Mathematical Model of Plasmid-Mediated Resistance to Ceftiofur in Commensal Enteric Escherichia coli of Cattle

Antimicrobial use in food animals may contribute to antimicrobial resistance in bacteria of animals and humans. Commensal bacteria of animal intestine may serve as a reservoir of resistance-genes. To understand the dynamics of plasmid-mediated resistance to cephalosporin ceftiofur in enteric commensals of cattle, we developed a deterministic mathematical model of the dynamics of ceftiofur-sensitive and resistant commensal enteric Escherichia coli (E. coli) in the absence of and during parenteral therapy with ceftiofur. The most common treatment scenarios including those using a sustained-release drug formulation were simulated; the model outputs were in agreement with the available experimental data. The model indicated that a low but stable fraction of resistant enteric E. coli could persist in the absence of immediate ceftiofur pressure, being sustained by horizontal and vertical transfers of plasmids carrying resistance-genes, and ingestion of resistant E. coli. During parenteral therapy with ceftiofur, resistant enteric E. coli expanded in absolute number and relative frequency. This expansion was most influenced by parameters of antimicrobial action of ceftiofur against E. coli. After treatment (>5 weeks from start of therapy) the fraction of ceftiofur-resistant cells among enteric E. coli, similar to that in the absence of treatment, was most influenced by the parameters of ecology of enteric E. coli, such as the frequency of transfer of plasmids carrying resistance-genes, the rate of replacement of enteric E. coli by ingested E. coli, and the frequency of ceftiofur resistance in the latter

The role of epigenetic dysregulation in the epidemic of allergic disease

The epidemic of allergic disease in early life is one of the clearest indicators that the developing immune system is vulnerable to modern environmental changes. A range of environmental exposures epidemiologically associated with allergic disease have been shown to have effects on the foetal immune function in pregnancy, including microbial burden, dietary changes and environmental pollutants. Preliminary studies now suggest that these early effects on immune development may be mediated epigenetically through a variety of processes that collectively modify gene expression and allergic susceptibility and that these effects are potentially heritable across generations. It is also possible that rising rates of maternal allergy, a recognised direct risk factor for infant allergic disease, may be further amplifying the effects of environmental changes. Whilst effective prevention strategies are the ultimate goal in reversing the allergy epidemic, the specific environmental drivers, target genes, and intracellular pathways and mechanisms of early life immune programming are still unclear. It is hoped that identifying genes that are differentially regulated in association with subsequent allergic disease will assist in identifying causal pathways and upstream contributing environmental factors. In this way, epigenetic paradigms are likely to provide valuable insights into how the early environment can be modified to more favourably drive immune development and reverse the allergic epidemic

NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns

Purpose: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy. / Methods: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy. / Results: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism. / Conclusion: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic–atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants

Italian guidelines for primary headaches: 2012 revised version

The first edition of the Italian diagnostic and therapeutic guidelines for primary headaches in adults was published in J Headache Pain 2(Suppl. 1):105–190 (2001). Ten years later, the guideline committee of the Italian Society for the Study of Headaches (SISC) decided it was time to update therapeutic guidelines. A literature search was carried out on Medline database, and all articles on primary headache treatments in English, German, French and Italian published from February 2001 to December 2011 were taken into account. Only randomized controlled trials (RCT) and meta-analyses were analysed for each drug. If RCT were lacking, open studies and case series were also examined. According to the previous edition, four levels of recommendation were defined on the basis of levels of evidence, scientific strength of evidence and clinical effectiveness. Recommendations for symptomatic and prophylactic treatment of migraine and cluster headache were therefore revised with respect to previous 2001 guidelines and a section was dedicated to non-pharmacological treatment. This article reports a summary of the revised version published in extenso in an Italian version

Search for supersymmetry in final states with missing transverse energy and 0, 1, 2, or >= 3 b-quark jets in 7 TeV pp collisions using the variable alpha(T)

A search for supersymmetry in final states with jets and missing transverse energy is performed in pp collisions at a centre-of-mass energy of root s = 7 TeV. The data sample corresponds to an integrated luminosity of 4.98 fb(-1) collected by the CMS experiment at the LHC. In this search, a dimensionless kinematic variable, alpha(T), is used as the main discriminator between events with genuine and misreconstructed missing transverse energy. The search is performed in a signal region that is binned in the scalar sum of the transverse energy of jets and the number of jets identified as originating from a bottom quark. No excess of events over the standard model expectation is found. Exclusion limits are set in the parameter space of the constrained minimal supersymmetric extension of the standard model, and also in simplified models, with a special emphasis on compressed spectra and third-generation scenarios

Prevalence of spinal abnormalities in Chinook salmon smolt and influence of early rearing temperature and growth rates

"This is the peer reviewed version of the following article: Munday, J. S., et al. (2018). "Prevalence of spinal abnormalities in Chinook salmon smolt and influence of early rearing temperature and growth rates." Journal of Fish Diseases 41(7): 1111-1116, which has been published in final form at https://onlinelibrary.wiley.com/doi/full/10.1111/jfd.12804. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.Publishe

The neuromuscular transform of the lobster cardiac system explains the opposing effects of a neuromodulator on muscle output

Motor neuron activity is transformed into muscle movement through a cascade of complex molecular and biomechanical events. This nonlinear mapping of neural inputs to motor behaviors is called the neuromuscular transform (NMT). We examined the NMT in the cardiac system of the lobster Homarus americanus by stimulating a cardiac motor nerve with rhythmic bursts of action potentials and measuring muscle movements in response to different stimulation patterns. The NMT was similar across preparations, which suggested that it could be used to predict muscle movement from spontaneous neural activity in the intact heart. We assessed this possibility across semi-intact heart preparations in two separate analyses. First, we performed a linear regression analysis across 122 preparations in physiological saline to predict muscle movements from neural activity. Under these conditions, the NMT was predictive of contraction duty cycle but was unable to predict contraction amplitude, likely as a result of uncontrolled interanimal variability. Second, we assessed the ability of the NMT to predict changes in motor output induced by the neuropeptide C-type allatostatin. Wiwatpanit et al. (2012) showed that bath application of C-type allatostatin produced either increases or decreases in the amplitude of the lobster heart contractions. We show that an important component of these preparation-dependent effects can arise from quantifiable differences in the basal state of each preparation and the nonlinear form of the NMT. These results illustrate how properly characterizing the relationships between neural activity and measurable physiological outputs can provide insight into seemingly idiosyncratic effects of neuromodulators across individuals. © 2013 the authors