Non-invasive molecular imaging of inflammatory macrophages in allograft rejection.

BackgroundMacrophages represent a critical cell type in host defense, development and homeostasis. The ability to image non-invasively pro-inflammatory macrophage infiltrate into a transplanted organ may provide an additional tool for the monitoring of the immune response of the recipient against the donor graft. We therefore decided to image in vivo sialoadhesin (Sn, Siglec 1 or CD169) using anti-Sn mAb (SER-4) directly radiolabelled with (99m)Tc pertechnetate.MethodsWe used a heterotopic heart transplantation model where allogeneic or syngeneic heart grafts were transplanted into the abdomen of recipients. In vivo nanosingle-photon emission computed tomography (SPECT/CT) imaging was performed 7 days post transplantation followed by biodistribution and histology.ResultsIn wild-type mice, the majority of (99m)Tc-SER-4 monoclonal antibody cleared from the blood with a half-life of 167 min and was located predominantly on Sn(+) tissues in the spleen, liver and bone marrow. The biodistribution in the transplantation experiments confirmed data derived from the non-invasive SPECT/CT images, with significantly higher levels of (99m)Tc-SER-4 observed in allogeneic grafts (9.4 (±2.7) %ID/g) compared to syngeneic grafts (4.3 (±10.3) %ID/g) (p = 0.0022) or in mice which received allogeneic grafts injected with (99m)Tc-IgG isotype control (5.9 (±0.6) %ID/g) (p = 0.0185). The transplanted heart to blood ratio was also significantly higher in recipients with allogeneic grafts receiving (99m)Tc-SER-4 as compared to recipients with syngeneic grafts (p = 0.000004) or recipients with allogeneic grafts receiving (99m)Tc-IgG isotype (p = 0.000002).ConclusionsHere, we demonstrate that imaging of Sn(+) macrophages in inflammation may provide an important additional and non-invasive tool for the monitoring of the pathophysiology of cellular immunity in a transplant model

Lifetime cigarette smoking and chronic widespread and regional pain in later adulthood: Evidence from the 1946 British birth cohort study

© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY. Published by BMJ. Objective To examine whether different lifetime patterns of cigarette smoking are associated with chronic widespread pain (CWP) and chronic regional pain (CRP) at age 68. Design Prospective cohort study. Setting England, Scotland and Wales. Participants Up to 2347 men and women from the Medical Research Council National Survey of Health and Development, who have been followed up since birth in 1946 and provided sufficient information on cigarette smoking across adulthood to be classified as never smoker, predominantly non-smoker, predominantly smoker or lifelong smoker and pain assessment at age 68. Primary outcome measures Pain was self-reported at age 68, and CWP was defined according to American College of Rheumatology criteria. Participants who reported having pain for ≥3 months but who did not meet the CWP definition were classified as having CRP; those who reported pain which had lasted for <3 months were classified as 'other' pain. No pain was the reference group. Results Findings from multinomial logistic regression models indicated that compared with never smokers, predominantly non-smokers, predominantly smokers and lifelong smokers all had an increased risk of CWP; relative risk ratios=1.70(95% CI 1.16 to 2.49); 2.10(95% CI 1.34 to 3.28) and 1.88(95% CI 0.99 to 3.57), respectively, after adjusting for sex, own occupational class, educational level, body mass index, leisure time physical activity, alcohol intake, long-standing illness and symptoms of anxiety and depression. No association was observed between smoking history and CRP or other pain. Conclusions These results suggest that exposure to cigarette smoking at any stage in adulthood was associated with higher risk of CWP in later adulthood; highlighting the ongoing importance of smoking prevention programmes. It also suggests that assessment of lifetime smoking behaviour may be more useful in identifying those at greater risk of CWP in later life than assessment of current smoking status

Longitudinal profiles of back pain across adulthood and their relationship with childhood factors: Evidence from the 1946 British birth cohort

Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain. This study aimed to (1) characterise long-term profiles of back pain across adulthood and (2) examine whether childhood risk factors were associated with these profiles, using data from 3271 participants in the Medical Research Council National Survey of Health and Development. A longitudinal latent class analysis was conducted on binary outcomes of back pain at ages 31, 36, 43, 53, 60 to 64, and 68 years. Multinomial logistic regression models were used to examine associations between selected childhood risk factors and class membership; adjusted for sex, adult body size, health status and behaviours, socioeconomic position, and family history of back pain. Four profiles of back pain were identified: no or occasional pain (57.7%), early-adulthood only (16.1%), mid-adulthood onset (16.9%), and persistent (9.4%). The "no or occasional" profile was treated as the referent category in subsequent analyses. After adjustment, taller height at age 7 years was associated with a higher likelihood of early-adulthood only (relative risk ratio per 1 SD increase in height = 1.31 [95% confidence interval: 1.05-1.65]) and persistent pain (relative risk ratio = 1.33 [95% confidence interval: 1.01-1.74]) in women (P for sex interaction = 0.01). Factors associated with an increased risk of persistent pain in both sexes were abdominal pain, poorest care in childhood, and poorer maternal health. Abdominal pain and poorest housing quality were also associated with an increased likelihood of mid-adulthood onset pain. These findings suggest that there are different long-term profiles of back pain, each of which is associated with different early life risk factors. This highlights the potential importance of early life interventions for the prevention and management of back pain

From fields to a super-cluster: the role of the environment at z=0.84 with HiZELS

At z=0, clusters are primarily populated by red, elliptical and massive galaxies, while blue, spiral and lower-mass galaxies are common in low-density environments. Understanding how and when these differences were established is of absolute importance for our understanding of galaxy formation and evolution, but results at high-z remain contradictory. By taking advantage of the widest and deepest H-alpha narrow-band survey at z=0.84 over the COSMOS and UKIDSS UDS fields, probing a wide range of densities (from poor fields to rich groups and clusters, including a confirmed super-cluster with a striking filamentary structure), we show that the fraction of star-forming galaxies falls continuously from ~40% in fields to approaching 0% in rich groups/clusters. We also find that the median SFR increases with environmental density, at least up to group densities - but only for low and medium mass galaxies, and thus such enhancement is mass-dependent at z~1. The environment also plays a role in setting the faint-end slope (alpha) of the H-alpha luminosity function. Our findings provide a sharper view on galaxy formation and evolution and reconcile previously contradictory results at z~1: stellar mass is the primary predictor of star formation activity, but the environment also plays a major role.Comment: 5 pages, 4 figures, to appear in the proceedings of JENAM 2010 S2: `Environment and the Formation of Galaxies: 30 years later', ASSP, Springe

Lifetime socioeconomic circumstances and chronic pain in later adulthood: Findings from a British birth cohort study

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ. Objectives To investigate associations between a range of different indicators of socioeconomic position (SEP: occupational class, education, household overcrowding and tenure, and experience of financial hardship) across life and chronic widespread and regional pain (CWP and CRP) at age 68. Design Prospective birth cohort; the Medical Research Council National Survey of Health and Development. Setting England, Scotland and Wales. Participants Up to 2378 men and women who have been followed-up since birth in 1946 to age 68. Primary outcome measures On the basis of their self-report of pain at age 68, participants were classified as: CWP (American College of Rheumatology criteria), CRP (pain of at least 3 months' duration but that does not meet the definition of CWP), other pain (<3 months in duration) or no pain. Results At age 68, the prevalence of CWP was 13.3% and 7.8% in women and men, respectively, and that of CRP was 32.3% and 28.7% in women and men, respectively. There was no clear evidence that indicators of SEP in childhood or later adulthood were associated with pain. Having experienced (vs not) financial hardship and being a tenant (vs owner-occupier) in earlier adulthood were both associated with an increased risk of CWP; for example, moderate hardship adjusted relative risk ratio (RRR adj) 2.32 (95% CI: 1.19 to 4.52) and most hardship RRR adj 4.44 (95% CI: 2.02 to 9.77). Accumulation of financial hardship across earlier and later adulthood was also associated with an increased risk of CWP. Conclusions Consideration of socioeconomic factors in earlier adulthood may be important when identifying targets for intervention to prevent CWP in later life

Tissue inflammation signatures point towards resolution in adhesive capsulitis

Proresolving receptors, macrophage and fibroblast activation point towards a resolving inflammatory milieu in adhesive capsulitis

Structure-activity relationships for analogs of the tuberculosis drug bedaquiline with the naphthalene unit replaced by bicyclic heterocycles

Replacing the naphthalene C-unit of the anti-tuberculosis drug bedaquiline with a range of bicyclic heterocycles of widely differing lipophilicity gave analogs with a 4.5-fold range in clogP values. The biological results for these compounds indicate on average a lower clogP limit of about 5.0 in this series for retention of potent inhibitory activity (MIC90s) against M.tb in culture. Some of the compounds also showed a significant reduction in inhibition of hERG channel potassium current compared with bedaquiline, but there was no common structural feature that distinguished these

Lightweighting design optimisation for additively manufactured mirrors

Design for additive manufacture (AM; 3D printing) is significantly different than design for subtractive machining. Although there are some limitations on the designs that can be printed, the increase in the AM design-space removes some of the existing challenges faced by the traditional lightweight mirror designs; for example, sandwich mirrors are just as easy to fabricate as open-back mirrors via AM, and they provide an improvement in structural rigidity. However, the ability to print a sandwich mirror as a single component does come with extra considerations; such as orientation upon the build plate and access to remove any temporary support material. This paper describes the iterations in optimisation applied to the lightweighting of a small, 84 mm diameter by 20 mm height, spherical concave mirror intended for CubeSat applications. The initial design, which was fabricated, is discussed in terms of the internal lightweighting design and the design constraints that were imposed by printing and post-processing. Iterations on the initial design are presented; these include the use of topology optimisation to minimise the total internal strain energy during mirror polishing and the use of lattices combined with thickness variation i.e. having a thicker lattice in strategic support locations. To assess the suitability of each design, finite element analysis is presented to quantify the print-through of the lightweighting upon the optical surface for a given mass reduction

Perforated mixed carcinoid-adenocarcinoma in transverse colon and at gastroenterostomy site: case report

Goblet cell carcinoid of the large intestine is a rare neoplasm, usually located in ascending colon and rectum. A 60-year-old male patient underwent surgery after the diagnosis of acute abdomen. Exploratory laparotomy revealed perforation with a diameter of 1 cm at the site of the previously performed gastroenterostomy and dilatation of the right colic flexure, secondary to a solid obstructive mass located in the mid-portion of transverse colon. Histopathological investigation of the biopsies, taken from the gastroenterostomy site and the tumor, revealed mixed carcinoid-adenocarcinoma with carcinoid component, predominantly composed of goblet cells. Three cycles of FOLFOX-4 protocol was administered. Following respiratory distress secondary to pulmonary metastasis, the patient's condition deteriorated and subsequently died in the fourth postoperative month. Our aim with this paper is to point out that more cases should be reported for more effective diagnosis, histopathological study, clinical investigation, treatment and prognosis of this specific neoplasm

7-Substituted 2-Nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines: Novel Antitubercular Agents Lead to a New Preclinical Candidate for Visceral Leishmaniasis.

Within a backup program for the clinical investigational agent pretomanid (PA-824), scaffold hopping from delamanid inspired the discovery of a novel class of potent antitubercular agents that unexpectedly possessed notable utility against the kinetoplastid disease visceral leishmaniasis (VL). Following the identification of delamanid analogue DNDI-VL-2098 as a VL preclinical candidate, this structurally related 7-substituted 2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazine class was further explored, seeking efficacious backup compounds with improved solubility and safety. Commencing with a biphenyl lead, bioisosteres formed by replacing one phenyl by pyridine or pyrimidine showed improved solubility and potency, whereas more hydrophilic side chains reduced VL activity. In a Leishmania donovani mouse model, two racemic phenylpyridines (71 and 93) were superior, with the former providing &gt;99% inhibition at 12.5 mg/kg (b.i.d., orally) in the Leishmania infantum hamster model. Overall, the 7R enantiomer of 71 (79) displayed more optimal efficacy, pharmacokinetics, and safety, leading to its selection as the preferred development candidate