vaccination. In mice, life-replicating vector formats of these two viruses delivering a self-antigen in a heterologous prime-boost regimen induce tumor-specific CTL responses up to 50% of the circulating CD8 T cell pool. This CTL attack eliminates established solid tumors in a significant proportion of animals, accompanied by protection against tumor rechallenge. The magnitude of CTL responses is alarmin driven and requires combining two genealogically distantly related arenaviruses. Vector-neutralizing antibodies do not inhibit booster immunizations by the same vector or by closely related vectors. Rather, CTL immunodominance hierarchies favor vector backbone-targeted responses at the expense of self-reactive CTLs. These findings establish an arenavirus-based immunotherapy regimen that allows reshuffling of immunodominance hierarchies and breaking self-directed tolerance for efficient tumor control.
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http://dx.doi.org/10.1016/j.xcrm.2021.100209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7974551PMC
March 2021

Use of Procalcitonin in a Febrile Infant Clinical Pathway and Impact on Infants Aged 29 to 60 Days.

Hosp Pediatr 2021 Mar;11(3):223-230

Sections of Hospital Medicine and.

Objectives: Recent evidence suggests that measuring the procalcitonin level may improve identification of low-risk febrile infants who may not need intervention. We describe outcomes after the implementation of a febrile infant clinical pathway recommending measurement of the procalcitonin level for risk stratification.

Methods: In this single-center retrospective pre-post intervention study of febrile infants aged 29 to 60 days, we used interrupted time series analyses to evaluate outcomes of lumbar puncture (LP), antibiotic administration, hospital admission, and emergency department (ED) length of stay (LOS). A multivariable logistic regression was used to evaluate the odds of LP.

Results: Data were analyzed between January 2017 and December 2019 and included 740 participants. Procalcitonin use increased post-pathway implementation (PI). The proportion of low-risk infants receiving an LP decreased significantly post-PI ( = .001). In the adjusted interrupted time series analysis, there was no immediate level change (shift) post-PI for LP (0.98 [95% confidence interval (CI): 0.49-1.97]), antibiotics (1.17 [95% CI: 0.56-2.43]), admission (1.07 [95% CI: 0.59-1.96]), or ED LOS (1.08 [95% CI: 0.92-1.28]), and there was no slope change post-PI versus pre-PI for any measure (LP: 1.01 [95% CI: 0.94-1.08]; antibiotics: 1.00 [95% CI: 0.93-1.08]; admission: 1.03 [95% CI: 0.97-1.09]; ED LOS: 1.01 [95% CI: 0.99-1.02]). More patients were considered high risk, and fewer had incomplete laboratory test results post-PI ( < .001). There were no missed serious bacterial infections. A normal procalcitonin level significantly decreased the odds of LP ( < .001).

Conclusions: Clinicians quickly adopted procalcitonin testing. Resource use for low-risk infants decreased; however, there was no change to resource use for the overall population because more infants underwent laboratory evaluation and were classified as high risk post-PI.
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http://dx.doi.org/10.1542/hpeds.2020-000380DOI Listing
March 2021

Live-attenuated lymphocytic choriomeningitis virus-based vaccines for active immunotherapy of HPV16-positive cancer.

Oncoimmunology 2020 09 15;9(1):1809960. Epub 2020 Sep 15.

Hookipa Pharma Inc., New York, NY, USA.

Infection with human papillomavirus (HPV) is associated with a variety of cancer types and limited therapy options. Therapeutic cancer vaccines targeting the HPV16 oncoproteins E6 and E7 have recently been extensively explored as a promising immunotherapy approach to drive durable antitumor T cell immunity and induce effective tumor control. With the goal to achieve potent and lasting antitumor T cell responses, we generated a novel lymphocytic choriomeningitis virus (LCMV)-based vaccine, TT1-E7E6, targeting HPV16 E6 and E7. This replication-competent vector was stably attenuated using a three-segmented viral genome packaging strategy. Compared to wild-type LCMV, TT1-E7E6 demonstrated significantly reduced viremia and CNS immunopathology. Intravenous vaccination of mice with TT1-E7E6 induced robust expansion of HPV16-specific CD8 T cells producing IFN-γ, TNF-α and IL-2. In the HPV16 E6 and E7-expressing TC-1 tumor model, mice immunized with TT1-E7E6 showed significantly delayed tumor growth or complete tumor clearance accompanied with prolonged survival. Tumor control by TT1-E7E6 was also achieved in established large-sized tumors in this model. Furthermore, a combination of TT1-E7E6 with anti-PD-1 therapy led to enhanced antitumor efficacy with complete tumor regression in the majority of tumor-bearing mice that were resistant to anti-PD-1 treatment alone. TT1-E7E6 vector itself did not exhibit oncolytic properties in TC-1 cells, while the antitumor effect was associated with the accumulation of HPV16-specific CD8 T cells with reduced PD-1 expression in the tumor tissues. Together, our results suggest that TT1-E7E6 is a promising therapeutic vaccine for HPV-positive cancers.
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http://dx.doi.org/10.1080/2162402X.2020.1809960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781782PMC
September 2020

Complex effects of eslicarbazepine on inhibitory micro networks in chronic experimental epilepsy.

Epilepsia 2021 02 16;62(2):542-556. Epub 2021 Jan 16.

Medical Faculty, Institute for Experimental Epileptology and Cognition Research, University of Bonn, Bonn, Germany.

Objective: Many antiseizure drugs (ASDs) act on voltage-dependent sodium channels, and the molecular basis of these effects is well established. In contrast, how ASDs act on the level of neuronal networks is much less understood.

Methods: In the present study, we determined the effects of eslicarbazepine (S-Lic) on different types of inhibitory neurons, as well as inhibitory motifs. Experiments were performed in hippocampal slices from both sham-control and chronically epileptic pilocarpine-treated rats.

Results: We found that S-Lic causes an unexpected reduction of feed-forward inhibition in the CA1 region at high concentrations (300 µM), but not at lower concentrations (100 µM). Concurrently, 300 but not 100 μM S-Lic significantly reduced maximal firing rates in putative feed-forward interneurons located in the CA1 stratum radiatum of sham-control and epileptic animals. In contrast, feedback inhibition was not inhibited by S-Lic. Instead, application of S-Lic, in contrast to previous data for other drugs like carbamazepine (CBZ), resulted in a lasting potentiation of feedback inhibitory post-synaptic currents (IPSCs) only in epileptic and not in sham-control animals, which persisted after washout of S-Lic. We hypothesized that this plasticity of inhibition might rely on anti-Hebbian potentiation of excitatory feedback inputs onto oriens-lacunosum moleculare (OLM) interneurons, which is dependent on Ca -permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Indeed, we show that blocking Ca -permeable AMPA receptors completely prevents upmodulation of feedback inhibition.

Significance: These results suggest that S-Lic affects inhibitory circuits in the CA1 hippocampal region in unexpected ways. In addition, ASD actions may not be sufficiently explained by acute effects on their target channels, rather, it may be necessary to take plasticity of inhibitory circuits into account.
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http://dx.doi.org/10.1111/epi.16808DOI Listing
February 2021

Genomic profiling is a supplemental diagnostic and therapeutic modality for hairy cell leukemia variant.

Ann Hematol 2021 Jan 12. Epub 2021 Jan 12.

University of Oklahoma Health Sciences Center, Stephenson Cancer Center, 800 NE 10th street, Oklahoma City, OK, 73104, USA.

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http://dx.doi.org/10.1007/s00277-021-04408-zDOI Listing
January 2021

Supramodal neural networks support top-down processing of social signals.

Hum Brain Mapp 2021 Feb 19;42(3):676-689. Epub 2020 Oct 19.

Department of Psychiatry, Psychotherapy, and Psychosomatics, Medical School, RWTH Aachen, Aachen, Germany.

The perception of facial and vocal stimuli is driven by sensory input and cognitive top-down influences. Important top-down influences are attentional focus and supramodal social memory representations. The present study investigated the neural networks underlying these top-down processes and their role in social stimulus classification. In a neuroimaging study with 45 healthy participants, we employed a social adaptation of the Implicit Association Test. Attentional focus was modified via the classification task, which compared two domains of social perception (emotion and gender), using the exactly same stimulus set. Supramodal memory representations were addressed via congruency of the target categories for the classification of auditory and visual social stimuli (voices and faces). Functional magnetic resonance imaging identified attention-specific and supramodal networks. Emotion classification networks included bilateral anterior insula, pre-supplementary motor area, and right inferior frontal gyrus. They were pure attention-driven and independent from stimulus modality or congruency of the target concepts. No neural contribution of supramodal memory representations could be revealed for emotion classification. In contrast, gender classification relied on supramodal memory representations in rostral anterior cingulate and ventromedial prefrontal cortices. In summary, different domains of social perception involve different top-down processes which take place in clearly distinguishable neural networks.
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http://dx.doi.org/10.1002/hbm.25252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814753PMC
February 2021

Letter to the Editor Regarding "Pathology Informatics Education Committee of the American College of Veterinary Pathologists (ACVP)".

Toxicol Pathol 2020 Oct 12:192623320962427. Epub 2020 Oct 12.

Department of Biomedical Sciences & Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech University, VA, USA.

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http://dx.doi.org/10.1177/0192623320962427DOI Listing
October 2020

Crosstalk Between Pheromone Signaling and NADPH Oxidase Complexes Coordinates Fungal Developmental Processes.

Front Microbiol 2020 28;11:1722. Epub 2020 Jul 28.

Allgemeine und Molekulare Botanik, Ruhr-Universität Bochum, Bochum, Germany.

Sexual and asexual development in filamentous ascomycetes is controlled by components of conserved signaling pathways. Here, we investigated the development of mutant strains lacking genes for kinases MAK2, MEK2, and MIK2, as well as the scaffold protein HAM5 of the pheromone response (PR) pathway. All had a defect in fruiting body development and hyphal fusion. Another phenotype was a defect in melanin-dependent ascospore germination. However, this deficiency was observed only in kinase deletion mutants, but not in strains lacking HAM5. Notably, the same developmental phenotypes were previously described for nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 1 (NOX1) mutants, but the germination defect was only seen in NOX2 mutants. These data suggest a molecular link between the pheromone signaling pathway and both NOX complexes. Using data from yeast two-hybrid (Y2H) analysis, we found that the scaffolding protein HAM5 interacts with NOR1, the regulator of NOX1 and NOX2 complexes. This interaction was further confirmed using differently fluorescent-labeled proteins to demonstrate that NOR1 and HAM5 co-localize at cytoplasmic spots and tips of mature hyphae. This observation was supported by phenotypic characterization of single and double mutants. The oxidative stress response and the initiation of fruiting bodies were similar in Δham5Δnor1 and Δham5, but distinctly reduced in Δnor1, indicating that the double deletion leads to a partial suppression of the Δnor1 phenotype. We conclude that the PR and NOX1 complexes are connected by direct interaction between HAM5 and NOR1. In contrast, PR kinases are linked to the NOX2 complex without participation of HAM5.
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http://dx.doi.org/10.3389/fmicb.2020.01722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401384PMC
July 2020

Material efficiency to measure the environmental performance of waste management systems: A case study on PET bottle recycling in Austria, Germany and Serbia.

Waste Manag 2020 Jun 24;110:74-86. Epub 2020 May 24.

University of Novi Sad, Faculty of Technical Sciences, Department of Environmental Engineering, Trg Dositeja Obradovica 6, 21000 Novi Sad, Serbia.

Material efficiency measures, such as recycling rates, are often used to set circular economy targets to achieve higher resource efficiency and lower environmental impact. The aim of this study was to identify material efficiency indicators suitable to reflect the environmental performance of waste and recycling systems using PET bottle waste management in three European countries with diverse waste management structures and recycling performance levels. Material flow analysis and life cycle assessment were performed to assess the material efficiency and environmental impacts of each system as a basis to analyze the relation between these two dimensions. PET bottle waste generation was 5.4 kg/person and year (pa) in Austria in 2013, 6.0 kg/pa in Germany in 2017 and 6.9 kg/pa in Serbia in 2015. Out of this waste flow 41%, 91%, and 11% were directed into PET recyclate in Austria, Germany and Serbia, respectively. For all systems, higher material efficiency translated into lower environmental impact and vice versa. However, linear regression analysis between different material efficiency indicators and environmental impacts showed that indicators targeted at actual recycling, specifically at closed loop, were better suited to reflect environmental performance than input-based indicators. Therefore, whenever data are available, output-based quality-related indicators should be used to measure the material efficiency of waste and resource systems because they correlate best with the goals of increasing resource efficiency and decreasing environmental impacts.
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http://dx.doi.org/10.1016/j.wasman.2020.05.011DOI Listing
June 2020

The evolving landscape around genome editing in agriculture: Many countries have exempted or move to exempt forms of genome editing from GMO regulation of crop plants.

EMBO Rep 2020 06 19;21(6):e50680. Epub 2020 May 19.

Heinrich Heine University, Düsseldorf, Germany.

The EU and New Zealand are the only legislations where genome-edited plants are considered and regulated as GMOs while many other countries move to exempt genome-edited crops.
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http://dx.doi.org/10.15252/embr.202050680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271327PMC
June 2020

The Role of Donor Lymphocyte Infusion (DLI) in Post-Hematopoietic Cell Transplant (HCT) Relapse for Chronic Myeloid Leukemia (CML) in the Tyrosine Kinase Inhibitor (TKI) Era.

Biol Blood Marrow Transplant 2020 06 14;26(6):1137-1143. Epub 2020 Feb 14.

CIBMTR (Center for International Blood and Marrow Transplant Research), Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.

Treatment for relapse of chronic myeloid leukemia (CML) following hematopoietic cell transplantation (HCT) includes tyrosine kinase inhibitors (TKIs) with or without donor lymphocyte infusions (DLIs), but the most effective treatment strategy is unknown. This study was performed through the Center for International Blood and Marrow Transplant Research (CIBMTR) database. We retrospectively reviewed all patients reported to the CIBMTR registry from 2002 to 2014 who underwent HCT for CML and were alive 30 days postrelapse. A total of 215 HCT recipients relapsed and were analyzed in the following groups: (1) TKI alone (n = 128), (2) TKI with DLI (n = 48), and (3) DLI without TKI (n = 39). In multivariate analysis, disease status prior to HCT had a significant effect on overall survival (OS). Patients who received a DLI alone compared with a TKI with a DLI had inferior survival (hazard ratio, 2.28; 95% confidence interval, 1.23 to 4.24; P= .009). Those who received a TKI alone had similar survival compared with those who received a TKI with a DLI (P = .81). These data support that despite use of TKIs pretransplantation, TKI salvage therapy continues to provide significant survival following relapse in patients with CML following HCT. These data do not suggest that adding a DLI to a TKI adds an improvement in OS.
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http://dx.doi.org/10.1016/j.bbmt.2020.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367282PMC
June 2020

Breathing Easier: Decreasing Tracheal Intubation-associated Adverse Events in the Pediatric ED and Urgent Care.

Pediatr Qual Saf 2019 Nov-Dec;4(6):e230. Epub 2019 Nov 19.

Department of Pediatric Emergency Medicine, University of Colorado, Aurora, CO, USA.

Tracheal intubation is a high-risk procedure in the pediatric emergency department (PED) and pediatric urgent care (PUC) settings. We aimed to develop an airway safety intervention to decrease severe tracheal intubation-associated adverse events (TIAEs) by decreasing process variation.

Methods: After gathering baseline data on TIAE, an interdisciplinary team underwent a mini-Delphi process to identify key drivers for decreasing severe TIAE rates. We launched a 4-part airway safety bundle that included: (1) color-coded weight-based equipment chart, (2) visual schematic of airway equipment, (3) recommended medication dosing, and (4) safety checklist across a single, tertiary PED and 5 satellite community PUCs/PEDs. Multiple plan-do-study-act cycles were undertaken, and results were monitored using statistical process control charts. Charts were restaged when special cause variation was achieved. This study aimed to decrease the severe TIAE rate from a baseline of 23% in the tertiary site and 25% in the community sites to <15% within 12 months and to sustain these outcomes for 6 months.

Results: During the study period, we noted decreased rates of severe TIAE in both the PED and PUC setting during the intervention period, and we have sustained this improvement for more than 6 months in all sites with no associated change in balancing measures.

Conclusions: Implementation of an airway safety bundle over a wide geographic area and among personnel with variable levels of training is possible and has the potential to decrease severe TIAE across multiple clinical settings.
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http://dx.doi.org/10.1097/pq9.0000000000000230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946226PMC
November 2019

Diagnostic kit for rice blight resistance.

Nat Biotechnol 2019 11 28;37(11):1372-1379. Epub 2019 Oct 28.

Institute for Molecular Physiology and Cluster of Excellence on Plant Sciences (CEPLAS), Heinrich Heine University of Düsseldorf, Düsseldorf, Germany.

Blight-resistant rice lines are the most effective solution for bacterial blight, caused by Xanthomonas oryzae pv. oryzae (Xoo). Key resistance mechanisms involve SWEET genes as susceptibility factors. Bacterial transcription activator-like (TAL) effectors bind to effector-binding elements (EBEs) in SWEET gene promoters and induce SWEET genes. EBE variants that cannot be recognized by TAL effectors abrogate induction, causing resistance. Here we describe a diagnostic kit to enable analysis of bacterial blight in the field and identification of suitable resistant lines. Specifically, we include a SWEET promoter database, RT-PCR primers for detecting SWEET induction, engineered reporter rice lines to visualize SWEET protein accumulation and knock-out rice lines to identify virulence mechanisms in bacterial isolates. We also developed CRISPR-Cas9 genome-edited Kitaake rice to evaluate the efficacy of EBE mutations in resistance, software to predict the optimal resistance gene set for a specific geographic region, and two resistant 'mega' rice lines that will empower farmers to plant lines that are most likely to resist rice blight.
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http://dx.doi.org/10.1038/s41587-019-0268-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831515PMC
November 2019

Broad-spectrum resistance to bacterial blight in rice using genome editing.

Nat Biotechnol 2019 11 28;37(11):1344-1350. Epub 2019 Oct 28.

Division of Plant Sciences, Bond Life Sciences Center, University of Missouri, Columbia, MO, USA.

Bacterial blight of rice is an important disease in Asia and Africa. The pathogen, Xanthomonas oryzae pv. oryzae (Xoo), secretes one or more of six known transcription-activator-like effectors (TALes) that bind specific promoter sequences and induce, at minimum, one of the three host sucrose transporter genes SWEET11, SWEET13 and SWEET14, the expression of which is required for disease susceptibility. We used CRISPR-Cas9-mediated genome editing to introduce mutations in all three SWEET gene promoters. Editing was further informed by sequence analyses of TALe genes in 63 Xoo strains, which revealed multiple TALe variants for SWEET13 alleles. Mutations were also created in SWEET14, which is also targeted by two TALes from an African Xoo lineage. A total of five promoter mutations were simultaneously introduced into the rice line Kitaake and the elite mega varieties IR64 and Ciherang-Sub1. Paddy trials showed that genome-edited SWEET promoters endow rice lines with robust, broad-spectrum resistance.
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http://dx.doi.org/10.1038/s41587-019-0267-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831514PMC
November 2019

Altered Dynamics of Canonical Feedback Inhibition Predicts Increased Burst Transmission in Chronic Epilepsy.

J Neurosci 2019 11 13;39(45):8998-9012. Epub 2019 Sep 13.

Institute of Experimental Epileptology and Cognition Research, University of Bonn, 53105 Bonn, Germany,

Inhibitory interneurons, organized into canonical feedforward and feedback motifs, play a key role in controlling normal and pathological neuronal activity. We demonstrate prominent quantitative changes in the dynamics of feedback inhibition in a rat model of chronic epilepsy (male Wistar rats). Systematic interneuron recordings revealed a large decrease in intrinsic excitability of basket cells and oriens-lacunosum moleculare interneurons in epileptic animals. Additionally, the temporal dynamics of interneuron recruitment by recurrent feedback excitation were strongly altered, resulting in a profound loss of initial feedback inhibition during synchronous CA1 pyramidal activity. Biophysically constrained models of the complete feedback circuit motifs of normal and epileptic animals revealed that, as a consequence of altered feedback inhibition, burst activity arising in CA3 is more strongly converted to a CA1 output. This suggests that altered dynamics of feedback inhibition promote the transmission of epileptiform bursts to hippocampal projection areas. We quantitatively characterized changes of the CA1 feedback inhibitory circuit in a model of chronic temporal lobe epilepsy. This study shows, for the first time, that dynamic recruitment of inhibition in feedback circuits is altered and establishes the cellular mechanisms for this change. Computational modeling revealed that the observed changes are likely to systematically alter CA1 input-output properties leading to (1) increased seizure propagation through CA1 and (2) altered computation of synchronous CA3 input.
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http://dx.doi.org/10.1523/JNEUROSCI.2594-18.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832680PMC
November 2019

Extubation Readiness in Critically Ill Stroke Patients.

Stroke 2019 08 8;50(8):1981-1988. Epub 2019 Jul 8.

From the Department of Neurology, University of Muenster, Germany (S.S.-K., S.S., T.W., P.M., J.B.S., B.L., J.M., R.D.).

Background and Purpose- Predicting safe extubation represents a clinical challenge in acute stroke patients. Classical respiratory weaning criteria have not proven reliable. Concerning the paramount relevance of postextubation dysphagia in this population, criteria related to airway safety seem to perform better, but diagnostic standards are lacking. We compare clinical and instrumental swallowing examination tools to assess extubation readiness and propose a simple Determine Extubation Failure in Severe Stroke score for decision making. Methods- Data of 133 orally intubated acute stroke patients were prospectively collected in this observational study. Classical extubation criteria, a modified semiquantitative airway score, and an oral motor function score were assessed before extubation. A 3-ounce water swallow test and validated 6-point fiberoptic endoscopic dysphagia severity scoring were performed thereafter. Association of demographic and clinical parameters with extubation failure (EF) was investigated. Independent predictors of EF were translated into a point scoring system. Ideal cutoff values were determined by receiver operator characteristics analyses. Results- Patients with EF (24.1% after 24±43 hours) performed worse in all swallowing assessments (P<0.001). Fiberoptic endoscopic dysphagia severity scoring was the only independent predictor of EF (adjusted odds ratio, 4.2; P<0.007) with optimal cutoff ≥5 (sensitivity 84.6% and specificity 76.5%). Restricting regression analysis to parameters collected before extubation, a 4-item Determine Extubation Failure in Severe Stroke score (duration of ventilation, the examination of oral motor function, infratentorial lesion, and stroke severity) was derived. The score demonstrated excellent discrimination (area under the curve 0.89; 95% CI, 0.83-0.95) and calibration (Nagelkerkes R=0.54) with an ideal cutoff ≥4 (sensitivity: 81.3% and specificity: 78.2%). Conclusions- Risk of EF is strongly correlated with postextubation dysphagia severity in stroke. Fiberoptic endoscopic examination of swallowing best predicts necessity of reintubation but requires a trial of extubation. The Determine Extubation Failure In Severe Stroke score is based on easy to collect clinical data and may guide extubation decision making in critically ill stroke patients.
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http://dx.doi.org/10.1161/STROKEAHA.118.024643DOI Listing
August 2019

Efficacy of novel selective NLRP3 inhibitors in human and murine retinal pigment epithelial cells.

J Mol Med (Berl) 2019 04 10;97(4):523-532. Epub 2019 Feb 10.

Department of Ophthalmology, University of Bonn, Ernst-Abbe-Str. 2, Bonn, 53127, Germany.

NLRP3 inflammasome activation in the retinal pigment epithelium (RPE) is observed in atrophic age-related macular degeneration (AMD), and pharmacological NLRP3 inhibition may provide a therapeutic strategy to halt disease progression. We tested selective NLRP3 inhibitors (IFM-514, IFM-632, and CRID3) for their efficacy in human and murine RPE cells. Inflammasome activation was induced in primary human RPE cells and ARPE-19 cells following priming with IL-1α by different stimuli, including lysosomal membrane permeabilization by leucyl-leucine methyl ester (Leu-Leu-OMe), oxidative damage induced by hydrogen peroxide, lipofuscin-mediated photooxidative damage induced by incubation with 4-hydroxynonenal-modified photoreceptor outer segments and subsequent blue light irradiation, and P2X7 receptor activation by benzoylbenzoyl-ATP. Independent of the applied activation mechanism, treatment with the NLRP3 inhibitors IFM-632, IFM-514, and CRID3 resulted in a significant suppression of inflammasome activation as assessed by IL-1β and LDH release. Likewise, inflammasome activation in blue light-irradiated Abca4-/- mouse and Leu-Leu-OMe-treated wild-type mouse RPE/choroid/sclera eye cups was significantly reduced by treatment with the NLRP3 inhibitors. These results indicate that the investigated selective NLRP3 inhibitors are effective in human and murine RPE cells, thus representing promising agents for the future evaluation of inflammasome inhibition as a therapeutic strategy in atrophic AMD. KEY MESSAGES: • NLRP3 inhibitors suppress inflammasome activation in human RPE cells independent of trigger. • Light-induced inflammasome activation in Abca4-/- mouse eye cups is reduced by NLRP3 inhibitors. • Novel selective NLRP3 inhibitors are effective in human and murine RPE cells. • Promising compounds for pharmaceutical intervention in atrophic AMD.
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http://dx.doi.org/10.1007/s00109-019-01753-5DOI Listing
April 2019

Ibritumomab tiuxetan (Zevalin) and elevated serum human anti-murine antibody (HAMA).

Hematol Oncol Stem Cell Ther 2018 Sep 1;11(3):187-188. Epub 2018 Feb 1.

Hematology-Oncology Section, Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

Ibritumomab Tiuxetan (Zevalin) is an anti CD-20 murine monoclonal antibody linked to the radio-isotope 90-yttrium (90Y) by the chelator Tiuxetan. It is FDA approved for treatment of relapsed low grade or follicular B-cell Non-Hodgkin's Lymphoma (NHL) or newly diagnosed follicular NHL following an initial response to first-line chemotherapy. Patients may develop Human Anti-Murine Antibodies (HAMA), following exposure to murine antibodies. There is a concern for development of hypersensitivity reactions with Ibritumomab, especially in patients with an elevated HAMA titer. Here we describe a case of a 66 year old male with elevated HAMA titer successfully treated with Zevalin without any hypersensitivity reactions. Existing literature supports our observation that Zevalin can be safely used in most patients with elevated HAMA titers.
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http://dx.doi.org/10.1016/j.hemonc.2017.12.004DOI Listing
September 2018

Frequency and Characterization of Tracheal Intubation Adverse Events in Pediatric Sepsis.

Pediatr Crit Care Med 2018 02;19(2):e80-e87

Section of Pediatric Emergency Medicine, Department of Pediatrics, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, CO.

Objectives: Intubation in critically ill pediatric patients is associated with approximately 20% rate of adverse events, but rates in the high-risk condition of sepsis are unknown. Our objectives were to describe the frequency and characteristics of tracheal intubation adverse events in pediatric sepsis.

Design: Retrospective cohort study of a sepsis registry.

Setting: Two tertiary care academic emergency departments and four affiliated urgent cares within a single children's hospital health system.

Patients: Children 60 days and older to 18 years and younger who required nonelective intubation within 24 hours of emergency department arrival. Exclusion criteria included elective intubation, intubation prior to emergency department arrival, presence of tracheostomy, or missing intubation chart data.

Interventions: Not applicable.

Measurements And Main Results: The outcome was tracheal intubation adverse event as defined by the National Emergency Airway Registry Tool 4 KIDS. During the study period, 118 of 2,395 registry patients met inclusion criteria; 100% of intubations were successful. First attempt success rate was 57% (95% CI, 48-65%); 59% were intubated in the emergency department, and 28% were intubated in the PICU. First attempts were by a resident (30%), a fellow (42%), attending (6%), and anesthesiologist (13%). Tracheal intubation adverse events were reported in 61 (43%; 95% 43-61%) intubations with severe tracheal intubation adverse events in 22 (17%; 95 CI, 13-27%) intubations. Hypotension was the most common severe event (n = 20 [17%]) with 14 novel occurrences during intubation. Mainstem bronchial intubation was the most common nonsevere event (n = 28 [24%]). Residents, advanced practice providers, and general pediatricians in urgent care settings had the lowest rates of first-pass success.

Conclusions: The rates of tracheal intubation adverse events in this study are higher than in nonelective pediatric intubations in all conditions and highlight the high-risk nature of intubations in pediatric sepsis. Further research is needed to identify optimal practices for intubation in pediatric sepsis.
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http://dx.doi.org/10.1097/PCC.0000000000001398DOI Listing
February 2018

Clostridium difficile treatment in neutropenic patients: Clinical outcomes of metronidazole, vancomycin, combinations, and switch therapy.

J Oncol Pharm Pract 2019 Apr 20;25(3):520-528. Epub 2017 Nov 20.

6 Department of Pharmacy Practice, School of Pharmacy, Texas Tech University Health Sciences Center, Dallas, TX, USA.

Background: Clostridium difficile infection treatment guidelines exist for immunocompetent patients; however, there is a paucity of data evaluating clinical outcomes and time to C. difficile-associated diarrhea resolution in neutropenic patients.

Objective: To assess clinical outcomes in neutropenic patients treated with metronidazole, oral vancomycin, the combination of metronidazole plus oral vancomycin, and switch of metronidazole to oral vancomycin.

Methods: This retrospective, observational cohort study assessed adult neutropenic inpatients with C. difficile-associated diarrhea treated with metronidazole, oral vancomycin, combination (metronidazole and oral vancomycin), or switch therapy (metronidazole to oral vancomycin). The primary outcome was time to diarrhea resolution based on treatment regimen. Secondary outcomes included C. difficile-associated diarrhea resolution of diarrhea by day 14, recurrence, and occurrence of major complications.

Results: Overall, 44 patients met full inclusion criteria (52.2% metronidazole monotherapy, 22.7% combination, and 25.0% switch therapy). Two patients on oral vancomycin monotherapy were excluded due to insufficient sample size. Overall time to C. difficile-associated diarrhea resolution was 9.1 ± 10.7 days. The Cox regression results suggested both switch and combination therapy were associated with 65.5% (p = 0.002) and 65.9% (p = 0.046) longer time to C. difficile-associated diarrhea resolution compared to metronidazole monotherapy, respectively. An increasing absolute neutrophil count was associated with an increase in C. difficile-associated diarrhea resolution (p = 0.007).

Conclusion: Switch or combination therapy was associated with a prolonged time to C. difficile-associated diarrhea resolution. The decision to use switch or combination therapy may represent a surrogate marker for more severe disease and need for therapy escalation. It is unknown if initial therapy with oral vancomycin would provide better outcomes as this could not be assessed.
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http://dx.doi.org/10.1177/1078155217740945DOI Listing
April 2019

Silica Nanoparticles for Intracellular Protein Delivery: a Novel Synthesis Approach Using Green Fluorescent Protein.

Nanoscale Res Lett 2017 Sep 25;12(1):545. Epub 2017 Sep 25.

Leibniz Institute for New Materials, Campus D2 2, 66123, Saarbrücken, SL, Germany.

In this study, a novel approach for preparation of green fluorescent protein (GFP)-doped silica nanoparticles with a narrow size distribution is presented. GFP was chosen as a model protein due to its autofluorescence. Protein-doped nanoparticles have a high application potential in the field of intracellular protein delivery. In addition, fluorescently labelled particles can be used for bioimaging. The size of these protein-doped nanoparticles was adjusted from 15 to 35 nm using a multistep synthesis process, comprising the particle core synthesis followed by shell regrowth steps. GFP was selectively incorporated into the silica matrix of either the core or the shell or both by a one-pot reaction. The obtained nanoparticles were characterised by determination of particle size, hydrodynamic diameter, ζ-potential, fluorescence and quantum yield. The measurements showed that the fluorescence of GFP was maintained during particle synthesis. Cellular uptake experiments demonstrated that the GFP-doped nanoparticles can be used as stable and effective fluorescent probes. The study reveals the potential of the chosen approach for incorporation of functional biological macromolecules into silica nanoparticles, which opens novel application fields like intracellular protein delivery.
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http://dx.doi.org/10.1186/s11671-017-2280-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5612907PMC
September 2017

Biomacromolecules as tools and objects in nanometrology-current challenges and perspectives.

Anal Bioanal Chem 2017 Oct 14;409(25):5901-5909. Epub 2017 Aug 14.

Institute for Physical and Theoretical Chemistry, Braunschweig Integrated Centre of Systems Biology (BRICS), and Laboratory for Emerging Nanometrology (LENA), Technische Universität Braunschweig, 38106, Braunschweig, Germany.

Nucleic acids, proteins, and polysaccharides are the most important classes of biopolymers. The inherent properties of biomacromolecules are contrary to those of well-defined small molecules consequently raising a number of specific challenges which become particularly apparent if biomacromolecules are treated as objects in quantitative analysis. At the same time, their specific functional ability of molecular recognition and self-organization (e.g., enzymes, antibodies, DNA) enables us to make biomacromolecules serving as molecular tools in biochemistry and molecular biology, or as precisely controllable dimensional platforms for nanometrological applications. Given the complexity of biomacromolecules, quantitative analysis is not limited to the measurement of their concentration but also involves the determination of numerous descriptors related to structure, interaction, activity, and function. Among the biomacromolecules, glycans set examples that quantitative characterization is not necessarily directed to the measurement of amount-of-substance concentration but instead involves the determination of relative proportions (molar ratios) of structural features for comparison with theoretical models. This article addresses current activities to combine optical techniques such as Raman spectroscopy with isotope dilution approaches to realize reference measurement procedures for the quantification of protein biomarkers as an alternative to mass spectrometry-based techniques. Furthermore, it is explored how established ID-MS protocols are being modified to make them applicable for quantifying virus proteins to measure the HIV viral load in blood samples. As an example from the class of carbohydrates, the challenges in accurate determination of substitution patterns are outlined and discussed. Finally, it is presented that biomacromolecules can also serve as tools in quantitative measurements of dimensions with an example of DNA origami to generate defined dimensional standards to be used for calibration in super-resolution fluorescence microscopy. Graphical abstract Quantitative analysis of biomacromolecules is accompanied with special challenges different from low molecular weight compounds. In addition, they are not only objects but also tools applicable for quantitative measurements.
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http://dx.doi.org/10.1007/s00216-017-0554-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5602082PMC
October 2017

The Caregiver Perspective on Unscheduled 72-Hour Return Visits to Pediatric Acute Care Sites: A Focus on Discharge Processes.

Acad Pediatr 2017 Sep - Oct;17(7):755-761. Epub 2017 Feb 12.

Section of Pediatric Emergency Medicine, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora.

Objective: To characterize pediatric caregivers' reasons for 72-hour emergency department (ED) and urgent care (UC) returns.

Methods: A sample of caregivers returning within 72 hours of initial visit to a pediatric ED or affiliated UC site was surveyed from November 2014 to June 2015; patients evaluated at outside ED/UC, scheduled for return, or non-English/Spanish speaking were excluded. Caregiver surveys underwent item generation, validation, and pilot testing. Survey items included caregiver reasons for unscheduled returns, with a specific assessment of delivery of key components of discharge instructions (diagnosis, duration of illness, home care, return precautions). Complete delivery of instructions was defined by caregiver reported receipt of instructions on all 4 components.

Results: Of the 500 caregiver surveys analyzed 495 children received a 72-hour return ED/UC visit. Mean age of caregivers was 33 years, 62% completed college. Children were 2 years of age or younger (47%), male (52%), Caucasian (55%), and publicly insured (64%). Reported reasons for ED/UC return included belief that their child's illness had not resolved (51%) or worsened (41%). Many caregivers (41%) were not instructed on all key components of discharge. Almost half of caregivers (47%) were not educated on anticipated duration of illness. Complete delivery of discharge instructions was associated with ED/UC satisfaction (odds ratio, 5.7; 95% confidence interval, 3.8-8.5).

Conclusions: Among caregivers of children returning for an unscheduled ED/UC visit, most do not receive complete discharge instructions at initial visit. Improving delivery of key components of discharge instructions has the potential to increase ED/UC satisfaction and reduce unscheduled 72-hour returns.
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http://dx.doi.org/10.1016/j.acap.2017.02.003DOI Listing
June 2018

Transcription Factors Encoded on Core and Accessory Chromosomes of Fusarium oxysporum Induce Expression of Effector Genes.

PLoS Genet 2016 Nov 17;12(11):e1006401. Epub 2016 Nov 17.

Molecular Plant Pathology, University of Amsterdam, The Netherlands.

Proteins secreted by pathogens during host colonization largely determine the outcome of pathogen-host interactions and are commonly called 'effectors'. In fungal plant pathogens, coordinated transcriptional up-regulation of effector genes is a key feature of pathogenesis and effectors are often encoded in genomic regions with distinct repeat content, histone code and rate of evolution. In the tomato pathogen Fusarium oxysporum f. sp. lycopersici (Fol), effector genes reside on one of four accessory chromosomes, known as the 'pathogenicity' chromosome, which can be exchanged between strains through horizontal transfer. The three other accessory chromosomes in the Fol reference strain may also be important for virulence towards tomato. Expression of effector genes in Fol is highly up-regulated upon infection and requires Sge1, a transcription factor encoded on the core genome. Interestingly, the pathogenicity chromosome itself contains 13 predicted transcription factor genes and for all except one, there is a homolog on the core genome. We determined DNA binding specificity for nine transcription factors using oligonucleotide arrays. The binding sites for homologous transcription factors were highly similar, suggesting that extensive neofunctionalization of DNA binding specificity has not occurred. Several DNA binding sites are enriched on accessory chromosomes, and expression of FTF1, its core homolog FTF2 and SGE1 from a constitutive promoter can induce expression of effector genes. The DNA binding sites of only these three transcription factors are enriched among genes up-regulated during infection. We further show that Ftf1, Ftf2 and Sge1 can activate transcription from their binding sites in yeast. RNAseq analysis revealed that in strains with constitutive expression of FTF1, FTF2 or SGE1, expression of a similar set of plant-responsive genes on the pathogenicity chromosome is induced, including most effector genes. We conclude that the Fol pathogenicity chromosome may be partially transcriptionally autonomous, but there are also extensive transcriptional connections between core and accessory chromosomes.
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http://dx.doi.org/10.1371/journal.pgen.1006401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5140021PMC
November 2016

Adipose tissue remodeling in late-lactation dairy cows during feed-restriction-induced negative energy balance.

J Dairy Sci 2016 Dec 5;99(12):10009-10021. Epub 2016 Oct 5.

Department of Animal Science, Michigan State University, East Lansing 48824.

Excessive rates of demand lipolysis in the adipose tissue (AT) during periods of negative energy balance (NEB) are associated with increased susceptibility to disease and limited lactation performance. Lipolysis induces a remodeling process within AT that is characterized by an inflammatory response, cellular proliferation, and changes in the extracellular matrix (ECMT). The adipose tissue macrophage (ATM) is a key component of the inflammatory response. Infiltration of ATM-forming cellular aggregates was demonstrated in transition cows, suggesting that ATM trafficking and phenotype changes may be associated with disease. However, it is currently unknown if ATM infiltration occurs in dairy cows only during NEB states related to the transition period or also during NEB-induced lipolysis at other stages of lactation. The objective of this study was to evaluate changes in ATM trafficking and inflammatory phenotypes, and the expression of genetic markers of AT remodeling in healthy late-lactation cows during feed restriction-induced NEB. After a 14-d (d -14 to d -1) preliminary period, Holstein cows were randomly assigned to 1 of 2 feeding protocols, ad libitum (AL) or feed restriction (FR), for 4 d (d 1-4). Caloric intake was reduced in FR to achieve a targeted energy balance of -15 Mcal/d of net energy for lactation. Omental and subcutaneous AT samples were collected laparoscopically to harvest stromal vascular fraction (SVF) cells on d -3 and 4. The FR induced a NEB of -14.1±0.62 Mcal/d of net energy for lactation, whereas AL cows remained in positive energy balance (3.2±0.66 Mcal/d of NE). The FR triggered a lipolytic response reflected in increased plasma nonesterified fatty acids (0.65±0.05 mEq/L on d 4), enhanced phosphorylation of hormone sensitive lipase, and reduced adipocyte diameter. Flow cytometry and immunohistochemistry analysis revealed that on d 4, FR cows had increased numbers of CD172a, an ATM (M1 and M2) surface marker, cells in SVF that were localized in aggregates. However, FR did not alter the number of SVF cells expressing M1 markers (CD14 and CD11c) or M2 markers (CD11b and CD163). This finding contrasts with the predominately M1 phenotype observed previously in ATM from clinically diseased cows. No changes were observed in the expression of ECMT-related or cell proliferation markers. In summary, an acute 4-d lipolytic stimulus in late-lactation dairy cows led to ATM infiltration with minimal changes in inflammatory phenotype and no changes in ECMT. These results underscore that physiological changes related to parturition, the onset of lactation, extended periods of lipolysis, or a combination of these can induce intense AT remodeling with enhanced ATM inflammatory phenotype expression that may impair the metabolic function of AT in transition dairy cattle.
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http://dx.doi.org/10.3168/jds.2016-11552DOI Listing
December 2016

Effector profiles distinguish formae speciales of Fusarium oxysporum.

Environ Microbiol 2016 11 29;18(11):4087-4102. Epub 2016 Jul 29.

Molecular Plant Pathology, Swammerdam Institute for Life Sciences, University of Amsterdam, The Netherlands.

Formae speciales (ff.spp.) of the fungus Fusarium oxysporum are often polyphyletic within the species complex, making it impossible to identify them on the basis of conserved genes. However, sequences that determine host-specific pathogenicity may be expected to be similar between strains within the same forma specialis. Whole genome sequencing was performed on strains from five different ff.spp. (cucumerinum, niveum, melonis, radicis-cucumerinum and lycopersici). In each genome, genes for putative effectors were identified based on small size, secretion signal, and vicinity to a "miniature impala" transposable element. The candidate effector genes of all genomes were collected and the presence/absence patterns in each individual genome were clustered. Members of the same forma specialis turned out to group together, with cucurbit-infecting strains forming a supercluster separate from other ff.spp. Moreover, strains from different clonal lineages within the same forma specialis harbour identical effector gene sequences, supporting horizontal transfer of genetic material. These data offer new insight into the genetic basis of host specificity in the F. oxysporum species complex and show that (putative) effectors can be used to predict host specificity in F. oxysporum.
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http://dx.doi.org/10.1111/1462-2920.13445DOI Listing
November 2016

Dispensable chromosomes in Fusarium oxysporum f. sp. lycopersici.

Mol Plant Pathol 2016 12 21;17(9):1455-1466. Epub 2016 Aug 21.

Molecular Plant Pathology, University of Amsterdam, Amsterdam, 1098 XH, the Netherlands.

The genomes of many filamentous fungi consist of a 'core' part containing conserved genes essential for normal development as well as conditionally dispensable (CD) or lineage-specific (LS) chromosomes. In the plant-pathogenic fungus Fusarium oxysporum f. sp. lycopersici, one LS chromosome harbours effector genes that contribute to pathogenicity. We employed flow cytometry to select for events of spontaneous (partial) loss of either the two smallest LS chromosomes or two different core chromosomes. We determined the rate of spontaneous loss of the 'effector' LS chromosome in vitro at around 1 in 35 000 spores. In addition, a viable strain was obtained lacking chromosome 12, which is considered to be a part of the core genome. We also isolated strains carrying approximately 1-Mb deletions in the LS chromosomes and in the dispensable core chromosome. The large core chromosome 1 was never observed to sustain deletions over 200 kb. Whole-genome sequencing revealed that some of the sites at which the deletions occurred were the same in several independent strains obtained for the two chromosomes tested, indicating the existence of deletion hotspots. For the core chromosome, this deletion hotspot was the site of insertion of the marker used to select for loss events. Loss of the core chromosome did not affect pathogenicity, whereas loss of the effector chromosome led to a complete loss of pathogenicity.
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http://dx.doi.org/10.1111/mpp.12440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6638487PMC
December 2016

Bidirectional electromagnetic control of the hypothalamus regulates feeding and metabolism.

Nature 2016 Mar 23;531(7596):647-50. Epub 2016 Mar 23.

Laboratory of Molecular Genetics, Rockefeller University, New York, New York 10065, USA.

Targeted, temporally regulated neural modulation is invaluable in determining the physiological roles of specific neural populations or circuits. Here we describe a system for non-invasive, temporal activation or inhibition of neuronal activity in vivo and its use to study central nervous system control of glucose homeostasis and feeding in mice. We are able to induce neuronal activation remotely using radio waves or magnetic fields via Cre-dependent expression of a GFP-tagged ferritin fusion protein tethered to the cation-conducting transient receptor potential vanilloid 1 (TRPV1) by a camelid anti-GFP antibody (anti-GFP-TRPV1). Neuronal inhibition via the same stimuli is achieved by mutating the TRPV1 pore, rendering the channel chloride-permeable. These constructs were targeted to glucose-sensing neurons in the ventromedial hypothalamus in glucokinase-Cre mice, which express Cre in glucose-sensing neurons. Acute activation of glucose-sensing neurons in this region increases plasma glucose and glucagon, lowers insulin levels and stimulates feeding, while inhibition reduces blood glucose, raises insulin levels and suppresses feeding. These results suggest that pancreatic hormones function as an effector mechanism of central nervous system circuits controlling blood glucose and behaviour. The method we employ obviates the need for permanent implants and could potentially be applied to study other neural processes or used to regulate other, even dispersed, cell types.
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http://dx.doi.org/10.1038/nature17183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4894494PMC
March 2016

Endoscopic vs Open Decompression of the Ulnar Nerve in Cubital Tunnel Syndrome: A Prospective Randomized Double-Blind Study.

Neurosurgery 2015 Dec;77(6):960-70; discussion 970-1

Departments of *Neurosurgery and ‡Neurology, Ernst Moritz Arndt University, Greifswald, Germany.

Background: Prospective randomized data for comparison of endoscopic and open decompression methods are lacking.

Objective: To compare the long- and short-term results of endoscopic and open decompression in cubital tunnel syndrome.

Methods: In a prospective randomized double-blind study, 54 patients underwent ulnar nerve decompression for 56 cubital tunnel syndromes from October 2008 to April 2011. All patients presented with typical clinical and neurophysiological findings and underwent preoperative nerve ultrasonography. They were randomized for either endoscopic (n = 29) or open (n = 27) surgery. Both patients and the physician performing the follow-up examinations were blinded. The follow-up took place 3, 6, 12, and 24 months postoperatively. The severity of symptoms was measured by McGowan and Dellon Score, and the clinical outcome by modified Bishop Score. Additionally, the neurophysiological data were evaluated.

Results: No differences were found regarding clinical or neurophysiological outcome in both early and late follow-up between both groups. Hematomas were more frequent after endoscopic decompression (P = .05). The most frequent constrictions were found at the flexor carpi ulnaris (FCU) arch and the retrocondylar retinaculum. We found no compressing structures more than 4 cm distal from the sulcus in the endoscopic group. The outcome was classified as "good" or "excellent" in 46 out of 56 patients (82.1%). Eight patients did not improve sufficiently or had a relapse and underwent a second surgery.

Conclusion: The endoscopic technique showed no additional benefits to open surgery. We could not detect relevant compressions distal to the FCU arch. Therefore, an extensive far distal endoscopic decompression is not routinely required. The open decompression remains the procedure of choice at our institution.

Abbreviation: Dig, digitFCU, flexor carpi ulnarisNAS, numeric analog scale.
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http://dx.doi.org/10.1227/NEU.0000000000000981DOI Listing
December 2015