Formalin injection causes a coordinated spinal cord CO/NO-cGMP signaling system response

BACKGROUND: The CO/NO-cGMP signalling system participates in the regulation of many physiological processes. The roles this system plays in spinal cord nociceptive signalling are particularly important. While individual components have been examined in isolation, little study has been dedicated to understanding the regulation and functioning of the system as a whole. RESULTS: In these studies we examined the time course of expression of 13 genes coding for components of this system including isoforms of the heme oxygenase (HO), nitric oxide synthase (NOS), soluble guanylate cyclase (sGC), cGMP dependent protein kinase (PKG) and phosphodiesterase (PDE) enzyme systems. Of the 13 genes studied, 11 had spinal cord mRNA levels elevated at one or more time points up to 48 hours after hindpaw formalin injection. Of the 11 with elevated mRNA, 8 had elevated protein levels 48 hours after formalin injection when mechanical allodynia was maximal. No component had an increased protein level which did not have an increased mRNA level at one or more time points. Injection of morphine 10 mg/kg prior to formalin completely abolished the acute nociceptive behaviours, but did not alter the degree of sensitivity which developed in the formalin treated hind paws during the subsequent 48 hours. Morphine treatment did, however, eliminate formalin induced increases in enzyme protein levels. CONCLUSION: Our results indicate that the expression of the components of the CO/NO-cGMP signalling system seems to be coordinated in such a way that a generalized multi-level enhancement rather than a tightly limited step specific response occurs with noxious stimulation. Furthermore, the analgesic morphine administered prior to noxious stimulation can prevent long-term changes in gene expression though not necessarily nociceptive sensitisation

Treatment prescribing patterns in patients with juvenile idiopathic arthritis (JIA): Analysis from the UK Childhood Arthritis Prospective Study (CAPS)

OBJECTIVE: Initial treatment of juvenile idiopathic arthritis (JIA) is largely based on the extent of joint involvement, disease severity and ILAR category. The licensing of biologic therapies for JIA has expanded treatment options. The aims of the study are (1) to describe treatment prescribing patterns in JIA over the first 3 years following first presentation to paediatric rheumatology and (2) to determine whether patterns of treatment have changed as biologics have become more widely available. METHODS: Children with at least 3 years of follow-up within the Childhood Arthritis Prospective Study (CAPS) were included. For analysis, children were placed into one of five groups according to their initial presentation to paediatric rheumatology: oligoarthritis (oJIA), polyarthritis (pJIA), systemic (sJIA), enthesitis-related arthritis (ERA) and psoriatic arthritis (PsA). Treatment patterns over 3 years were described. RESULTS: Of 1051 children, 58% received synthetic disease-modifying anti-rheumatic drugs (sDMARD) and 20% received biologics over the 3 years. Use of sDMARDs and biologics was higher in more severe disease presentations (sJIA and pJIA); however, 35% and 10% who presented with oJIA were also treated with sDMARDs and biologics, respectively. The number of children receiving sDMARD after 2006 was higher (p = 0.02); however, there was no difference in biologic prescribing before and after 2006 (p = 0.4). CONCLUSIONS: A high proportion of children presenting with JIA received sDMARDs plus/minus biologics during 3 years of follow-up. This was most common for patients with severe JIA but was also prescribed for patients with oligoarticular disease, despite the lack of evidence for effectiveness in this category

Red supergiants as cosmic abundance probes: The first direct metallicity determination of NGC 4038 in the antennae.

We present a direct determination of the stellar metallicity in the close pair galaxy NGC 4038 (D= 20 Mpc) based on the quantitative analysis of moderate resolution KMOS/VLT spectra of three super star clusters (SSCs). The method adopted in our analysis has been developed and optimised to measure accurate metallicities from atomic lines in the J-band of single red supergiant (RSG) or RSG-dominated star clusters. Hence, our metallicity measurements are not a_ected by the biases and poorly understood systematics inherent to strong line H II methods which are routinely applied to massive data sets of galaxies. We _nd [Z]= +0.07 _ 0.03 and compare our measurements to H II strong line calibrations. Our abundances and literature data suggest the presence of a at metallicity gradient, which can be explained as redistribution of metal-rich gas following the strong interaction

Therapeutic vulnerability to PARP1,2 inhibition in RB1-mutant osteosarcoma

Loss-of-function mutations in the RB1 tumour suppressor are key drivers in cancer, including osteosarcoma. RB1 loss-of-function compromises genome-maintenance and hence could yield vulnerability to therapeutics targeting such processes. Here we demonstrate selective hypersensitivity to clinically-approved inhibitors of Poly-ADP-Polymerase1,2 inhibitors (PARPi) in RB1-defective cancer cells, including an extended panel of osteosarcoma-derived lines. PARPi treatment results in extensive cell death in RB1-defective backgrounds and prolongs survival of mice carrying human RB1-defective osteosarcoma grafts. PARPi sensitivity is not associated with canonical homologous recombination defect (HRd) signatures that predict PARPi sensitivity in cancers with BRCA1,2 loss, but is accompanied by rapid activation of DNA replication checkpoint signalling, and active DNA replication is a prerequisite for sensitivity. Importantly, sensitivity in backgrounds with natural or engineered RB1 loss surpasses that seen in BRCA-mutated backgrounds where PARPi have established clinical benefit. Our work provides evidence that PARPi sensitivity extends beyond cancers identifiable by HRd and advocates PARP1,2 inhibition as a personalised strategy for RB1-mutated osteosarcoma and other cancers

Physical properties of the first spectroscopically confirmed red supergiant stars in the Sculptor Group galaxy NGC 55

We present K-band Multi-Object Spectrograph (KMOS) observations of 18 red supergiant (RSG) stars in the Sculptor Group galaxy NGC 55. Radial velocities are calculated and are shown to be in good agreement with previous estimates, confirming the supergiant nature of the targets and providing the first spectroscopically confirmed RSGs in NGC 55. Stellar parameters are estimated for 14 targets using the J-band analysis technique, making use of state-of-the-art stellar model atmospheres. The metallicities estimated confirm the low-metallicity nature of NGC 55, in good agreement with previous studies. This study provides an independent estimate of the metallicity gradient of NGC 55, in excellent agreement with recent results published using hot massive stars. In addition, we calculate luminosities of our targets and compare their distribution of effective temperatures and luminosities to that of other RSGs, in different environments, estimated using the same technique

Persistence of clinically relevant levels of SARS-CoV2 envelope gene subgenomic RNAs in non-immunocompromised individuals

This is the final version. Available on open access from Elsevier via the DOI in this recordOBJECTIVES: This study aimed to evaluate the associations between COVID-19 severity and active viral load, and to characterize the dynamics of active SARS-CoV-2 clearance in a series of archival samples taken from patients in the first wave of COVID-19 infection in the South West of the UK. METHODS: Subgenomic RNA (sgRNA) and E-gene genomic sequences were measured in a retrospective collection of PCR-confirmed SARS-CoV-2-positive samples from 176 individuals, and related to disease severity. Viral clearance dynamics were then assessed in relation to symptom onset and last positive test. RESULTS: Whilst E-gene sgRNAs declined before E-gene genomic sequences, some individuals retained sgRNA positivity for up to 68 days. 13% of sgRNA-positive cases still exhibited clinically relevant levels of virus after 10 days, with no clinical features previously associated with prolonged viral clearance times. CONCLUSIONS: Our results suggest that potentially active virus can sometimes persist beyond a 10-day period, and could pose a potential risk of onward transmission. Where this would pose a serious public health threat, additional mitigation strategies may be necessary to reduce the risk of secondary cases in vulnerable settings.National Institute for Health Research (NIHR

Eta Carinae and the Luminous Blue Variables

We evaluate the place of Eta Carinae amongst the class of luminous blue variables (LBVs) and show that the LBV phenomenon is not restricted to extremely luminous objects like Eta Car, but extends luminosities as low as log(L/Lsun) = 5.4 - corresponding to initial masses ~25 Msun, and final masses as low as ~10-15 Msun. We present a census of S Doradus variability, and discuss basic LBV properties, their mass-loss behaviour, and whether at maximum light they form pseudo-photospheres. We argue that those objects that exhibit giant Eta Car-type eruptions are most likely related to the more common type of S Doradus variability. Alternative atmospheric models as well as sub-photospheric models for the instability are presented, but the true nature of the LBV phenomenon remains as yet elusive. We end with a discussion on the evolutionary status of LBVs - highlighting recent indications that some LBVs may be in a direct pre-supernova state, in contradiction to the standard paradigm for massive star evolution.Comment: 27 pages, 6 figures, Review Chapter in "Eta Carinae and the supernova imposters" (eds R. Humphreys and K. Davidson) new version submitted to Springe