An oxygen-rich atmosphere or systemic fluoxetine extend the time to respiratory arrest in a rat model of obstructive apnea

© 2019 Elsevier Inc. Audiogenic seizure-prone mice can be protected from seizure-associated death by exposure to an oxygen atmosphere or treatment with selective serotonergic reuptake inhibitors (SSRIs). We have shown previously in a rat model that epileptic seizure activity can spread through brainstem areas to cause sufficient laryngospasm for obstructive apnea and that the period of seizure-associated obstructive apnea can last long enough for respiratory arrest to occur. We hypothesized that both the oxygen-rich atmosphere and SSRIs function by prolonging the time to respiratory arrest, thus ensuring that seizure activity stops before the point of respiratory arrest to allow recovery of respiratory function. To test this hypothesis, we evaluated each preventative treatment in a rat model of controlled airway occlusion where the times to respiratory arrest can be measured. Adult male Sprague Dawley rats (median age = 66 days) were studied in the absence of any seizure activity. By directly studying responses to controlled airway occlusion, rather than airway occlusion secondary to seizure activity, we could isolate the effects of manipulations that might prolong respiratory arrest from the effects of those manipulations on seizure intensity. All group sizes were ≥ 8 animals per group. We found that both oxygen exposure and fluoxetine significantly increased the time to respiratory arrest by up to 65% (p \u3c .0001 for 5 min oxygen exposure; p = .031 for 25 mg/kg fluoxetine tested 60 min after injection) and, given that neither treatment has been shown to significantly alter seizure duration, these increases can account for the protection of either manipulation against death in sudden death models. Importantly, we found that 30 s of exposure to oxygen produced nearly the same protection as 5 min exposure suggesting that oxygen exposure could start after a seizure starts (p = .0012 for 30 s oxygen exposure). Experiments with 50% oxygen/50% air mixtures indicate that the oxygen concentration needs to be above about 60% to ensure that times to respiratory arrest will always be longer than a period of seizure-induced airway occlusion. Selective serotonin reuptake inhibitors, while instructive with regard to mechanism, require impractical dosing and may carry additional risk in the form of greater challenges for resuscitation. We conclude that oxygen exposure or SSRI treatment prevent seizure associated death by sufficiently prolonging the time to respiratory arrest so that respiratory function can recover after the seizure abates and eliminates the stimulus for seizure-induced apnea

The low-lying excitations of polydiacetylene

The Pariser-Parr-Pople Hamiltonian is used to calculate and identify the nature of the low-lying vertical transition energies of polydiacetylene. The model is solved using the density matrix renormalisation group method for a fixed acetylenic geometry for chains of up to 102 atoms. The non-linear optical properties of polydiacetylene are considered, which are determined by the third-order susceptibility. The experimental 1Bu data of Giesa and Schultz are used as the geometric model for the calculation. For short chains, the calculated E(1Bu) agrees with the experimental value, within solvation effects (ca. 0.3 eV). The charge gap is used to characterise bound and unbound states. The nBu is above the charge gap and hence a continuum state; the 1Bu, 2Ag and mAg are not and hence are bound excitons. For large chain lengths, the nBu tends towards the charge gap as expected, strongly suggesting that the nBu is the conduction band edge. The conduction band edge for PDA is agreed in the literature to be ca. 3.0 eV. Accounting for the strong polarisation effects of the medium and polaron formation gives our calculated E(nBu) ca. 3.6 eV, with an exciton binding energy of ca. 1.0 eV. The 2Ag state is found to be above the 1Bu, which does not agree with relaxed transition experimental data. However, this could be resolved by including explicit lattice relaxation in the Pariser- Parr-Pople-Peierls model. Particle-hole separation data further suggest that the 1Bu, 2Ag and mAg are bound excitons, and that the nBu is an unbound exciton.Comment: LaTeX, 23 pages, 4 postscript tables and 8 postscript figure

Barley Ror1 encodes a class XI myosin required for mlo-based broad-spectrum resistance to the fungal powdery mildew pathogen

Loss-of-function alleles of plant MLO genes confer broad-spectrum resistance to powdery mildews in many eudicot and monocot species. Although barley (Hordeum vulgare) mlo mutants have been used in agriculture for more than 40 years, understanding of the molecular principles underlying this type of disease resistance remains fragmentary. Forward genetic screens in barley have revealed mutations in two Required for mlo resistance (Ror) genes that partially impair immunity conferred by mlo mutants. While Ror2 encodes a soluble N-ethylmaleimide-sensitive factor-attached protein receptor (SNARE), the identity of Ror1, located at the pericentromeric region of barley chromosome 1H, remained elusive. We report the identification of Ror1 based on combined barley genomic sequence information and transcriptomic data from ror1 mutant plants. Ror1 encodes the barley class XI myosin Myo11A (HORVU.MOREX.r3.1HG0046420). Single amino acid substitutions of this myosin, deduced from non-functional ror1 mutant alleles, map to the nucleotide-binding region and the interface between the relay-helix and the converter domain of the motor protein. Ror1 myosin accumulates transiently in the course of powdery mildew infection. Functional fluorophore-labeled Ror1 variants associate with mobile intracellular compartments that partially colocalize with peroxisomes. Single-cell expression of the Ror1 tail region causes a dominant-negative effect that phenocopies ror1 loss-of-function mutants. We define a myosin motor for the establishment of mlo-mediated resistance, suggesting that motor protein-driven intracellular transport processes are critical for extracellular immunity, possibly through the targeted transfer of antifungal and/or cell wall cargoes to pathogen contact sites

Therapeutic hypothermia for acute ischaemic stroke. Results of a European multicentre, randomised, phase III clinical trial

Introduction: We assessed whether modest systemic cooling started within 6 hours of symptom onset improves functional outcome at three months in awake patients with acute ischaemic stroke. Patients and methods: In this European randomised open-label clinical trial with blinded outcome assessment, adult patients with acute ischaemic stroke were randomised to cooling to a target body temperature of 34.0–35.0°C, started within 6 h after stroke onset and maintained for 12 or 24 h , versus standard treatment. The primary outcome was the score on the modified Rankin Scale at 91 days, as analysed with ordinal logistic regression. Results: The trial was stopped after inclusion of 98 of the originally intended 1500 patients because of slow recruitment and cessation of funding. Forty-nine patients were randomised to hypothermia versus 49 to standard treatment. Four patients were lost to follow-up. Of patients randomised to hypothermia, 15 (31%) achieved the predefined cooling targets. The primary outcome did not differ between the groups (odds ratio for good outcome, 1.01; 95% confidence interval, 0.48–2.13; p = 0.97). The number of patients with one or more serious adverse events did not differ between groups (relative risk, 1.22; 95% confidence interval, 0.65–1.94; p = 0.52). Discussion: In this trial, cooling to a target of 34.0–35.0°C and maintaining this for 12 or 24 h was not feasible in the majority of patients. The final sample was underpowered to detect clinically relevant differences in outcomes. Conclusion: Before new trials are launched, the feasibility of cooling needs to be improved

Comparative genomic analysis of the arthropod muscle myosin heavy chain genes allows ancestral gene reconstruction and reveals a new type of 'partially' processed pseudogene

<p>Abstract</p> <p>Background</p> <p>Alternative splicing of mutually exclusive exons is an important mechanism for increasing protein diversity in eukaryotes. The insect <it>Mhc </it>(myosin heavy chain) gene produces all different muscle myosins as a result of alternative splicing in contrast to most other organisms of the Metazoa lineage, that have a family of muscle genes with each gene coding for a protein specialized for a functional niche.</p> <p>Results</p> <p>The muscle myosin heavy chain genes of 22 species of the Arthropoda ranging from the waterflea to wasp and <it>Drosophila </it>have been annotated. The analysis of the gene structures allowed the reconstruction of an ancient muscle myosin heavy chain gene and showed that during evolution of the arthropods introns have mainly been lost in these genes although intron gain might have happened in a few cases. Surprisingly, the genome of <it>Aedes aegypti </it>contains another and that of <it>Culex pipiens quinquefasciatus </it>two further muscle myosin heavy chain genes, called <it>Mhc3 </it>and <it>Mhc4</it>, that contain only one variant of the corresponding alternative exons of the <it>Mhc1 </it>gene. <it>Mhc3 </it>transcription in <it>Aedes aegypti </it>is documented by EST data. <it>Mhc3 </it>and <it>Mhc4 </it>inserted in the <it>Aedes </it>and <it>Culex </it>genomes either by gene duplication followed by the loss of all but one variant of the alternative exons, or by incorporation of a transcript of which all other variants have been spliced out retaining the exon-intron structure. The second and more likely possibility represents a new type of a 'partially' processed pseudogene.</p> <p>Conclusion</p> <p>Based on the comparative genomic analysis of the alternatively spliced arthropod muscle myosin heavy chain genes we propose that the splicing process operates sequentially on the transcript. The process consists of the splicing of the mutually exclusive exons until one exon out of the cluster remains while retaining surrounding intronic sequence. In a second step splicing of introns takes place. A related mechanism could be responsible for the splicing of other genes containing mutually exclusive exons.</p

Improved survival in liver transplant recipients receiving prolonged-release tacrolimus in the European liver transplant registry

This study was a retrospective analysis of the European Liver Transplant Registry (ELTR) performed to compare long-term outcomes with prolonged-release tacrolimus versus tacrolimus BD in liver transplantation (January 2008-December 2012). Clinical efficacy measures included univariate and multivariate analyses of risk factors influencing graft and patient survival at 3 years posttransplant. Efficacy measures were repeated using propensity score-matching for baseline demographics. Patients with <1 month of follow-up were excluded from the analyses. In total, 4367 patients (prolonged-release tacrolimus: n = 528; BD: n = 3839) from 21 European centers were included. Tacrolimus BD treatment was significantly associated with inferior graft (risk ratio: 1.81; p = 0.001) and patient survival (risk ratio: 1.72; p = 0.004) in multivariate analyses. Similar analyses performed on the propensity score-matched patients confirmed the significant survival advantages observed in the prolonged-release tacrolimus- versus tacrolimus BD-treated group. This large retrospective analysis from the ELTR identified significant improvements in long-term graft and patient survival in patients treated with prolonged-release tacrolimus versus tacrolimus BD in primary liver transplant recipients over 3 years of treatment. However, as with any retrospective registry evaluation, there are a number of limitations that should be considered when interpreting these data

Granulocyte-colony stimulating factor (G-CSF) for stroke: an individual patient data meta-analysis

Granulocyte colony stimulating factor (G-CSF) may enhance recovery from stroke through neuroprotective mechanisms if administered early, or neurorepair if given later. Several small trials suggest administration is safe but effects on efficacy are unclear. We searched for randomised controlled trials (RCT) assessing G-CSF in patients with hyperacute, acute, subacute or chronic stroke, and asked Investigators to share individual patient data on baseline characteristics, stroke severity and type, end-of trial modified Rankin Scale (mRS), Barthel Index, haematological parameters, serious adverse events and death. Multiple variable analyses were adjusted for age, sex, baseline severity and time-to-treatment. Individual patient data were obtained for 6 of 10 RCTs comprising 196 stroke patients (116 G-CSF, 80 placebo), mean age 67.1 (SD 12.9), 92% ischaemic, median NIHSS 10 (IQR 5-15), randomised 11 days (interquartile range IQR 4-238) post ictus; data from three commercial trials were not shared. G-CSF did not improve mRS (ordinal regression), odds ratio OR 1.12 (95% confidence interval 0.64 to 1.96, p=0.62). There were more patients with a serious adverse event in the G-CSF group (29.6% versus 7.5%, p=0.07) with no significant difference in all-cause mortality (G-CSF 11.2%, placebo 7.6%, p=0.4). Overall, G-CSF did not improve stroke outcome in this individual patient data meta-analysis