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Objectives Men with SSc have a more severe clinical phenotype and reduced survival compared with women. No previous psychosocial studies have focused solely on men with SSc. This study aimed to explore experiences, coping strategies and support preferences of men with SSc. Material and methods An international qualitative research study comprising seven focus groups (three USA, four UK) of 25 men with SSc. Transcripts were analysed using reflexive thematic analysis. Results Three overarching themes and one underpinning theme were identified. In ‘impact of SSc on masculinity’, the men described an ‘impact on roles and activities’, reported ‘sex, intimacy, and erectile dysfunction’ as a salient issue that may be overlooked by clinicians, and experienced challenges to ‘masculine self-image’. ‘Dealing with SSc’ meant ‘always being prepared’, ‘becoming an expert’ and ‘balancing priorities’ in responsibilities, activities and symptom management. In ‘support for living with SSc’ men were selective in ‘(Not) talking about SSc’, would ‘(reluctantly) accept help’ and described ‘preferences for support’. Underpinning these experiences was ‘facing an uncertain future’ with some participants preferring not to focus on an unpredictable future, and others worrying about disease progression. Conclusion These novel data suggest SSc impacts male patients’ masculine identity and roles, and although they will accept practical help, they may mask the full emotional impact. Sex and intimacy are important overlooked issues with erectile dysfunction often not discussed at diagnosis. Further research should develop a self-management intervention for men with rheumatic diseases with a combination of disease-specific and common core components.

Acaeruloplasminemia is a rare autosomal recessive condition caused by inactivating mutations of the CP gene encoding caeruloplasmin (ferroxidase). Caeruloplasmin is a copper‐containing plasma ferroxidase enzyme with a key role in facilitating cellular iron efflux. We describe a case of a patient with acaeruloplasminemia, confirmed by genetic analysis, treated with combination therapy of monthly fresh‐frozen plasma (FFP) or Octaplas and iron chelation over a 3‐year period. This 19‐year‐old male was diagnosed at the age of 14 after developing issues with social interaction at school prompting investigation. Prior to this, he had been well with a normal childhood. He was found to have an iron deficient picture with a paradoxically high ferritin, with low serum copper and undetectable caeruloplasmin. Genetic testing identified a homozygous splicing mutation, c.(1713 + delG);(c.1713 + delG), in intron 9 of the caeruloplasmin gene. Ferriscan showed a high liver iron concentration of 5.3 mg/g dry tissue (0.17‐1.8). Brain and cardiac T2‐weighted magnetic resonance (MR) imaging did not detect iron deposition of the brain or heart respectively. Treatment with monthly Octaplas infusion was commenced alongside deferasirox (540 mg o.d.) in an attempt to increase caeruloplasmin levels and reduce iron overload, respectively. After 3 years of treatment, there was biochemical improvement with a reduction in ferritin from 1084 (12‐250) to 457 μg/L, ALT from 87 (

As we age, the nature of our sleep – in terms of architecture and duration – changes. But in addition, the accrual of morbidities throughout life frequently gives rise to an increasing pharmacological burden, with polypharmacy a commonly encountered situation. Many medications have an under-recognised impact on sleep, through their effects on neurotransmitter function and alteration of sleep architecture, although often, the mechanism whereby a drug causes a disruption of sleep/wakefulness is not fully understood. In many cases, a simple amendment to the dose regime may address the problem (eg changing the timing of doses), but in others an alternative should be sought. In any patient with a sleep complaint, the drug history – both for prescribed and non-prescribed medications – should be carefully examined. This chapter will briefly address drugs causing sleepiness, drugs causing insomnias, and medications used in the management of sleep disorders.

Clinical coding uses a classification system to assign standard codes to clinical terms and so facilitates good clinical practice through audit, service design and research. However, despite clinical coding being mandatory for inpatient activity, this is often not so for outpatient services, where most neurological care is delivered. Recent reports by the UK National Neurosciences Advisory Group and NHS England’s ‘Getting It Right First Time’ initiative recommend implementing outpatient coding. The UK currently has no standardised system for outpatient neurology diagnostic coding. However, most new attendances at general neurology clinics appear to be classifiable with a limited number of diagnostic terms. We present the rationale for diagnostic coding and its benefits, and the need for clinical engagement to develop a system that is pragmatic, quick and easy to use. We outline a scheme developed in the UK that could be used elsewhere.

© 2018 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health. Background: Diagnosis of attention deficit hyperactivity disorder (ADHD) relies on subjective methods which can lead to diagnostic uncertainty and delay. This trial evaluated the impact of providing a computerised test of attention and activity (QbTest) report on the speed and accuracy of diagnostic decision-making in children with suspected ADHD. Methods: Randomised, parallel, single-blind controlled trial in mental health and community paediatric clinics in England. Participants were 6–17years-old and referred for ADHD diagnostic assessment; all underwent assessment-as-usual, plus QbTest. Participants and their clinician were randomised to either receive the QbTest report immediately (QbOpen group) or the report was withheld (QbBlind group). The primary outcome was number of consultations until a diagnostic decision confirming/excluding ADHD within 6-months from baseline. Health economic cost-effectiveness and cost utility analysis was conducted. Assessing QbTest Utility in ADHD: A Randomised Controlled Trial was registered at ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT02209116). Results: One hundred and thirty-two participants were randomised to QbOpen group (123 analysed) and 135 to QbBlind group (127 analysed). Clinicians with access to the QbTest report (QbOpen) were more likely to reach a diagnostic decision about ADHD (hazard ratio 1.44, 95% CI 1.04–2.01). At 6-months, 76% of those with a QbTest report had received a diagnostic decision, compared with 50% without. QbTest reduced appointment length by 15% (time ratio 0.85, 95% CI 0.77–0.93), increased clinicians’ confidence in their diagnostic decisions (odds ratio 1.77, 95% CI 1.09–2.89) and doubled the likelihood of excluding ADHD. There was no difference in diagnostic accuracy. Health economic analysis showed a position of strict dominance; however, cost savings were small suggesting that the impact of providing the QbTest report within this trial can best be viewed as ‘cost neutral’. Conclusions: QbTest may increase the efficiency of ADHD assessment pathway allowing greater patient throughput with clinicians reaching diagnostic decisions faster without compromising diagnostic accuracy.

Background and Purpose— The characteristics of intracerebral hemorrhage (ICH) may vary by ICH location because of differences in the distribution of underlying cerebral small vessel diseases. Therefore, we investigated the incidence, characteristics, and outcome of lobar and nonlobar ICH. Methods— In a population-based, prospective inception cohort study of ICH, we used multiple overlapping sources of case ascertainment and follow-up to identify and validate ICH diagnoses in 2010 to 2011 in an adult population of 695 335. Results— There were 128 participants with first-ever primary ICH. The overall incidence of lobar ICH was similar to nonlobar ICH (9.8 [95% confidence interval, 7.7–12.4] versus 8.6 [95% confidence interval, 6.7–11.1] per 100 000 adults/y). At baseline, adults with lobar ICH were more likely to have preceding dementia (21% versus 5%; P =0.01), lower Glasgow Coma Scale scores (median, 13 versus 14; P =0.03), larger ICHs (median, 38 versus 11 mL; P P P =0.02) than those with nonlobar ICH. One-year case fatality was lower after lobar ICH than after nonlobar ICH (adjusted odds ratio for death at 1 year: lobar versus nonlobar ICH 0.21; 95% confidence interval, 0.07–0.63; P =0.006, after adjustment for known predictors of outcome). There were 4 recurrent ICHs, which occurred exclusively in survivors of lobar ICH (annual risk of recurrent ICH after lobar ICH, 11.8%; 95% confidence interval, 4.6%–28.5% versus 0% after nonlobar ICH; log-rank P =0.04). Conclusions— The baseline characteristics and outcome of lobar ICH differ from other locations.

Central sleep apnoea and Cheyne-Stokes respiration are common forms of sleep-disordered breathing, particularly in patients with co-morbidities such as cardiac and renal disease which, however, often do not require specific treatment. Physicians may encounter such patients in their outpatient clinics or as ward referrals in hospital. A typical case is presented to aid the approach to such patients, including how to make an accurate diagnosis, which of the various treatment modalities to use, and what to do if a treatment fails. The evidence for the different interventions is explored, including oxygen, modes of non-invasive positive airway pressure, and drug treatments, with particular attention to groundbreaking studies.

OBJECTIVES: To measure pre-intervention quality of routine antenatal and childbirth care in rural districts of Burkina Faso Ghana and Tanzania and to identify shortcomings. METHODS: In each country we selected two adjoining rural districts. Within each district we randomly sampled 6 primary healthcare facilities. Quality of care was assessed through health facility surveys direct observation of antenatal and childbirth care exit interviews and review of patient records. RESULTS: By and large quality of antenatal and childbirth care in the six districts was satisfactory but we did identify some critical gaps common to the study sites in all three countries. Counselling and health education practices are poor; laboratory investigations are often not performed; examination and monitoring of mother and newborn during childbirth are inadequate; partographs are not used. Equipment required to provide assisted vaginal deliveries (vacuum extractor or forceps) was absent in all surveyed facilities. CONCLUSION: Quality of care in the three study sites can be improved with the available human resources and without major investments. This improvement could reduce maternal and neonatal mortality and morbidity. (c) 2013 Blackwell Publishing Ltd.

Summary Background Surgical intervention for advanced Parkinson's disease is an option if medical therapy fails to control symptoms adequately. We aimed to assess whether surgery and best medical therapy improved self-reported quality of life more than best medical therapy alone in patients with advanced Parkinson's disease. Methods The PD SURG trial is an ongoing randomised, open-label trial. At 13 neurosurgical centres in the UK, between November, 2000, and December, 2006, patients with Parkinson's disease that was not adequately controlled by medical therapy were randomly assigned by use of a computerised minimisation procedure to immediate surgery (lesioning or deep brain stimulation at the discretion of the local clinician) and best medical therapy or to best medical therapy alone. Patients were analysed in the treatment group to which they were randomised, irrespective of whether they received their allocated treatment. The primary endpoint was patient self-reported quality of life on the 39-item Parkinson's disease questionnaire (PDQ-39). Changes between baseline and 1 year were compared by use of t tests. This trial is registered with Current Controlled Trials, number ISRCTN34111222. Findings 366 patients were randomly assigned to receive immediate surgery and best medical therapy (183) or best medical therapy alone (183). All patients who had surgery had deep brain stimulation. At 1 year, the mean improvement in PDQ-39 summary index score compared with baseline was 5·0 points in the surgery group and 0·3 points in the medical therapy group (difference −4·7, 95% CI −7·6 to −1·8; p=0·001); the difference in mean change in PDQ-39 score in the mobility domain between the surgery group and the best medical therapy group was −8·9 (95% CI −13·8 to −4·0; p=0·0004), in the activities of daily living domain was −12·4 (−17·3 to −7·5; p

The quality, functionality and performance of the virtual reality (VR) system used at JET for preparation and implementation of remote handling (RH) operations has been progressively enhanced since its first use in the original JET remote handling shutdown in 1998. As preparation began for the JET EP2 (Enhanced Performance 2) shutdown it was recognised that the VR system being used was unable to cope with the increased functionality and the large number of 3D models needed to fully represent the JET in-vessel components and tooling planned for EP2. A bespoke VR software application was developed in collaboration with the OEM, which allowed enhancements to be made to the VR system to meet the requirements of JET remote handling in preparation for EP2. Performance improvements required to meet the challenges of EP2 could not be obtained from the development of the new VR software alone. New methodologies were also required to prepare source, CATIA models for use in the VR using a collection of 3D software packages. In collaboration with the JET drawing office, techniques were developed within CATIA using polygon reduction tools to reduce model size, while retaining surface detail at required user limits. This paper will discuss how these developments have played an essential part in facilitating EP2 remote handling task development and examine their impact during the EP2 shutdown.

The three-step manufacturing process used in the synthesis of tenofovir disoproxil fumarate (1) was studied and optimized, leading to a more productive and robust process. The yield was improved from about 13% overall to 24%. Key process improvements identified included implementation of a telescoped process for the second stage that obviated the need for an extraction and solvent exchange, and significant optimization of the final reaction, including the beneficial effect of adding a quaternary ammonium salt to the alkylation reaction and development of a nonaqueous process for removal of NMP and triethylamine from the product mixture to decrease the level of decomposition of product during the isolation.

This paper presents the preliminary design of the "In-Vessel Magnetic platform", which is a subsystem of the magnetic diagnostics formed by all the components necessary for guaranteeing the thermomechanical interface of the actual magnetic sensors with the vacuum vessel (VV), their protection and the electrical connection to the in-vessel wiring for the transmission of the detected signal with a minimum level of noise. The design has been developed in order to comply with different functional requirements: the mechanical attachment to the VV; the electrical connection to the in-vessel wiring; efficient heat transfer to the VV; the compatibility with Remote Handling (RH) system for replacement; the integration of metrology features for post-installation control; the Electro Magnetic Interference (EMI) shielding from Electron Cyclotron Heating (ECH) stray radiation without compromising the sensor pass band (15 kHz). Significant effort has been dedicated to develop the CAD model, integrated within the ITER In-Vessel configuration model, taking care of the geometrical compliance with the Blanket modules (modified in order to accommodate the magnetic sensors in suitable grooves) and the RH compatibility. Thorough thermo-mechanical and electro-magnetic Finite Element Method (FEM) analyses have been performed to assess the reliability of the system in standard and off-normal operating conditions for the low frequency magnetic sensors. (C) 2016 Consorzio RFX. Published by Elsevier B.V. All rights reserved.

Self-assembled InGaN quantum dots were grown in the Stranski-Krastanov mode by plasma-assisted molecular beam epitaxy. The average dot height, diameter and density are 3 nm, 30 nm and 7 x 1010 cm -2 , respectively. The dot density was found to decrease as the growth temperature increases. The cathodoluminescence emission peak of the InGaN/GaN multiple layer quantum dots (MQDs) was found to red shift 330 meV with respect to the emission peak of the uncapped single layer of InGaN QDs due to Quantum Confined Stark effect. Blue LEDs based on InGaN/GaN multiple quantum wells (MQWs) as well as green and red LEDs based on InGaN MQDs emitting at 440, 560 and 640 nm, respectively, were grown and fabricated. The electroluminescence peak positions of both the green and red InGaN MQD LEDs are shown to be more blue-shifted with increasing injection current than that of the blue InGaN/GaN MQW LEDs.

The decomposition numbers d λμ for Specht modules S λ of partitions λ with three parts and whose third part is at most p − 1 are obtained by induction and by using “node removal rules” developed in James and Williams (2000).

The paper describes Western Australian examples and causes of land degradation. It outlines shortcomings in the methodologies used to rehabilitate these areas. From this a protocol is suggested for an ‘holistic’ approach to land rehabilitation.

Cysteine dioxygenase (CDO) converts cysteine to cysteinesulphinic acid and is the rate-limiting step in sulphate production. Most studies have centred upon the hepatic form of the enzyme, but several studies have investigated brain CDO using activity assays and western blotting. The aim of this study was to investigate the expression of CDO in the rat brain using a combination of immunohistochemistry and in situ hybridisation. Affinity-purified anti-R and anti-H CDO antibodies were immunoprecipitated using rat brain homogenate to determine whether the antibodies could remove enzyme activity. Immunohistochemistry and in situ hybridisation were then used to determine the cellular and regional expression of both CDO protein and mRNA. Immunoprecipitation of rat brain homogenate removed up to 98% and 70% (anti-R and anti-H, respectively) of enzyme activity. Nonimmune sheep serum had no effect upon enzyme activity. CDO protein and mRNA was localised solely to the neurones of the brain, including the pyramidal cells of the hippocampus and the Purkinje cells of the cerebellum. Regional localisation varied, with high levels of expression in the hippocampus, the dentate gyrus, the outer cortices of the brain, and the substantia nigra. The relative expression of CDO activity and protein in these regions is most probably a result of the relative abundance of neurones in these regions. CDO expression in the brain may have several possibile functions, the most likely being the prevention of free radical production by the autoxidation of cysteine and dopamine. J. Neurosci. Res. 65:78–84, 2001. © 2001 Wiley-Liss, Inc.

Introduction The upper reaches of the Manchester Ship Canal (MSC) and associated dock basins have been polluted by operational discharges, surface water runoff as well as upstream inputs from the River Irwell. The resulting poor water quality has been exacerbated by the deep (7 m) water column and limited water exchange. In this chapter, we describe the water quality management strategies put in place since the late 1980s to address poor water quality, specifically oxygenation of the water column of the MSC and isolation of the docks from the canal followed by destratification of the water column and habitat diversification. We then examine the effectiveness of these strategies in improving water quality, increasing biodiversity and enhancing the recreational potential of the enclosed dock basins and the MSC. Establishing an inland port at Manchester Long before the Industrial Revolution in the late eighteenth century Manchester was already at the centre of numerous industrial settlements located in the foothills of the southwestern Pennines (Gray 1993). The success of local industry rendered the use of traditional transport such as pack-horses and horse-drawn carts inadequate to meet its needs, leading to the increased use of river navigation. The main navigable rivers are the Irwell and Mersey, although water shortages, siltation and mudbanks were obstacles to the reliable transport of goods (Gray 1993). Obstructions had already been cleared in the Mersey estuary to allow vessels to reach Bank Quay, Warrington, and it was suggested that clearing and dredging the Rivers Mersey and Irwell would enable vessels to proceed as far as Manchester (Gray 1993).

In this paper, we report the development of blue-green-red LEDs based on InGaN quantum dots (QDs) and quantum wells in the active region, and GaN QDs in the nucleation layer for dislocation filtering, by plasma assisted molecular beam epitaxy. Self-assembled InGaN QDs and GaN QDs were grown in the Stranski-Krastanov mode. For the GaN QDs grown at 770 °C, the height distribution of the dots shows a bimodal distribution, which can be attributed to the interaction of the GaN QDs with the threading dislocations. TEM and XRD studies indicate that GaN QDs in the nucleation region help threading dislocations to deviate and annihilate. The average dot height, diameter and density of the InGaN QDs were estimated to be 3 nm, 30 nm and 7×1010 cm−2, respectively. The cathodoluminescence emission peak of the InGaN/GaN multiple layer quantum dots (MQDs) was found to red shift 330 meV with respect to the emission peak of the uncapped single layer of InGaN QDs due to Quantum Confined Stark effect. Blue LEDs based on InGaN/GaN multiple quantum wells (MQWs) as well as green and red LEDs based on InGaN MQDs emitting at 440 nm, 560 nm and 640 nm with FWHM of 30 nm, 87 nm and 97 nm, respectively, were grown and fabricated. The electroluminescence peak positions of both the green and red InGaN MQD LEDs are shown to be more blue-shifted with increasing injection current than that of the blue InGaN/GaN MQW LEDs.

Dopamine agonists have been recommended as early treatment for Parkinson's disease (PD), alone or combined with levodopa. Piribedil is a non-ergot selective D(2)/D(3) agonist with alpha(2) antagonist properties shown to be effective in the treatment of PD. This 12-month international, randomized, double-blind trial aimed to assess the efficacy of piribedil 150 mg versus bromocriptine 25 mg, in early combination with levodopa in Stage I to III PD patients. Motor efficacy was assessed using the Unified Parkinson's Disease Rating Scale (UPDRS III, Items 18-31) as improvement from baseline. Response rate was defined as a 30% improvement. Among the 425 randomly assigned patients, 178 were also included in a substudy on cognitive follow-up evaluated by a dysexecutive syndrome oriented battery. A relevant improvement in UPDRS III over the 12-month study duration was observed both in the piribedil and bromocriptine groups (-7.9 +/- 9.7 points from baseline versus -8.0 +/- 9.5; not significant [n.s.]) with a response rate of 58.4% and 55.3% (n.s.), respectively. Piribedil and bromocriptine resulted in similar improvement on all UPDRS III subscores. Piribedil patients required less levodopa dose increase than those on bromocriptine. Cognitive performance remained generally unchanged in both groups, with a significant effect of piribedil limited to the Wisconsin Card Sorting Test. An overall good tolerability of piribedil was observed. Early combination of piribedil 150 mg with levodopa resulted in significant long-term improvement of all motor symptoms in PD patients insufficiently controlled by levodopa alone. Taking into account both efficacy and acceptability in the long-term, piribedil proved in this bromocriptine controlled study to be an effective and safe treatment for PD.

Much of the work on III-Nitride-based LEDs that has been published and applied commercially has been done using metal-organic chemical vapor deposition (MOCVD) as a method of film growth. We report on the growth and fabrication of visible light emitting diodes, by combining hydride vapor-phase epitaxy (HVPE) and rf plasma-assisted MBE (PAMBE) methods. Thick (∼7 μm to 10 μm) HVPE n+-GaN smooth and textured templates, were used as substrates for the growth of LED structures by rf-PAMBE. The active regions of the LED structures, which consist of InGaN/GaN MQWs, were grown using the pulsed nitrogen plasma technique leading to abrupt well and barrier interfaces as confirmed by x-ray diffraction (XRD) measurements. Using this method, we obtained InGaN/GaN MQWs whose room temperature photoluminescence (PL) spectra have a full width at half maximum (FWHM) of 12 nm (105 meV). Visible LEDs on smooth GaN templates emitting in the blue to green were produced with EL spectrum FWHM as narrow as 27 nm. On the other hand, white LEDs without the use of phosphor have been produced utilizing textured MQWs as the active region, a phenomenon we initially attribute to different incorporation of In on the different QW-planes. The growth and fabrication of these devices was preceded by detailed growth and doping studies of the various layers of the LED structure. These include detailed nucleation studies on (0001) sapphire substrates as well as identification of kinetic factors which lead to good crystalline-quality InGaN alloys and InGaN/GaN MQWs.

The role of defective 'sulphur xenobiotic' biotransformations in the aetiology of Parkinson's and motor neurone diseases has been in the literature for over a decade. Problems in the S-oxidation of aliphatic thioethers, sulphation of phenolic compounds and the S-methylation of aliphatic sulphydryl groups have all been reported. These reports have also been consistent in observing that only a 'significant minority' of patients express these problems in sulphur biotransformation pathways. However, no investigation has yet reported on the incidence of these three defective pathways in control invididuals and in patients with Parkinson's and motor neurone disease. This investigation has found that: 1. Forty percent of patients with Parkinson's and motor neurone disease have a defect in the S-oxidation of S-carboxymethyl-L-cysteine compared to 4% of controls. 2. 35-40% of patients with Parkinson's and motor neurone disease have a defect in the sulphation of paracetamol compared to 4% of controls. 3. 60% of patients with motor neurone disease have a high capacity for the S-methylation of 2-mercaptoethanol compared to 4% of controls. 4. 38% of patients with Parkinson's disease have a low capacity for the S-methylation of 2-mercaptoethanol compared to 4% of controls. 5. There is no correlation between the S-oxidation phenotype, low paracetamol sulphation phenotype and low or high S-methylation phenotype in controls or patients with Parkinson's or motor neurone disease. 6. The number of controls that expressed one of the aberrant phenotypes was 4% compared to 38% of the patients with Parkinson's disease and 47% of the patients with motor neurone disease. 7. The number of controls that expressed two of the aberrant phenotypes was 0% compared to 18% of the patients with Parkinson's disease and 19% of those with motor neurone disease. 8. No controls or patients with Parkinson's disease or motor neurone disease expressed all three of the aberrant phenotypes. The results indicate that the three xeno-biotransformation pathways are under separate genetic control in the three population groups studied and that patients with Parkinson's and motor neurone disease do not have a widespread defect in their sulphur xenobiochemistry capacity.

Aims: The lung is one of the major sites of phase I cytochrome P450 enzyme and phase II sulfotransferase expression, which together are thought to act as an enzymic barrier against the unimpeded transfer of airborne xenobiotics into the lung parenchyma and systemic circulation. Sulfate for conjugation is produced primarily from the oxidation of cysteine, begun by cysteine dioxygenase (CDO), and completed with the conversion of sulfite to sulfate via sulfite oxidase (SO). Little is known about the site of expression of these two enzymes in the alveoli of the human lung. Methods: Antibodies and oligonucleotide probes raised against both CDO and SO were used for immunohistochemistry and in situ hybridisation, respectively, to investigate the expression of CDO and SO in human lung alveoli. Results: CDO and SO were expressed in alveolar epithelial cells, which is also the site of expression of cytochrome P450 1B1. Conclusions: These results demonstrate that the two key enzymes in sulfate production are expressed in the same locale as phase I and phase II enzymes, and that these two enzymes may be involved in the production of sulfate for the maintenance of a metabolic barrier against the entry of airborne xenobiotics and the synthesis of important structural proteins and proteoglycans.

Background/Aims: Cysteine dioxygenase (CDO, EC 1.13.11.20) catalyses the conversion of cysteine to cysteine sulphinic acid and controls the rate-limiting step of sulphate production. Many neurological and non-neurological diseases are associated with abnormalities in CDO activity, giving rise to reduced availability of sulphate. The importance of the kidney in the sulphation of xenobiotics has long been recognised, but little is known about the renal expression of key enzymes in this pathway. In order to address this, this report demonstrates the expression of CDO in the kidney. Methods: Two previously characterised antibodies were used to investigate the localisation and expression of CDO using immunohistochemistry, in-situ hybridisation and Western blotting. Results: Renal CDO was shown to exist as a 68-kDa protein, which was unaffected by levels of cysteine and methionine that had been previously shown to induce hepatic CDO. CDO protein expression was present in the proximal convoluted tubules of the cortex and the collecting ducts of both the medulla and papilla. Discussion: These results suggest that renal CDO is immunologically identical to that of the liver. Its expression in the kidney tubules, the major site of sulphation in the kidney, suggests that CDO in the kidney may play a role in both xenobiotic metabolism and sodium and water homeostasis.

Ten years ago, when I was a medical student, my father developed a neurological problem. He went for his regular eye test, but also had his visual fields checked on the new Humphrey Field Analyser recently bought by the optometrists. Trouble followed. The test was repeated in greater detail, and he appeared to have a bitemporal superior quadrantanopia (Fig. 1a). He was referred to his general practitioner who referred him on to the local neurology department for further investigation. More trouble followed as my parents telephoned me (the only faintly medical person in the family) to ask for the potential causes, tests, treatments, operations and outlook. My father was completely well, and had noticed no visual problem. My differential diagnosis then only consisted of one possibility – a pituitary tumour pressing on the optic chiasm. It had taken most of my second year at medical school to come to grips with

Glutamine is an essential nutrient for cancer cells and increased glutaminolysis is widely recognised as a key feature of the metabolic reprogramming that occurs during malignant transformation. As a consequence of the role glutamine plays in cancer biology, targeting glutamine metabolism is of considerable interest with inhibition of the mitochondrial enzyme glutaminase showing promise in experimental models. An alternative or adjunct to the strategy of inhibiting glutamine metabolism intracellularly is to deplete extracellular pools of glutamine. L-asparaginases are known to possess glutaminase activity and the purpose of this study is to characterise the kinetics of the glutaminase activity of two clinically approved L-asparaginases, Kidrolase (derived from E. coli) and Erwinase (derived from Erwinia chrysanthemi). Glutaminase activity was measured using a two step reaction: initial reduction of glutamine to glutamate by Kidrolase/Erwinase followed by the NAD dependent conversion of glutamate to ammonia by L-glutamate dehydrogenase (GDH). Each reaction consisted of NAD (2mM), K2PO4 (50mM), GDH (3U), Erwinase or Kidrolase (10U), L-glutamine (concentrations ranged from 5mM to 1.25 μM) in a final volume of 1 ml Tris Acetate buffer (50mM, pH8.6). The reaction was started by the addition of Erwinase/Kidrolase and the formation of NADH monitored for 30 seconds at 340nm using a Cary UV/Vis spectrophotometer and a NADH molar extinction coefficient of 6,220 M-1cm-1. The reaction was linear between glutamine concentrations 100 and 1.25 μM. Using 10U in each reaction, Hanes Woolf kinetic plots generated Vmax parameters of 46.29 and 7.57 μM/min for Erwinase and Kidrolase respectively. Km values were 96.05 and 33.06 μM for Erwinase and Kidrolase respectively. Preliminary studies demonstrate that glutamine depletion induced a dose dependent reduction in cell proliferation in HCT116 p53+/+, HCT116 p53-/-, MDA-MD-231, MDA-MB-453, MCF7, TK10, A549 and T47D cell lines in vitro. In conclusion, these studies demonstrate that Erwinase has significant glutaminase activity and is superior to Kidrolase in terms of glutaminase activity. Erwinase is a good candidate for exploring the efficacy of glutamine depletion strategies and further studies are required to determine whether Erwinase can potentiate the activity of other approaches aimed at restricting the glutamine dependence of tumors. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C154. Citation Format: Roger M. Phillips, Mohammed U. Saleem, Adrian Williams, Jon Morgan. Kinetic analysis of the glutaminase activity of L-asparaginases derived from Erwinia chrysanthemi (Erwinase®) and Eshericia coli (Kidrolase). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C154.

The interpretation of recently acquired regional-deep, 2D seismic data across the Timor/Tanimbar Trough has provided a new insight into the structure of this continent/arc collision zone. This data is mostly recorded to 10–12 seconds with an 8 km dual sensor streamer, providing increased resolution and improved penetration compared with vintage data, particularly in the deeper part of the section. A major improvement in the new data is the imaging of the Australian continental margin succession continuously from the Australian side of the Timor-Tanimbar Trough for a distance of a few tens of km underneath the accretionary prism on the northwest side of the trough. Structures observed in the accretionary prism itself include fold and thrust belts, imbricate thrusts and extensional half grabens. The detachment surface at its base may provide a regional seal for traps involving Jurassic and Triassic reservoirs in underlying thrusts for which there is some evidence on the seismic data. The improved visibility of the Mesozoic succession below the accretionary prism allows possible Jurassic source rocks to be followed to the northwest below a growing overburden to a depth at which maturity may be expected. There is also a graben, probably including a greater Jurassic thickness, under the Timor Trough.