Technetium counting in rheumatoid arthritis evaluation in the small joints of the hand

An apparatus is described for external directional technetium counting of the proximal interphalangeal joints of the hand. In 11 normal and 14 rheumatoid subjects a significantly higher count rate was reached in the rheumatoid group (t = 3.79 P < 0.005). There was a good correlation between the rate of uptake and total count rate of technetium over an inflamed joint and this was taken to demonstrate the importance of the effect of vascularity on technetium kinetics. Clinical improvement following gold and penicillamine therapy was reflected in a fall in count rates which closely paralleled a reduction in ring sizes.     

The NHS England 100,000 Genomes Project: feasibility and utility of centralised genome sequencing for children with cancer

Background Whole-genome sequencing (WGS) of cancers is becoming an accepted component of oncological care, and NHS England is currently rolling out WGS for all children with cancer. This approach was piloted during the 100,000 genomes (100 K) project. Here we share the experience of the East of England Genomic Medicine Centre (East-GMC), reporting the feasibility and clinical utility of centralised WGS for individual children locally.Methods Non-consecutive children with solid tumours were recruited into the pilot 100 K project at our Genomic Medicine Centre. Variant catalogues were returned for local scrutiny and appraisal at dedicated genomic tumour advisory boards with an emphasis on a detailed exploration of potential clinical value.Results Thirty-six children, representing one-sixth of the national 100 K cohort, were recruited through our Genomic Medicine Centre. The diagnoses encompassed 23 different solid tumour types and WGS provided clinical utility, beyond standard-of-care assays, by refining (2/36) or changing (4/36) diagnoses, providing prognostic information (8/36), defining pathogenic germline mutations (1/36) or revealing novel therapeutic opportunities (8/36).Conclusion Our findings demonstrate the feasibility and clinical value of centralised WGS for children with cancer. WGS offered additional clinical value, especially in diagnostic terms. However, our experience highlights the need for local expertise in scrutinising and clinically interpreting centrally derived variant calls for individual children.Subject terms: Cancer genomics, Cancer genomics     

Structure and function of delta-atracotoxins: lethal neurotoxins targeting the voltage-gated sodium channel.

Delta-atracotoxins (delta-ACTX), isolated from the venom of Australian funnel-web spiders, are responsible for the potentially lethal envenomation syndrome seen following funnel-web spider envenomation. They are 42-residue polypeptides with four disulfides and an "inhibitor cystine-knot" motif with structural but not sequence homology to a variety of other spider and marine snail toxins. Delta-atracotoxins induce spontaneous repetitive firing and prolongation of action potentials resulting in neurotransmitter release from somatic and autonomic nerve endings. This results from a slowing of voltage-gated sodium channel inactivation and a hyperpolarizing shift of the voltage-dependence of activation. This action is due to voltage-dependent binding to neurotoxin receptor site-3 in a similar, but not identical, fashion to scorpion alpha-toxins and sea anemone toxins. Unlike other site-3 neurotoxins, however, delta-ACTX bind with high affinity to both cockroach and mammalian sodium channels but low affinity to locust sodium channels. At present the pharmacophore of delta-ACTX is unknown but is believed to involve a number of basic residues distributed in a topologically similar manner to scorpion alpha-toxins and sea anemone toxins despite distinctly different protein scaffolds. As such, delta-ACTX provide us with specific tools with which to study sodium channel structure and function and determinants for phyla- and tissue-specific actions of neurotoxins interacting with site-3.     

L-454,560, a potent and selective PDE4 inhibitor with in vivo efficacy in animal models of asthma and cognition

Type 4 phosphodiesterases (PDE4) inhibitors are emerging therapeutics in the treatment of a number of chronic disorders including asthma, chronic obstructive pulmonary disease (COPD) and cognitive disorders. This study delineates the preclinical profile of L-454,560, which is a potent, competitive and preferential inhibitor of PDE4A, 4B, and 4D with IC50 values of 1.6, 0.5 and 1.2 nM, respectively. In contrast to the exclusive binding of cilomilast and the preferential binding of roflumilast to the PDE4 holoenzyme state (Mg2+-bound form), L-454,560 binds to both the apo-(Mg2+-free) and holoenzyme states of PDE4. The intrinsic enzyme potency for PDE4 inhibition by L-454,560 also results in an effective blockade of LPS-induced TNFalpha formation in whole blood (IC50 = 161 nM) and is comparable to the human whole blood potency of roflumilast. The cytokine profile of inhibition of L-454,560 is mainly a Th1 profile with significant inhibition of IFNgamma and no detectable inhibition of IL-13 formation up to 1 microM. L-454,560 was also found to be efficacious in two models of airway hyper-reactivity, the ovalbumin (OVA) sensitized and challenged guinea pig and the ascaris sensitized sheep model. Furthermore, L-454560 was also effective in improving performance in the delayed matching to position (DMTP) version of the Morris watermaze, at a dose removed from that associated with potential emesis. Therefore, L-454,560 is a novel PDE4 inhibitor with an overall in vivo efficacy profile at least comparable to roflumilast and clearly superior to cilomilast.     

The clinical relevance of ultra-widefield angiography findings in patients with central retinal vein occlusion and macular oedema receiving anti-VEGF therapy

AimsTo report, using ultra-widefield angiography (UWFA) the area, distribution, and change in retinal capillary nonperfusion (RCNP) at baseline and 100 weeks in eyes with central retinal vein occlusion (CRVO) receiving anti-VEGF for macula oedema.MethodsProspective longitudinal multi-centre cohort study. Adults with CRVO treated with anti-VEGF therapy for macular oedema underwent UWFA at baseline and week-100. The area, distribution, and change in total, peripheral and posterior pole RCNP were determined.ResultsOf 153 eyes at baseline, mean area of RCNP was 34.3DA and 12 (7.8%) had ≥75DA RCNP. More than 10DA RCNP was present in the temporal periphery in 75.8% of eyes vs. 10.5% in the nasal periphery. At week-100, mean RCNP was 42.1DA with a median change from baseline of 3.3DA 95% CI [0.4, 7.3]; p < 0.01. Of 146 eyes with ≤10DA of posterior pole RCNP at baseline, 16/146 (11.0%) progressed to >10DA at week-100. These eyes had a median increase in total RCNP of 69.7DA [95% CI 27.2–85.4] vs 0DA [0.0–1.4]; p < 0.001 for those who did not, and two developed neovascular glaucoma. Larger baseline area of RCNP and history of glaucoma were risk factors for posterior pole RCNP developing.ConclusionsWith UWFA, significant baseline RCNP was identified in the majority of CRVO patients, notably in the temporal periphery, but large increases over 100 weeks were uncommon. Development of >10DA posterior pole RCNP is a marker for widespread RCNP and in such cases the risk of anterior segment neovascularisation is not abolished by concomitant anti-VEGF therapy.Subject terms: Retinal diseases, Vision disorders