Adiponectin is associated with insulin sensitivity in white European men but not black African men.

AIMS: We aimed to assess ethnic differences in inflammatory markers and their relationships with insulin sensitivity and regional adiposity between white European and black African men. METHODS: A total of 53 white European and 53 black African men underwent assessment of inflammatory markers alongside Dixon-magnetic resonance imaging to quantify subcutaneous and visceral adipose tissue and intrahepatic lipid. A hyperinsulinaemic-euglycaemic clamp was used to measure whole-body and adipose tissue insulin sensitivity. To assess ethnic differences in relationships, the statistical significance of an interaction term between adipokines and ethnic group was tested in multivariable regression models. RESULTS: The black African men exhibited significantly lower adiponectin and tumour necrosis factor-α (TNF-α) and greater interleukin-10 (IL-10) compared to white European men (all p < 0.05). There were no statistically significant ethnic differences in leptin, resistin, IL-6, interferon-γ, IL-13, IL-1ß, IL-8 and vascular endothelial growth factor. Several relationships differed significantly by ethnicity such that they were stronger in white European than black African men including IL-6 with visceral adipose tissue; adiponectin with subcutaneous adipose tissue; leptin with intrahepatic lipid; adiponectin, IL-6 and TNF-α with whole-body insulin sensitivity and TNF-α with adipose tissue insulin sensitivity (all pinteraction <0.05). Leptin significantly predicted whole-body insulin sensitivity in white European (R2  = 0.51) and black African (R2  = 0.29) men; however, adiponectin was a statistically significant predictor in only white European men (R2  = 0.22). CONCLUSIONS: While adiponectin is lower in black African men, its insulin sensitising effects may be greater in white men suggesting that the role of adipokines in the development of type 2 diabetes may differ by ethnicity.

Effect of Iron Isomaltoside on Skeletal Muscle Energetics in Patients With Chronic Heart Failure and Iron Deficiency.

BACKGROUND: Iron repletion augments exercise capacity in chronic heart failure (HF), but there is a lack of mechanistic data explaining how iron could augment exercise performance despite minimal changes in hemoglobin (Hb). Besides Hb, iron is an obligate component of mitochondrial enzymes that generate cellular energy in the form of adenosine triphosphate and phosphocreatine (PCr). Dynamic phosphorus magnetic resonance spectroscopy is a noninvasive tool that quantifies in vivo muscle energetics by measuring the kinetics of PCr recovery after exertion. We tested the hypothesis that intravenous iron repletion in chronic HF enhances skeletal muscle energetics as reflected by shorter PCr recovery half-times (PCr t1/2) on phosphorus magnetic resonance spectroscopy. METHODS: We enrolled 40 patients (50% anemic) with chronic HF, New York Heart Association class ≥II, left ventricular ejection fraction ≤45%, and iron deficiency (ferritin<100 µg/L or 100-300 µg/L with transferrin saturation <20%). Subjects underwent stratified (anemic versus nonanemic) randomization (1:1) to a single, double-blinded, total dose infusion of iron isomaltoside or saline placebo with end points reassessed early at 2 weeks posttreatment to minimize confounding from exercise adaptation. The primary end point was PCr t1/2 at 2 weeks. Secondary end points included ADP recovery half-time (ADP t1/2; energetic marker), iron status, symptoms, Hb, exercise capacity, and safety. RESULTS: In the total population, treatment groups were similar at baseline. At 2 weeks, iron isomaltoside improved PCr t1/2 (adjusted difference, -6.8 s; 95% CI, 11.5 to -2.1; P=0.006), ADP t1/2 (-5.3 s; 95% CI, -9.7 to -0.9; P=0.02), ferritin (304 ng/mL; 95% CI, 217-391; P<0.0001), transferrin saturation (6.8%; 95% CI, 2.7-10.8; P=0.002), New York Heart Association class (-0.23; 95% CI, -0.46 to -0.01; P=0.04), resting respiratory rate (-0.7 breaths/min; 95% CI, -1.2 to -0.2; P=0.009), and postexercise Borg dyspnea score (-2.0; 95% CI, -3.7 to -0.3; P=0.04), but not Hb (2.4 g/L; 95% CI, -3.5 to 8.4; P=0.41). Adverse events were similar between groups. In subgroup analyses, iron isomaltoside improved PCr t1/2 in anemic (-8.4 s; 95% CI, -16.7 to -0.2; P=0.04) and nonanemic (-5.2 s; 95% CI, -10.6 to 0.2; P=0.06) cohorts. CONCLUSIONS: In patients with chronic HF and iron deficiency, a total repletion dose of iron isomaltoside given at a single sitting is well tolerated and associated with faster skeletal muscle PCr t1/2 at 2 weeks, implying better mitochondrial function. Augmented skeletal muscle energetics might therefore be an important mechanism via which iron repletion confers benefits in chronic HF despite minimal Hb changes. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-005592-13/GB . Unique identifier: EudraCT 2012-005592-13.

Ethnic differences in intrahepatic lipid and its association with hepatic insulin sensitivity and insulin clearance between men of black and white ethnicity with early type 2 diabetes.

Intrahepatic lipid (IHL) is linked with reduced hepatic insulin sensitivity and insulin clearance. Despite their high risk for type 2 diabetes (T2D), there have been limited investigations of these relationships in black populations. We investigated these relationships in 18 white European (WE) and 18 black West African (BWA) men with T2D <5 years. They underwent magnetic resonance imaging to quantify IHL, a hyperinsulinemic euglycaemic clamp with [6,6 2 H2 ] glucose infusion to assess hepatic insulin sensitivity and a hyperglycaemic clamp to assess insulin clearance. BWA men had lower IHL than WE men (3.7 [5.3] vs 6.6 [10.6]%, P = 0.03). IHL was inversely associated with basal hepatic insulin sensitivity in WE but not BWA men (BWA: r = -0.01, P = 0.96; WE: r = -0.72, P = 0.006) with a significant interaction by ethnicity (Pinteraction = 0.05); however, IHL was not associated with % suppression of endogenous glucose production by insulin in either ethnicity. IHL showed a trend to an association with insulin clearance in BWA only (BWA: r = -0.42, P = 0.09; WE: r = -0.14, P = 0.58). The lack of association between IHL and hepatic insulin sensitivity in BWA men indicates IHL may play a lesser detrimental role in T2D in BWA men.

Glycine Amidinotransferase (GATM), Renal Fanconi Syndrome, and Kidney Failure.

Background For many patients with kidney failure, the cause and underlying defect remain unknown. Here, we describe a novel mechanism of a genetic order characterized by renal Fanconi syndrome and kidney failure.Methods We clinically and genetically characterized members of five families with autosomal dominant renal Fanconi syndrome and kidney failure. We performed genome-wide linkage analysis, sequencing, and expression studies in kidney biopsy specimens and renal cells along with knockout mouse studies and evaluations of mitochondrial morphology and function. Structural studies examined the effects of recognized mutations.Results The renal disease in these patients resulted from monoallelic mutations in the gene encoding glycine amidinotransferase (GATM), a renal proximal tubular enzyme in the creatine biosynthetic pathway that is otherwise associated with a recessive disorder of creatine deficiency. In silico analysis showed that the particular GATM mutations, identified in 28 members of the five families, create an additional interaction interface within the GATM protein and likely cause the linear aggregation of GATM observed in patient biopsy specimens and cultured proximal tubule cells. GATM aggregates-containing mitochondria were elongated and associated with increased ROS production, activation of the NLRP3 inflammasome, enhanced expression of the profibrotic cytokine IL-18, and increased cell death.Conclusions In this novel genetic disorder, fully penetrant heterozygous missense mutations in GATM trigger intramitochondrial fibrillary deposition of GATM and lead to elongated and abnormal mitochondria. We speculate that this renal proximal tubular mitochondrial pathology initiates a response from the inflammasome, with subsequent development of kidney fibrosis.

Tensor and non-tensor tractography for the assessment of the corticospinal tract of children with motor disorders: a comparative study.

INTRODUCTION: Non-invasive measures of corticospinal tract (CST) integrity may help to guide clinical interventions, particularly in children and young people (CAYP) with motor disorders. We compared diffusion tensor imaging (DTI) metrics extracted from the CST generated by tensor and non-tensor based tractography algorithms. METHODS: For a group of 25 CAYP undergoing clinical evaluation, the CST was reconstructed using (1) deterministic tensor-based tractography algorithm, (2) probabilistic tensor-based, and (3) constrained spherical deconvolution (CSD)-derived tractography algorithms. RESULTS: Choice of tractography algorithm significantly altered the results of tracking. Larger tracts were consistently defined with CSD, with differences in FA but not MD values for tracts to the pre- or post-central gyrus. Differences between deterministic and probabilistic tensor-based algorithms were minimal. Non-tensor reconstructed tracts appeared to be more anatomically representative. Examining metrics along the tract, difference in FA values appeared to be greatest in voxels with predominantly single-fibre orientations. Less pronounced differences were seen outwith of these regions. CONCLUSION: With an increasing interest in the applications of tractography analysis at all stages of movement disorder surgery, it is important that clinicians remain alert to the consequences of choice of tractography algorithm on subsequently generated tracts, including differences in volumes, anatomical reconstruction, and DTI metrics, the latter of which will have global as well as more regional effects. Tract-wide analysis of DTI based metrics is of limited utility, and a more segmental approach to analysis may be appropriate, particularly if disruption to a focal region of a white matter pathway is anticipated.

Fractional anisotropy in children with dystonia or spasticity correlates with the selection for DBS or ITB movement disorder surgery.

INTRODUCTION: There is increasing interest in neurosurgical interventions for hypertonicity in children and young people (CAYP), which often presents with a mixture of dystonia and spasticity. Significant spasticity would usually be considered a contraindication for deep brain stimulation (DBS) and more suitably treated with intrathecal baclofen (ITB). We aimed to explore whether white matter microstructure, as measured by Fractional Anisotropy (FA), differed between CAYP selected for DBS compared to ITB surgery. METHODS: We retrospectively analysed Diffusion Tensor Imaging for 31 CAYP selected for DBS surgery (14 primary dystonia, 17 secondary dystonia) and 10 CAYP selected for ITB surgery. A voxel-wise comparison of FA values was performed using tract-based spatial statistics, comparing primary and secondary dystonia groups to the ITB group, and the two dystonia groups. RESULTS: Widespread areas of reduced FA were demonstrated in ITB compared to either DBS group and in CAYP with secondary compared to primary dystonia. These changes were not restricted to motor pathways. Region of interest (ROI) analysis from the corticospinal tract (CST) demonstrated groupwise differences but overlapping values at the individual level. CONCLUSIONS: DTI measures may contribute to decision making for CAYP selection for movement disorder surgery. Significant differences in CAYP with secondary dystonia selected for DBS surgery compared to CAYP selected for ITB pump implants, suggesting that more extensive white matter injury may be a feature of the spastic motor phenotype. Altered white matter microstructure could potentially explain the reduced responsiveness to interventions such as DBS in secondary compared to primary dystonia.

A simple and robust test object for the assessment of isotropic diffusion kurtosis.

PURPOSE: To create a robust test object for the assessment of isotropic diffusion kurtosis and to investigate the relationships between barrier concentration and kurtosis and diffusion coefficients. THEORY AND METHODS: Diffusion kurtosis imaging is an extension of conventional diffusion-weighted magnetic resonance imaging which provides a means of assessing the degree to which diffusion processes of spin-bearing particles are non-Gaussian, a property that is quantified by the kurtosis. We present a set of test objects, each possessing a different concentration of colloidal dispersion, allowing barrier concentration of the dispersed colloidal particles to be related to the kurtosis of the water diffusion. Diffusion coefficients from the kurtosis model and the monoexponential model are compared. RESULTS: A relationship between barrier concentration and kurtosis is found, demonstrating that the diffusion process becomes less Gaussian as the barrier concentration is increased. Differences in the two estimates for the diffusion coefficients are examined. The test object is robust, displaying long-term reproducibility of results. CONCLUSIONS: Colloidal dispersions provide a suitable and stable test object for the assessment and reproducibility measurements of kurtosis.

Water-fat separation in diffusion-weighted EPI using an IDEAL approach with image navigator.

PURPOSE: Echo planar-based diffusion-weighted MRI (DW-MRI) requires robust suppression of fat signal. Fat suppression techniques such as inversion recovery or spectrally selective excitation with subsequent gradient spoiling can extend scan time or perform suboptimally in the presence of strong main field inhomogeneities. Chemical shift-encoded water-fat separation using iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) is robust in areas of main field inhomogeneity but requires accurate phase information, which can be distorted by patient motion during diffusion-weighting gradients. A method is proposed to overcome this with the use of image navigators. THEORY AND METHODS: A spin echo planar imaging (SE-EPI) diffusion-weighted sequence was modified to incorporate IDEAL acquisition in combination with an image navigator to correct for patient motion-induced phase effects. Images were acquired in phantoms and in healthy volunteers in brain, pelvic, and abdominal regions. RESULTS: Without navigator, diffusion-weighted IDEAL created artifacts in areas of motion. These were removed when the two-dimensional navigator was used to correct the phase, resulting in correct water-fat separation. CONCLUSION: DW-EPI with IDEAL and an integrated image navigator allows for robust water and fat separation in different body areas and are a time-efficient alternative to standard fat-suppression techniques in DW-MRI.

Intramuscular fat in ambulant young adults with bilateral spastic cerebral palsy.

BACKGROUND: It is known that individuals with bilateral spastic cerebral palsy (BSCP) have small and weak muscles. However, no studies to date have investigated intramuscular fat infiltration in this group. The objective of this study is to determine whether adults with BSCP have greater adiposity in and around their skeletal muscles than their typically developing (TD) peers as this may have significant functional and cardio-metabolic implications for this patient group. METHODS: 10 young adults with BSCP (7 male, mean age 22.5 years, Gross Motor Function Classification System (GMFCS) levels I-III), and 10 TD young adults (6 male, mean age 22.8 years) took part in this study. 11 cm sections of the left leg of all subjects were imaged using multi-echo gradient echo chemical shift imaging (mDixon). Percentage intermuscular fat (IMAT), intramuscular fat (IntraMF) and a subcutaneous fat to muscle volume ratio (SF/M) were calculated. RESULTS: IntraMF was higher with BSCP for all muscles (p = 0.001-0.013) and was significantly different between GMFCS levels (p < 0.001), with GMFCS level III having the highest IntraMF content. IMAT was also higher with BSCP p < 0.001). No significant difference was observed in SF/M between groups. CONCLUSION: Young adults with BSCP have increased intermuscular and intramuscular fat compared to their TD peers. The relationship between these findings and potential cardio-metabolic and functional sequelae are yet to be investigated.

Cardiac energetics in patients with chronic heart failure and iron deficiency: an in-vivo 31 P magnetic resonance spectroscopy study.

AIMS: Iron deficiency (ID) is prevalent and adverse in chronic heart failure (CHF) but few human studies have explored the myocardial mechanism(s) that potentially underlie this adversity. Because mitochondrial oxidative phosphorylation (OXPHOS) provides over 90% of the hearts adenosine triphosphate (ATP), and iron is critical for OXPHOS, we hypothesized that patients with CHF and ID would harbour greater cardiac energetic impairments than patients without ID. METHODS AND RESULTS: Phosphorus magnetic resonance spectroscopy was used to quantify the phosphocreatine (PCr) to ATP (PCr/ATP) ratio, an index of in-vivo cardiac energetics, in CHF patients and healthy volunteers. Cardiac structure and function was assessed from magnetic resonance short stack cines. Patients with (n = 27) and without (n = 12) ID, and healthy volunteers (n = 11), were similar with respect to age and gender. The PCr/ATP ratio was lower in patients with ID (1.03 [0.83-1.38]) compared to those without ID (1.72 [1.51-2.26], p < 0.01) and healthy volunteers (1.39 [1.10-3.68], p < 0.05). This was despite no difference in cardiac structure and function between patients with and without ID, and despite adjustment for the presence of anaemia, haemoglobin levels, cardiac rhythm, or New York Heart Association (NYHA) class. In the total CHF cohort, the PCr/ATP ratio correlated with ferritin levels (rho = 0.4, p < 0.01), and was higher in NYHA class I than class II or III patients (p = 0.02). CONCLUSION: Iron deficiency is associated with greater cardiac energetic impairment in patients with CHF irrespective of anaemia and cardiac structure and function. Suppression of cardiac mitochondrial function might therefore be a mechanism via which ID worsens human CHF.

Non-invasive detection and quantification of human foetal brain lactate in utero by magnetic resonance spectroscopy.

OBJECTIVE: To assess the feasibility of foetal cerebral lactate detection and quantification by proton magnetic resonance spectroscopy ((1)H-MRS) in pregnancies at increased risk of cerebral hypoxia, using a clinical 1.5 T magnetic resonance imaging (MRI) system. METHOD: Localised (1)H-MRS was performed in four patients with pregnancies in their third trimester complicated by intrauterine growth restriction (IUGR). A long echo time (TE) of 288 ms was used to maximise detection and conspicuity of the lactate methyl resonance, together with a short TE MRS acquisition to check for the presence of lipid contamination. Individual peaks in the resulting spectra were measured, corrected for relaxation and referenced to the unsuppressed water signal to provide metabolite concentrations. RESULTS: A resonance peak consistent with the presence of lactate was observed in all cases. In one subject, this was confounded by the identification of significant lipid contamination in the short TE MRS acquisition. The range of measured lactate concentrations was 2.0-3.3 mmol/kg and compared well with preterm neonatal MRS studies. CONCLUSION: The non-invasive detection and quantification of foetal cerebral lactate by MRS is achievable on a clinical 1.5 T MRI system.

Distribution and fibre field similarity mapping of the human anterior commissure fibres by diffusion tensor imaging.

OBJECT: The anterior commissure is a critical interhemispheric pathway in animals, yet its connections in humans are not clearly understood. Its distribution has shown to vary greatly between species, and it is thought that in humans it may convey axons from a larger territory than previously thought. The aim was to use an anatomical mapping tool to look at the anterior commissure fibres and to compare the distribution findings with published anatomical understanding. MATERIALS AND METHODS: Two different diffusion-weighted imaging data sets were acquired from eight healthy subjects using a 3 Tesla MR scanner with 32 gradient directions. Diffusion tensor imaging tractography was performed, and the anterior commissure fibres were selected using three-dimensional regions of interest. Distribution of the fibres was observed by means of registration with T2-weighted images. The fibre field similarity maps were produced for five of the eight subjects by comparing each subject's fibres to the combined map of the five data sets. RESULTS: Fibres were shown to lead into the temporal lobe and towards the orbitofrontal cortex in the majority of subjects. Fibres were also distributed to the parietal or occipital lobes in all five subjects in whom the anterior commissure was large enough for interhemispheric fibres to be tracked through. The fibre field similarity maps highlighted areas where the local distances of fibre tracts were displayed for each subject compared to the combined bundle map. CONCLUSION: The anterior commissure may play a more important role in interhemispheric communication than currently presumed by conveying axons from a wider territory, and the fibre field similarity maps give a novel approach to quantifying and visualising characteristics of fibre tracts.

The Link between Obesity and Inflammatory Markers in the Development of Type 2 Diabetes in Men of Black African and White European Ethnicity.

In this study, we aimed to assess ethnic differences in visceral (VAT), deep subcutaneous (dSAT), and superficial subcutaneous (sSAT) adipose tissue and their relationships with inflammatory markers between white European (WE) and black West African (BWA) men with normal glucose tolerance (NGT) and type 2 diabetes (T2D). Forty-two WE (23 NGT/19 T2D) and 43 BWA (23 NGT/20 T2D) men underwent assessment of plasma inflammatory markers using immunoassays alongside Dixon magnetic resonance imaging to quantify L4-5 VAT, dSAT and sSAT. Despite no ethnic differences in sSAT and dSAT, BWA men exhibited lower VAT (p = 0.002) and dSAT:sSAT (p = 0.047) than WE men. Adiponectin was inversely associated with sSAT in WE (p = 0.041) but positively associated in BWA (p = 0.031) men with T2D. Interleukin-6 (IL-6) was associated with VAT in WE but not in BWA men with NGT (WE: p = 0.009, BWA: p = 0.137) and T2D (WE: p = 0.070, BWA: p = 0.175). IL-6 was associated with dSAT in only WE men with NGT (WE: p = 0.030, BWA: p = 0.833). The only significant ethnicity interaction present was for the relationship between adiponectin and sSAT (Pinteraction = 0.003). The favourable adipose tissue distribution and the weaker relationships between adiposity and inflammation in BWA men suggest that adipose tissue inflammation may play a lesser role in T2D in BWA than WE men.

Snacking on whole almonds for 6 weeks improves endothelial function and lowers LDL cholesterol but does not affect liver fat and other cardiometabolic risk factors in healthy adults: the ATTIS study, a randomized controlled trial.

BACKGROUND: There is convincing evidence that daily whole almond consumption lowers blood LDL cholesterol concentrations, but effects on other cardiometabolic risk factors such as endothelial function and liver fat are still to be determined. OBJECTIVES: We aimed to investigate whether isoenergetic substitution of whole almonds for control snacks with the macronutrient profile of average snack intakes, had any impact on markers of cardiometabolic health in adults aged 30-70 y at above-average risk of cardiovascular disease (CVD). METHODS: The study was a 6-wk randomized controlled, parallel-arm trial. Following a 2-wk run-in period consuming control snacks (mini-muffins), participants consumed either whole roasted almonds (n = 51) or control snacks (n = 56), providing 20% of daily estimated energy requirements. Endothelial function (flow-mediated dilation), liver fat (MRI/magnetic resonance spectroscopy), and secondary outcomes as markers of cardiometabolic disease risk were assessed at baseline and end point. RESULTS: Almonds, compared with control, increased endothelium-dependent vasodilation (mean difference 4.1%-units of measurement; 95% CI: 2.2, 5.9), but there were no differences in liver fat between groups. Plasma LDL cholesterol concentrations decreased in the almond group relative to control (mean difference -0.25 mmol/L; 95% CI: -0.45, -0.04), but there were no group differences in triglycerides, HDL cholesterol, glucose, insulin, insulin resistance, leptin, adiponectin, resistin, liver function enzymes, fetuin-A, body composition, pancreatic fat, intramyocellular lipids, fecal SCFAs, blood pressure, or 24-h heart rate variability. However, the long-phase heart rate variability parameter, very-low-frequency power, was increased during nighttime following the almond treatment compared with control (mean difference 337 ms2; 95% CI: 12, 661), indicating greater parasympathetic regulation. CONCLUSIONS: Whole almonds consumed as snacks markedly improve endothelial function, in addition to lowering LDL cholesterol, in adults with above-average risk of CVD.This trial was registered at clinicaltrials.gov as NCT02907684.

Cholesteatoma: multishot echo-planar vs non echo-planar diffusion-weighted MRI for the prediction of middle ear and mastoid cholesteatoma.

OBJECTIVE: We aimed to compare a newer readout-segmented echoplanar imaging (RS-EPI) technique with the established single shot turbo spin echo (SS-TSE) non-EPI diffusion-weighted imaging (DWI) in detecting surgically validated cholesteatoma. METHODS: We retrospectively reviewed 358 consecutive MRI studies in 285 patients in which both RS-EPI and non-EPI DWI sequences were performed. Each diffusion sequence was reviewed independently and scored negative, indeterminate or positive for cholesteatoma in isolation and after reviewing the T 1W sequence. Average artefacts scores were evaluated and the lesion size measured as a distortion indicator. The imaging scores were correlated with surgical validation, clinical and imaging follow-up. RESULTS: There were 239 middle ear and central mastoid tract and 34 peripheral mastoid lesions. 102 tympanomastoid operations were performed. The positive predictive value ( PPV), post-operative PPV, primary PPV, negative predictive value were 93%, 95%, 87.5%, 70% for RS-EPI and 92.5%, 93.6%, 90%, 79% for non-EPI DWI. There was good agreement between the two techniques (k = 0.75). Non-EPI DWI is less susceptible to skull base artefacts although the mean cholesteatoma measurement difference was only 0.53 mm. CONCLUSION: RS-EPI has comparable PPV with non-EPI DWI in both primary and post-operative cholesteatoma but slightly lower negative predictive value. When there is a mismatch, non-EPI DWI better predicts the presence of cholesteatoma. There is good agreement between the sequences for cholesteatoma diagnosis. The T 1W sequence is very important in downgrading indeterminate DWI signal lesions to a negative score. ADVANCES IN KNOWLEDGE: This is, to our knowledge, the first study to compare a multishot EPI DWI technique with the established non- EPI DWI in cholesteatoma diagnosis.

Moderate hypothermia within 6 h of birth plus inhaled xenon versus moderate hypothermia alone after birth asphyxia (TOBY-Xe): a proof-of-concept, open-label, randomised controlled trial.

BACKGROUND: Moderate cooling after birth asphyxia is associated with substantial reductions in death and disability, but additional therapies might provide further benefit. We assessed whether the addition of xenon gas, a promising novel therapy, after the initiation of hypothermia for birth asphyxia would result in further improvement. METHODS: Total Body hypothermia plus Xenon (TOBY-Xe) was a proof-of-concept, randomised, open-label, parallel-group trial done at four intensive-care neonatal units in the UK. Eligible infants were 36-43 weeks of gestational age, had signs of moderate to severe encephalopathy and moderately or severely abnormal background activity for at least 30 min or seizures as shown by amplitude-integrated EEG (aEEG), and had one of the following: Apgar score of 5 or less 10 min after birth, continued need for resuscitation 10 min after birth, or acidosis within 1 h of birth. Participants were allocated in a 1:1 ratio by use of a secure web-based computer-generated randomisation sequence within 12 h of birth to cooling to a rectal temperature of 33·5°C for 72 h (standard treatment) or to cooling in combination with 30% inhaled xenon for 24 h started immediately after randomisation. The primary outcomes were reduction in lactate to N-acetyl aspartate ratio in the thalamus and in preserved fractional anisotropy in the posterior limb of the internal capsule, measured with magnetic resonance spectroscopy and MRI, respectively, within 15 days of birth. The investigator assessing these outcomes was masked to allocation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00934700, and with ISRCTN, as ISRCTN08886155. FINDINGS: The study was done from Jan 31, 2012, to Sept 30, 2014. We enrolled 92 infants, 46 of whom were randomly assigned to cooling only and 46 to xenon plus cooling. 37 infants in the cooling only group and 41 in the cooling plus xenon group underwent magnetic resonance assessments and were included in the analysis of the primary outcomes. We noted no significant differences in lactate to N-acetyl aspartate ratio in the thalamus (geometric mean ratio 1·09, 95% CI 0·90 to 1·32) or fractional anisotropy (mean difference -0·01, 95% CI -0·03 to 0·02) in the posterior limb of the internal capsule between the two groups. Nine infants died in the cooling group and 11 in the xenon group. Two adverse events were reported in the xenon group: subcutaneous fat necrosis and transient desaturation during the MRI. No serious adverse events were recorded. INTERPRETATION: Administration of xenon within the delayed timeframe used in this trial is feasible and apparently safe, but is unlikely to enhance the neuroprotective effect of cooling after birth asphyxia. FUNDING: UK Medical Research Council.

Central Motor Conduction Time and diffusion tensor imaging metrics in children with complex motor disorders.

OBJECTIVES: To explore potential correlations between Diffusion Tensor Imaging (DTI) metrics and Central Motor Conduction Time (CMCT) in a cohort of children with complex motor disorders. METHODS: For a group of 49 children undergoing assessment for potential Deep Brain Stimulation (DBS) surgery, CMCT was derived from the latency of MEPs invoked by transcranial magnetic stimulation of the contralateral motor cortex and from peripheral conduction times. Tract-Based Spatial Statistics (TBSS) was used to compare Diffusion Tensor Imaging (DTI) metrics between children with normal and abnormal CMCT. TBSS was also used to look for correlations between these metrics and CMCT across the group. RESULTS: Median age at assessment was 9years (range 3-19years). For 14/49 children a diagnosis of primary dystonia had been made. No correlation could be found between DTI metrics and CMCT, with no difference in metrics found between children with normal and abnormal CMCT. CONCLUSIONS: DTI metrics did not differ between children with normal and abnormal CMCT. Tissue properties determining CMCT may not be explained by existing DTI metrics. SIGNIFICANCE: DTI and CMCT measurements provide complementary information for the clinical assessment of children with complex motor disorders.

Observation and modeling of deep brain stimulation electrode depth in the pallidal target of the developing brain.

OBJECTIVE: It is unclear how brain growth with age affects electrode position in relation to target for children undergoing deep brain stimulation surgery. We aimed to model projected change in the distance between the entry point of the electrode into the brain and target during growth to adulthood. METHODS: Modeling was performed using a neurodevelopmental magnetic resonance imaging database of age-specific templates in 6-month increments from 4 to 18 years of age. Coordinates were chosen for a set of entry points into both cerebral hemispheres and target positions within the globus pallidus internus on the youngest magnetic resonance imaging template. The youngest template was nonlinearly registered to the older templates, and the transformations generated by these registrations were applied to the original coordinates of entry and target positions, mapping these positions with increasing age. Euclidean geometry was used to calculate the distance between projected electrode entry and target with increasing age. RESULTS: A projected increase in distance between entry point and target of 5-10 mm was found from age 4 to 18 years. Most change appeared to occur before 7 years of age, after which minimal change in distance was found. CONCLUSIONS: Electrodes inserted during deep brain stimulation surgery are tethered at the point of entry to the skull. Brain growth, which could result in a relative retraction with respect to the original target position, appears to occur before 7 years of age, suggesting careful monitoring is needed for children undergoing implantation before this age. Reengineering of electrode design could avoid reimplantation surgery in young children undergoing deep brain stimulation.

Radiotherapy treatment planning of prostate cancer using magnetic resonance imaging alone.

PURPOSE: Accurate anatomical delineation of the gross tumour volume (GTV) is crucial for effective radiotherapy (RT) treatment of prostate cancers. Although reference to pelvic magnetic resonance (MR) for improved delineation of the prostate is a regular practice in some clinics, MR has not replaced CT due to its geometrical distortions and lack of electron-density information. The possibility and practicality of using MR only for RT treatment planning were studied. MATERIALS AND METHODS: The addition of electron-density information to MR images for conformal radiotherapy (CRT) planning of the prostate was quantified by comparing dose distributions created on the homogeneous density- and bulk-density assigned images to original CT for four patients. To quantify the MR geometrical distortions measurements of a phantom imaged in CT (Siemens Somatom Plus 4) and FLASH 3D T1-weighted MR (1.5 T whole body Siemens Magnetom Vision) were compared. Dose statistics from CRT treatment plans made on CT and MR for five patient data were compared to determine if MR-only treatment plans can be made. RESULTS: The differences between dose-plans on bulk-density assigned images when compared to CT were less than 2% when water and bone values were assigned. Dose differences greater than 2% were observed when images of homogeneous-density assignment were compared to the CT. Phantom measurements showed that the distortions in the FLASH 3D T1-weighted MR averaged 2 mm in the volume of interest for prostate RT planning. For the CT and MR prostate planning study, doses delivered to the planning target volume (PTV) in CT and MR were always inside a 93-107% dose range normalised to the isocentre. Also, the doses to the organs-at-risk in the MR images were similar to the doses delivered to the volumes in the registered CT image when the organ volumes between the two images were similar. CONCLUSIONS: Negligible differences were observed in dose distribution between CRT plans using bone+water CT number bulk-assigned image and original CT. Also, the MR distortions were reduced to negligible amounts using large bandwidth MR sequence for prostate CRT planning. MR treatment planning was demonstrated using a large bandwidth sequence and bulk-assigned images. The development of higher quality, low distortion MR sequence will allow regular practice of this technique.