Search

Marie Bastin, Fabrizio Andreelli Diabetology-Metabolism Department, Sorbonne Université, ICAN, Assistance Publique Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, F-75013, FranceCorrespondence: Fabrizio AndreelliDiabetology-Metabolism Department, Pitié-Salpêtrière Hospital, 47-83 Boulevard de l’Hôpital, Paris cedex 13, 75951, FranceEmail fabrizio.andreelli@aphp.frAbstract: The need for efficient and safe therapy to improve such metabolic diseases as obesity and type 2 diabetes mellitus is currently unmet. The development of dual GIPR–GLP1R coagonists that bind to either one or the other receptor (sequence-mixed dual agonists) has emerged as an innovative therapeutic strategy for obesity and type 2 diabetes. Combined activation of both receptors may act synergistically providing additive effects on glucose and body weight in comparison of GLP1 analogues alone. Preclinical studies have confirmed that GIPR–GLP1R coagonists improve several hallmarks of metabolic syndrome, such as obesity, hyperglycemia, and dyslipidemia. These metabolic benefits have been translated from mice to nonhuman primates and humans. Recent clinical trials have shown that coagonists induce significant benefits on body weight, fasting, and postprandial glucose levels, insulin sensitivity, and total cholesterol. Combined GIP- and GLP1R activators have the potential to become a treatment option for patients with type 2 diabetes.Keywords: incretins, type 2 diabetes, coagonists, GLP1, GIP, body weight

This paper adapts the minimum-lap-time simulation technologies developed in Formula One to NASCAR. The adaptation process requires recognition of the variable lateral curvature of some tracks, as well as the asymmetries of NASCAR-specification race cars that have been configured for high-speed oval tracks that are dominated by left-hand cornering. These asymmetries include different suspension characteristics on the left- and right-hand ends of each axle, different left- and right-hand tyres on each axle, as well as asymmetries in the car's aerodynamic performance. The results compare optimal control calculations, industrial simulation-based predictions and race-captured telemetry data. For the most part, these various data sources are in good agreement, with the importance of variable lateral camber highlighted. It is demonstrated how race car drivers have to find the best compromise between the conflicting objectives of exploiting the additional camber available on the outside of variable-camber tracks and increasing the travelled distance and racing line cornering curvature. [ABSTRACT FROM AUTHOR]

Objective To investigate brain structural connectivity in relation to cognitive abilities and systemic damage in systemic lupus erythematosus (SLE). Methods Structural and diffusion MRI data were acquired from 47 patients with SLE. Brains were segmented into 85 cortical and subcortical regions and combined with whole brain tractography to generate structural connectomes using graph theory. Global cognitive abilities were assessed using a composite variable g, derived from the first principal component of three common clinical screening tests of neurological function. SLE damage (LD) was measured using a composite of a validated SLE damage score and disease duration. Relationships between network connectivity metrics, cognitive ability and systemic damage were investigated. Hub nodes were identified. Multiple linear regression, adjusting for covariates, was employed to model the outcomes g and LD as a function of network metrics. Results The network measures of density (standardised ß = 0.266, p = 0.025) and strength (standardised ß = 0.317, p = 0.022) were independently related to cognitive abilities. Strength (standardised ß = –0.330, p = 0.048), mean shortest path length (standardised ß = 0.401, p = 0.020), global efficiency (standardised ß = –0.355, p = 0.041) and clustering coefficient (standardised ß = –0.378, p = 0.030) were independently related to systemic damage. Network metrics were not related to current disease activity. Conclusion Better cognitive abilities and more SLE damage are related to brain topological network properties in this sample of SLE patients, even those without neuropsychiatric involvement and after correcting for important covariates. These data show that connectomics might be useful for understanding and monitoring cognitive function and white matter damage in SLE. [ABSTRACT FROM AUTHOR]

Background: Iodine deficiency is one of the three key micronutrient deficiencies highlighted as major public health issues by the World Health Organisation. Iodine deficiency is known to cause brain structural alterations likely to affect cognition. However, it is not known whether or how different (lifelong) levels of exposure to dietary iodine influences brain health and cognitive functions. Methods: From 1091 participants initially enrolled in The Lothian Birth Cohort Study 1936, we obtained whole diet data from 882. Three years later, from 866 participants (mean age 72 yrs, SD ±0.8), we obtained cognitive information and ventricular, hippocampal and normal and abnormal tissue volumes from brain structural magnetic resonance imaging scans (n=700). We studied the brain structure and cognitive abilities of iodine-rich food avoiders/low consumers versus those with a high intake in iodine-rich foods (namely dairy and fish). Results: We identified individuals (n=189) with contrasting diets, i) belonging to the lowest quintiles for dairy and fish consumption, ii) milk avoiders, iii) belonging to the middle quintiles for dairy and fish consumption, and iv) belonging to the middle quintiles for dairy and fish consumption. Iodine intake was secured mostly though the diet (n=10 supplement users) and was sufficient for most (75.1%, median 193 μg/day). In individuals from these groups, brain lateral ventricular volume was positively associated with fat, energy and protein intake. The associations between iodine intake and brain ventricular volume and between consumption of fish products (including fish cakes and fish-containing pasties) and white matter hyperintensities (p=0.03) the latest being compounded by sodium, proteins and saturated fats, disappeared after type 1 error correction. Conclusion: In this large Scottish older cohort, the proportion of individuals reporting extreme (low vs. high)/medium iodine consumption is small. In these individuals, low iodine-rich food intake was associated with increased brain volume shrinkage, raising an important hypothesis worth being explored for designing appropriate guidelines. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to investigate fatigue and cognitive impairments in systemic lupus erythematous (SLE) in relation to diffuse white matter microstructural brain damage. Methods: Diffusion tensor MRI, used to generate biomarkers of brain white matter microstructural integrity, was obtained in patients with SLE and age-matched controls. Fatigue and cognitive function were assessed and related to SLE activity, clinical data and plasma biomarkers of inflammation and endothelial dysfunction. Results: Fifty-one patients with SLE (mean age 48.8±14.3 years) were included. Mean diffusivity (MD) was significantly higher in all white matter fibre tracts in SLE patients versus age-matched healthy controls (p<0.0001). Fatigue in SLE was higher than a normal reference range (p<0.0001) and associated with lower MD (ß=-0.61, p=0.02), depression (ß=0.17, p=0.001), anxiety (ß=0.13, p=0.006) and higher body mass index (ß=0.10, p=0.004) in adjusted analyses. Poorer cognitive function was associated with longer SLE disease duration (p=0.003) and higher MD (p=0.03) and, in adjusted analysis, higher levels of IL-6 (ß=-0.15, p=0.02) but not with MD. Meta-analysis (10 studies, n=261, including the present study) confirmed that patients with SLE have higher MD than controls. Conclusion: Patients with SLE have more microstructural brain white matter damage for age than the general population, but this does not explain increased fatigue or lower cognition in SLE. The association between raised IL-6 and worse current cognitive function in SLE should be explored in larger datasets. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the hypothesis that idiopathic intracranial hypertension is associated with diffuse brain oedema, using quantitative magnetic resonance imaging.Methods: Values for the mean diffusivity of water () and the proton longitudinal relaxation time (T1) were measured for various brain regions in 10 patients with idiopathic intracranial hypertension and 10 age, sex, and weight matched controls.Results: No significant differences in and T1 values were found between patient and control groups in any of the brain regions investigated.Conclusions: The results suggest that idiopathic intracranial hypertension is not associated with abnormalities of convective transependymal water flow leading to diffuse brain oedema. [ABSTRACT FROM AUTHOR]

Background and purpose Several studies have reported associations between brain iron deposits ( IDs), white matter hyperintensities ( WMHs) and cognitive ability in older individuals. Whether the association between brain IDs and cognitive abilities in older people is mediated by or independent of total brain tissue damage represented by WMHs visible on structural magnetic resonance imaging ( MRI) was examined. Methods Data from 676 community-dwelling individuals from the Lothian Birth Cohort 1936, with Mini-Mental State Examination scores >24, who underwent detailed cognitive testing and multimodal brain MRI at mean age 72.7 years were analysed. Brain IDs were assessed automatically following manual editing. WMHs were assessed semi-automatically. Brain microbleeds were visually counted. Structural equation modelling was used to test for mediation. Results Overall, 72.8% of the sample had IDs with a median total volume of 0.040 ml (i.e. 0.004% of the total brain volume). The total volume of IDs, significantly and negatively associated with general cognitive function (standardized β = −0.17, P < 0.01), was significantly and positively associated with WMH volume (std β = 0.13, P = 0.03). WMH volume had a significant negative association with general cognitive function, independent of IDs (std β = −0.13, P < 0.01). The association between cognition and IDs in the brain stem (and minimally the total brain iron load) was partially and significantly mediated by WMH volume ( P = 0.03). Conclusions The negative association between brain IDs and cognitive ability in the elderly is partially mediated by WMHs, with this mediation mainly arising from the iron deposition load in the brain stem. IDs might be an indicator of small vessel disease that predisposes to white matter damage, affecting the neuronal networks underlying higher cognitive functioning. [ABSTRACT FROM AUTHOR]

Context: Brain Iron Deposits (IDs) are associated with neurodegenerative diseases and impaired cognitive function in later life, but their cause is unknown. Animal studies have found evidence of relationships between dietary iron, calorie and cholesterol intake and brain iron accumulation. Objectives: To investigate the relationship between iron, calorie, and cholesterol intake, blood indicators of iron status, and brain IDs in humans. Design, Setting and Participants: Cohort of 1063 community-dwelling older individuals born in 1936 (mean age 72.7years, SD=0.7) with dietary information, results from blood sample analyses and brain imaging data contemporaneously in old age. Measurements: Magnetic Resonance Imaging was used to assess regional volumes of brain IDs in basal ganglia, brainstem, white matter, thalamus, and cortex/border with the corticomedullary junction, using a fully automatic assessment procedure followed by individual checking/correction where necessary. Haemoglobin, red cell count, haematocrit, mean cell volume, ferritin and transferrin were obtained from blood samples and typical daily intake of iron, calories, and cholesterol were calculated from a validated food-frequency questionnaire. Results: Overall, 72.8% of the sample that had valid MRI (n=676) had brain IDs. The median total volume of IDs was 40mm3, inter-quartile range (IQR)=196. Basal ganglia IDs (median=35, IQR=159.5 mm3), were found in 70.6% of the sample. IDs in the brainstem were found in 12.9% of the sample, in the cortex in 1.9%, in the white matter in 6.1% and in the thalamus in 1.0%. The median daily intake of calories was 1808.5kcal (IQR=738.5), of cholesterol was 258.5mg (IQR=126.2) and of total iron was 11.7mg (IQR=5). Iron, calorie or cholesterol intake were not directly associated with brain IDs. However, caloric intake was associated with ferritin, an iron storage protein (p=0.01). Conclusion: Our results suggest that overall caloric, iron and cholesterol intake are not associated with IDs in brains of healthy older individuals but caloric intake could be associated with iron storage. Further work is required to corroborate our findings on other samples and investigate the underlying mechanisms of brain iron accumulation. [ABSTRACT FROM AUTHOR]

To investigate the potential of therapies which reduce glucocorticoid action in patients with Type 2 diabetes we performed a randomized, double-blinded, placebo-controlled crossover study of acute glucocorticoid blockade, using the glucocorticoid receptor antagonist RU38486 (mifepristone) and cortisol biosynthesis inhibitor (metyrapone), in 14 men with Type 2 diabetes. Stable isotope dilution methodologies were used to measure the rates of appearance of glucose, glycerol, and free fatty acids (FFAs), including during a low-dose (10 mU-m ~2-min_1) hyperinsulinemic clamp, and subgroup analysis was conducted in patients with high or low liver fat content measured by magnetic resonance spectroscopy (n = 7/group). Glucocorticoid blockade lowered fasting glucose and insulin levels and improved insulin sensitivity of FFA and glycerol turnover and hepatic glucose production. Among this population with Type 2 diabetes high liver fat was associated with hyperinsulinemia, higher fasting glucose levels, peripheral and hepatic insulin resistance, and impaired suppression of FFA oxidation and FFA and glycerol turnover during hyperinsulinemia. Glucocorticoid blockade had similar effects in those with and without high liver fat. Longer term treatments targeting glucocorticoid action may be useful in Type 2 diabetes with and without fatty liver. [ABSTRACT FROM AUTHOR]

Efficient in-vitro propagation of Tylophora ovata (Lind.) Hook. Ex. Steud was carried out in this present investigation. Nodal segments from the healthy grown plants were used as explants for culturing. Explants were cultured on standard Murashige and Skoog (MS) medium supplemented with different concentration of benzyl amino purine (BAP) and naphthalene acetic acid (NAA) for primary shoot proliferation. Remarkable shoot proliferation was observed in MS medium containing BAP (2.5 mg/L) and NAA (3.5 mg/L). For rooting of the micro shoot, half strength MS medium supplemented with indole acetic acid IAA (2 mg/L) and 3-indole butyric acid IBA (2.5 mg/L) showed the best result. After acclimatization and transplantation, 100% of the in-vitro shoot delivered was found healthy in ex vivo condition. [ABSTRACT FROM AUTHOR]

Background: Most empirically derived antidepressants increase monoamine levels. The nuclei of cells synthesising these monoamines are located in the brainstem, and projection tracts such as the medial forebrain bundle reach virtually all other brain areas. Two studies of unipolar depressive illness using transcranial ultrasound have reported reduced echogenicity of the brainstem midline in unipolar depressed patients. This may be consistent with disruption of white matter tracts, including the medial forebrain bundle, and it has been suggested that the effect of such disruption could be reversed by antidepressants.Objective: To replicate these findings in a group of unipolar depressed patients and controls.Methods: Fifteen unipolar depressed patients and 15 controls were studied using transcranial ultrasound imaging and diffusion tensor magnetic resonance imaging (DT-MRI).Results: No difference in echogenicity of the brainstem midline of unipolar depressed patients was found. A possible trend (Cohen's d = 0.39) in the direction of previous studies was found. Although the echogenicity of the brainstem midline of the control group was found to be similar to previous reports, there was no reduction in the patient group. Additionally, no structural abnormality of the brainstem was identified using DT-MRI.Conclusions: While these data do not replicate the findings of previous studies reporting a significant reduction in the echogenicity of the brainstem midline in unipolar depressed patients, the ultrasound investigation indicated that there may be a trend in this direction. Given the importance of identifying the causes of depressive illness, it is important that other groups attempt similar studies. [ABSTRACT FROM AUTHOR]

Objectives: Our purpose was to investigate whether differences exist in the values and temporal evolution of mean diffusivity () and fractional anisotropy (FA) of grey and white matter after human ischaemic stroke. Methods: Thirty two patients with lesions affecting both grey and white mailer underwent serial diffusion tensor magnetic resonance imaging (DT-MRI) within 24 hours, and at 4-7 days, 10-14 days, 1 month, and 3 months after stroke. Multiple small circular regions of interest (ROI) were placed in the grey and white mailer within the lesion and in the contralateral hemisphere. Values of {grey}, {white}, FA{grey} and FA{white} were measured in these ROI at each time point and the ratios of ischaemic to normal contralateral values (R and FAR) calculated. Results: and FA showed different patterns of evolution after stroke. After an initial decline, the rate of increase of {grey} was faster than {white} from 4-7 to 10-14 days. FA{white} decreased more rapidly than FA{grey} during the first week, thereafter for both tissue types the FA decreased gradually. However, FA{white} was still higher than FA{grey} at three months indicating that some organised axonal structure remained. This effect was more marked in some patients than in others. R{grey} was significantly higher than R{white} within 24 hours and at 10-14 days (p<0.05), and FAR{white} was significantly more reduced than FAR{grey} at all time points (p<0.001). Conclusions: The values and temporal evolution of and FA are different for grey and white mailer after human ischaemic stroke. The observation that there is patient-to-patient variability in the degree of white matter structure remaining within the infarct at three months may have implications for predicting patient outcome. [ABSTRACT FROM AUTHOR]

Objectives: Glucocorticoids (dexamethasone) are thought to reduce peritumoural brain oedema by decreasing the permeability of neoplastic capillaries and/or enhancing the clearance of extracellular water. Diffusion tensor magnetic resonance imaging (DT-MRI) was used to measure the water diffusion parameters of oedematous and normal brain in a group of patients with intracranial tumours before and after steroid treatment.Methods: Fifteen patients with intracranial tumours (seven with high-grade glioma, four with metastatic carcinoma and four with meningioma) were examined before and 48-72 h after dexamethasone treatment (16 mg/day). The mean diffusivity () and fractional anisotropy (FA) were measured for oedematous brain and apparently normal contralateral white matter before and after steroid therapy.Results: In all three patient groups there was a significant decrease in of oedematous brain after steroid treatment (p<0.01). There was no significant change in FA of oedematous brain after treatment in any of the three groups. There was also no significant change in either or FA of apparently normal contralateral white matter after treatment.Conclusion: These data indicate that dexamethasone produces a localised reduction in the magnitude of extracellular water molecule mobility, and hence water content, in peritumoural oedematous brain. Furthermore, the magnitude of these changes is similar for both intra- and extra-axial tumours. [ABSTRACT FROM AUTHOR]

Background: There is growing evidence that schizophrenia is a disorder of cortical connectivity. Specifically, frontotemporal and frontoparietal connections are thought to be functionally impaired. Diffusion tensor magnetic resonance imaging (DT-MRI) is a technique that has the potential to demonstrate structural disconnectivity in schizophrenia.Aims: To investigate the structural integrity of frontotemporal and frontoparietal white matter tracts in schizophrenia.Method: Thirty patients with DSM-IV schizophrenia and thirty matched control subjects underwent DT-MRI and structural MRI. Fractional anisotropy - an index of the integrity of white matter tracts - was determined in the uncinate fasciculus, the anterior cingulum and the arcuate fasciculus and analysed using voxel-based morphometry.Results: There was reduced fractional anisotropy in the left uncinate fasciculus and left arcuate fasciculus in patients with schizophrenia compared with controls.Conclusions: The findings of reduced white matter tract integrity in the left uncinate fasciculus and left arcuate fasciculus suggest that there is frontotemporal and frontoparietal structural disconnectivity in schizophrenia. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD), schizophrenia (SCZ) and bipolar disorder (BP) are common, disabling and heritable psychiatric diseases with a complex overlapping polygenic architecture. Individuals with these disorders, as well as their unaffected relatives, show widespread structural differences in corticostriatal and limbic networks. Structural variation in many of these brain regions is also heritable and polygenic but whether their genetic architecture overlaps with that of major psychiatric disorders is unknown. We sought to address this issue by examining the impact of polygenic risk of MDD, SCZ, and BP on subcortical brain volumes and white matter (WM) microstructure in a large single sample of neuroimaging data; the UK Biobank Imaging study. The first release of UK Biobank imaging data comprised participants with overlapping genetic data and subcortical volumes (N = 978) and WM measures (N = 816). The calculation of polygenic risk scores was based on genome-wide association study results generated by the Psychiatric Genomics Consortium. Our findings indicated no statistically significant associations between either subcortical volumes or WM microstructure, and polygenic risk for MDD, SCZ or BP. These findings suggest that subcortical brain volumes and WM microstructure may not be closely linked to the genetic mechanisms of major psychiatric disorders. [ABSTRACT FROM AUTHOR]

Discusses research being done on the effectiveness of magnetic resonance spectroscopic imaging in predicting clinical outcome after stroke. Reference to a study by C. Cvoro and colleagues, presented at the autumn meeting of the British Geriatrics Societies in October 2004; Magnetic resonance imaging techniques used in the study; Results and conclusion.