Controlling Influence of Phosphocitrate In Vitro and In Vivo on Calcium Oxalate Crystal Formation and Growth

Calcium oxalate (CaOx) crystallization in the presence of phosphocitrate (PC) was studied by both in vitro and in vivo techniques. Crystals of the monohydrate (COM) and the dihydrate (COD) forms were generated under controlled conditions in a silica gel matrix. Our data indicated only COD crystals formed when PC was present, inferring that the COD to COM transformation was being impeded. COD crystals were smaller in size than controls and there was evidence of interpenetral twinning. An in vivo study using a rat bladder implant model noted similar findings. Scanning electron microscopy (SEM) revealed that implants recovered from PC treated rats had primarily COD crystals deposited, whereas both the surface and inner layers of encrusted implants from normal rats contained predominantly COM crystals. Infrared (IR) analysis confirmed the visual findings indicating quantitatively that there was a higher proportion of COD present on the implants recovered from the treated rats than in the controls. It is concluded that although total CaOx crystallization cannot be eliminated by PC, its action could assist in reducing the harmful nature of such crystallites in the urine

The Impact of Tumour pH on Cancer Progression; Strategies for Clinical Intervention

Dysregulation of cellular pH is frequent in solid tumours and provides potential opportunities for therapeutic intervention. The acidic microenvironment within a tumour can promote migration, invasion and metastasis of cancer cells through a variety of mechanisms. Pathways associated with the control of intracellular pH that are under consideration for intervention include carbonic anhydrase IX, the monocarboxylate transporters (MCT, MCT1 and MCT4), the vacuolar-type H(+)-ATPase proton pump, and the sodium-hydrogen exchanger 1. This review will describe progress in the development of inhibitors to these targets

Nest Carbon Dioxide Masks GABA-Dependent Seizure Susceptibility in the Naked Mole-Rat

African naked mole-rats were likely the first mammals to evolve eusociality, and thus required adaptations to conserve energy and tolerate the low oxygen (O-2) and high carbon dioxide (CO2) of a densely populated fossorial nest. As hypercapnia is known to suppress neuronal activity, we studied whether naked mole-rats might demonstrate energy savings in GABAergic inhibition. Using whole-colony behavioral monitoring of captive naked mole-rats, we found a durable nest, characterized by high CO2 levels, where all colony members spent the majority of their time. Analysis of the naked mole-rat genome revealed, uniquely among mammals, a histidine point variation in the neuronal potassium-chloride cotransporter 2 (KCC2). A histidine missense substitution mutation at this locus in the human ortholog of KCC2, found previously in patients with febrile seizures and epilepsy, has been demonstrated to diminish neuronal Cl- extrusion capacity, and thus impairs GABAergic inhibition. Seizures were observed, without pharmacological intervention, in adult naked mole-rats exposed to a simulated hyperthermic surface environment, causing systemic hypocapnic alkalosis. Consistent with the diminished function of KCC2, adult naked mole-rats demonstrate a reduced efficacy of inhibition that manifests as triggering of seizures at room temperature by the GABA(A) receptor (GABA(A)R) positive allosteric modulator diazepam. These seizures are blocked in the presence of nest-like levels of CO2 and likely to be mediated through GABA(A)R activity, based on in vitro recordings. Thus, altered GABAergic inhibition adds to a growing list of adaptations in the naked mole-rat and provides a plausible proximate mechanism for nesting behavior, where a return to the colony nest restores GABA-mediated inhibition.Peer reviewe

Hypofractionated Stereotactic Ablative Radiotherapy for Recurrent or Oligometastatic Tumours in Children and Young Adults

AIMS Cancer remains a leading cause of death in children and adolescents in the developed world. Despite advances in oncological management, rates of primary treatment failure remain significant. Radiation of recurrent or metastatic disease improves survival in adults but there is little data to support clinical decision making in the paediatric/teenage and young adult population. Materials And Methods We present a retrospective case series of 14 patients treated with stereotactic ablative body radiotherapy or stereotactic radiosurgery at The Royal Marsden Hospital from September 2011 to December 2015. Eligible patients were aged <25 years, with Lansky/Karnofsky performance status ≥60 with confirmed relapsed or metastatic tumour in fewer than three sites. Follow-up was in accordance with standard clinical care and included regular outpatient review and radiological surveillance. Local control, progression-free survival and overall survival are presented. RESULTS Data for 14 patients with 18 treated lesions were included. The median patient age was 15 years (range 5–20 years). Nine patients were treated for local recurrence and five for metastatic lesions. All patients had already undergone multiple previous treatments. Eleven patients had undergone previous radiotherapy. The median interval between the completion of initial radiotherapy and reirradiation was 29.0 months (range 0.2–49.5 months). The median follow-up was 3.4 years (range 0.28–6.4 years). The 1-year local control rate was 78.6% and the 2-year local control rate was 57.1%. Overall median survival was 58.4 months (95% confidence interval 33.8–82.9 months). Cumulative biologically effective doses (BED) over 200 Gy were associated with late toxicity (P = 0.04). CONCLUSION Radical doses of short-course hypofractionated radiotherapy can achieve excellent local control and may contribute to the prolongation of overall survival. There is a need for prospective trials exploring the use of ablative radiotherapy in metastatic disease in paediatric/teenage and young adult patients in order to establish safe and effective treatment schedules

Hearing the voices of older adult patients: processes and findings to inform health services research

Background Clinical academic research and service improvement is planned using Patient and Public Involvement and Engagement (PPIE) but older PPIE participants are consulted less often due to the perception that they are vulnerable or hard to engage. Objectives To consult frail older adults about a recently adopted service, discharge to assess (D2A), and to prioritise services improvements and research topics associated with the design and delivery of discharge from hospital. To use successive PPIE processes to enable a permanent PPIE panel to be established. Participants Following guidance from an established hospital PPI panel 27 older adult participants were recruited. Participants from Black, Asian and Minority Ethnic (BAME) communities, affluent and non-affluent areas and varied social circumstances were included. Methods Focus groups and individual interviews were conducted in participants own homes or nearby social venues. Results Priorities for discharge included remaining independent despite often feeling lonely at home; to remain in hospital if needed; and for services to ensure effective communication with families. The main research priority identified was facilitating independence, whilst establishing a permanent PPIE panel involving older adults was viewed favourably. Conclusions Taking a structured approach to PPIE enabled varied older peoples’ voices to express their priorities and concerns into early discharge from hospital, as well as enabling the development of health services research into hospital discharge planning and management. Older people as participants identified research priorities after reflecting on their experiences. Listening and reflection enabled researchers to develop a new “Community PPIE Elders Panel” to create an enduring PPIE infrastructure for frail older housebound people to engage in research design, development and dissemination

Comparative genomics shows differences in the electron transport and carbon metabolic pathways of Mycobacterium africanum relative to Mycobacterium tuberculosis and suggests an adaptation to low oxygen tension

YesThe geographically restricted Mycobacterium africanum lineages (MAF) are primarily found in West Africa, where they account for a significant proportion of tuberculosis. Despite this phenomenon, little is known about the co-evolution of these ancient lineages with West Africans. MAF and M. tuberculosis sensu stricto lineages (MTB) differ in their clinical, in vitro and in vivo characteristics for reasons not fully understood. Therefore, we compared genomes of 289 MAF and 205 MTB clinical isolates from the 6 main human-adapted M. tuberculosis complex lineages, for mutations in their Electron Transport Chain and Central Carbon Metabolic pathway in order to explain these metabolic differences. Furthermore, we determined, in silico, whether each mutation could affect the function of genes encoding enzymes in these pathways. We found more mutations with the potential to affect enzymes in these pathways in MAF lineages compared to MTB lineages. We also found that similar mutations occurred in these pathways between MAF and some MTB lineages. Generally, our findings show further differences between MAF and MTB lineages that may have contributed to the MAF clinical and growth phenotype and indicate potential adaptation of MAF lineages to a distinct ecological niche, which we suggest includes areas characterized by low oxygen tension.European Research CouncilINTERRUPTB starting grant nr. 311725 (to BdJ, FG, CM, LR, BO, MA) and The UK Medical Research Council and the European & Developing Countries Clinical Trials Partnership (EDCTP) Grant No. CB. 2007. 41700.007.Research Development Fund Publication Prize Award winner, January 2020

Balancing selection on MHC class I in wild brown trout Salmo trutta

Evidence is reported for balancing selection acting on variation at major histocompatibility complex (MHC) in wild populations of brown trout Salmo trutta. First, variation at an MHC class I (satr-uba)–linked microsatellite locus (mhc1) is retained in small S. trutta populations isolated above waterfalls although variation is lost at neutral microsatellite markers. Second, populations across several catchments are less differentiated at mhc1 than at neutral markers, as predicted by theory. The population structure of these fish was also elucidated.HEA PRTLI Cycle 3; Beaufort Marine Research Award: Fish population genetics. Irish Government NDP (2007-2014) administered by the Marine Institute; Inland Fisheries Ireland; Science Foundation Ireland (Microbial Phylogeography 05/FE1/B882)

Measurement of the cross-section and charge asymmetry of WW bosons produced in proton-proton collisions at s=8\sqrt{s}=8 TeV with the ATLAS detector

This paper presents measurements of the $W^+ \rightarrow \mu^+\nu$ and $W^- \rightarrow \mu^-\nu$ cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton--proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2~\mbox{fb^{-1}}. The precision of the cross-section measurements varies between 0.8% to 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them.Comment: 38 pages in total, author list starting page 22, 5 figures, 4 tables, submitted to EPJC. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2017-13