John Radcliffe Hospital

About: John Radcliffe Hospital is a healthcare organization based out in Oxford, Oxfordshire, United Kingdom. It is known for research contribution in the topics: Population & Antigen. The organization has 14491 authors who have published 23670 publications receiving 1459015 citations.

Quantitative interpretation of bioenergetic data from 31P and 1H magnetic resonance spectroscopic studies of skeletal muscle: an analytical review.

Abstract: In the study of skeletal muscle bioenergetics, 31P magnetic resonance spectroscopy (MRS) allows frequent measurement of the cytosolic pH and the concentrations of phosphocreatine, inorganic phosphate, and adenosine diphosphate (ADP) during exercise and recovery, which can be supplemented by 1H MRS (or biopsy) measurements of muscle lactate content and 13C MRS (or biopsy) measurements of muscle glycogen. We review the many methods now described by which 31P MRS measurements can be made to yield quantitative estimates of adenosine triphosphate (ATP) turnover, oxidative capacity, and proton handling in skeletal muscle. In particular, we describe how to estimate the rates of glycogenolytic and aerobic ATP synthesis during exercise and oxidative ATP synthesis and proton efflux during recovery from exercise and how to assess oxidative capacity using data from steady-state exercise, work jumps, or recovery. We discuss the metabolic relationships that make these methods possible and the assumptions (e.g., about cytosolic buffer capacity and mitochondrial control mechanisms) on which they depend. We show how these methods, although sometimes based on apparently conflicting metabolic models, can be analysed in a common framework. Finally, we discuss some examples of the current and potential applications of these methods in clinical and experimental studies of skeletal muscle.

The 'Digital Twin' to enable the vision of precision cardiology.

Abstract: Providing therapies tailored to each patient is the vision of precision medicine, enabled by the increasing ability to capture extensive data about individual patients. In this position paper, we argue that the second enabling pillar towards this vision is the increasing power of computers and algorithms to learn, reason, and build the 'digital twin' of a patient. Computational models are boosting the capacity to draw diagnosis and prognosis, and future treatments will be tailored not only to current health status and data, but also to an accurate projection of the pathways to restore health by model predictions. The early steps of the digital twin in the area of cardiovascular medicine are reviewed in this article, together with a discussion of the challenges and opportunities ahead. We emphasize the synergies between mechanistic and statistical models in accelerating cardiovascular research and enabling the vision of precision medicine.

Disease-relevant autoantibodies in first episode schizophrenia

Abstract: Dear Sirs, Schizophrenia is a common, heterogenous and complex disorder with unknown aetiology [1]. There is established evidence for N-methyl-d-aspartate receptor (NMDAR) hypofunction [2] as a central component of the functional dysconnectivity that is the most accepted model for symptoms [3], and increasing evidence for potassium channel dysfunction [4]. Moreover, autoimmune mechanisms have been proposed, perhaps in subgroups of patients [5, 6]. In the last few years, antibodies to neuronal cell surface antigens have been identified in cases of autoimmune encephalitis that respond to immunotherapy [7, 8]. Over two-thirds of patients with NMDAR antibody encephalitis, and some with potassium channel antibody-associated limbic encephalitis, have prominent psychiatric symptoms, or may present to psychiatric services in the first instance [7, 9, 10]. The psychiatric symptoms are those seen in schizophrenia including delusions, hallucinations, and catatonic movement disorder. There is good evidence for specificity and pathogenicity of these antibodies, with absence in large numbers of healthy individuals and those with other neurological diseases [9, 11, 12]. However, there have been no cases of NMDAR or potassium channel antibodies identified in patients with purely psychiatric disorders. We hypothesized that these antibodies would be present in a proportion of patients with early schizophrenia, in the absence of overt seizures, movement disorders, or other neurological signs. Serum was obtained prospectively from a cohort (n = 46) of patients at first presentation of psychosis to an epidemiologically principled early intervention for psychosis service (http://www.cameo.nhs.uk), which provides 3 years of treatment and follow up when possible. We retrospectively measured NMDAR antibodies using a cell based assay and subjective visual scoring system [9]. We identified antibodies to components of potassium channel complexes (VGKCs) by radioimmunoassay [8]. The sera were tested blind to diagnostic status. Patients with positive results were retrospectively interviewed and extensively investigated. Full clinical details are given in the Table and supplementary information. Patients 1 and 2 had NMDAR antibodies, [patient 1: score 2, (range 0–4, normal 0–0.5, Fig. 1); patient 2: score 1]. Patient 1 was unwell for 6 months before recovering; he was well and antibody negative at 3 years. Patient 2 has had a protracted course; antibodies remained repeatedly positive at 24–35 months follow up, but were then negative at 36 months. Patient 3 had VGKC antibodies (1,435 pM; normal <100), was unwell for 6 months before recovering, but has subsequently relapsed after 1 year and has now been lost to follow up. There were no clinical features to differentiate these cases from other cases of psychosis in Cameo (Table 1), even in retrospect, and the autoantibody positive cases fulfilled criteria for DSM-IV schizophrenia. No patient had physical neurological symptoms or signs. Fig. 1 HEK cells co-transfected with NR1, NR2B and EGFP cDNA or transfected with EGFP cDNA alone. Serum of patient 1 bound to the surface of unpermeabilised cells transfected with NMDARs, but not EGFP alone. Healthy controls (Control) showed no binding Table 1 Demographic and clinical data for antibody positive cases A further patient, patient 4, with first episode psychosis identified after the prospective cohort, had NMDAR antibodies (score 1.5). He was unwell for 4 months, partially responsive and then relapsing despite treatment with antipsychotics. To reduce the levels of NMDAR antibodies he received plasmapheresis and made a significant clinical improvement 3 weeks later, improving further with prednisolone. He remains clinically and functionally improved at 7 month follow up, on no antipsychotic medication. This is the first case description, to our knowledge, of a patient with NMDAR antibodies and a purely psychiatric presentation responding to immunotherapy. These preliminary data show that some patients with schizophrenia have potentially pathogenic autoantibodies to relevant membrane proteins. Three of the patients had NMDAR antibodies, which have been shown to reduce NMDAR clusters in vivo [12], which mirrors that seen in models of schizophrenia [13]. All of our antibody positive cases (6.5% of 46) fulfilled DSMIV criteria for schizophrenia and the patients were tested early in the course of their illness. None of the chronic schizophrenia controls in our large case series had NMDAR antibodies [9], but this could be because NMDAR and VGKC antibodies spontaneously drop with time ([14]; SRI, AV unpublished data); this suggests a critical early period of illness for detection and treatment. We did not measure antibody in CSF, and future prospective systematic studies of antibody in paired serum and CSF will be informative. The 46 patients in the Cameo cohort were given DSM-IV diagnoses a year after intake to the service. Of these, 63% had a diagnosis of schizophrenia. Other psychotic diagnoses were psychosis not otherwise specified (15%), bipolar affective disorder (13%), schizoaffective disorder (4%), major depression with psychosis (2%) and delusional disorder (2%). It is therefore possible that the proportion of cases with diagnoses of schizophrenia that have specific antibodies is higher than the proportion described here. However, there is significant diagnostic instability in patients with early psychosis, due to the threshold of chronicity required for a diagnosis of schizophrenia. There is also increasing evidence of shared heritability between the psychotic disorders and consequently a move away from the use of categorical diagnoses in those with psychotic disorders. There is a need for a systematic screen of available neuronal surface antigens in first episode psychosis and schizophrenia to characterise the true prevalence of these antibodies among different population groups, with implications for diagnosis, prognosis and treatment.

The decline in paediatric malaria admissions on the coast of Kenya

Abstract: Background There is only limited information on the health impact of expanded coverage of malaria control and preventative strategies in Africa.