Hypoinsulinemia Regulates Amphetamine-Induced Reverse Transport of Dopamine

The behavioral effects of psychomotor stimulants such as amphetamine (AMPH) arise from their ability to elicit increases in extracellular dopamine (DA). These AMPH-induced increases are achieved by DA transporter (DAT)-mediated transmitter efflux. Recently, we have shown that AMPH self-administration is reduced in rats that have been depleted of insulin with the diabetogenic agent streptozotocin (STZ). In vitro studies suggest that hypoinsulinemia may regulate the actions of AMPH by inhibiting the insulin downstream effectors phosphotidylinositol 3-kinase (PI3K) and protein kinase B (PKB, or Akt), which we have previously shown are able to fine-tune DAT cell-surface expression. Here, we demonstrate that striatal Akt function, as well as DAT cell-surface expression, are significantly reduced by STZ. In addition, our data show that the release of DA, determined by high-speed chronoamperometry (HSCA) in the striatum, in response to AMPH, is severely impaired in these insulin-deficient rats. Importantly, selective inhibition of PI3K with LY294002 within the striatum results in a profound reduction in the subsequent potential for AMPH to evoke DA efflux. Consistent with our biochemical and in vivo electrochemical data, findings from functional magnetic resonance imaging experiments reveal that the ability of AMPH to elicit positive blood oxygen level–dependent signal changes in the striatum is significantly blunted in STZ-treated rats. Finally, local infusion of insulin into the striatum of STZ-treated animals significantly recovers the ability of AMPH to stimulate DA release as measured by high-speed chronoamperometry. The present studies establish that PI3K signaling regulates the neurochemical actions of AMPH-like psychomotor stimulants. These data suggest that insulin signaling pathways may represent a novel mechanism for regulating DA transmission, one which may be targeted for the treatment of AMPH abuse and potentially other dopaminergic disorders

Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.

CONTEXT: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. OBJECTIVE: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. DESIGN: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. SETTING: This was a multicenter retrospective study using information collected from 3 predominant centers. PATIENTS: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. MAIN OUTCOME MEASURES: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. RESULTS: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. CONCLUSIONS: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder

Higgs Physics at the CLIC Electron-Positron Linear Collider

The Compact Linear Collider (CLIC) is an option for a future e+e- collider operating at centre-of-mass energies up to 3 TeV, providing sensitivity to a wide range of new physics phenomena and precision physics measurements at the energy frontier. This paper is the first comprehensive presentation of the Higgs physics reach of CLIC operating at three energy stages: sqrt(s) = 350 GeV, 1.4 TeV and 3 TeV. The initial stage of operation allows the study of Higgs boson production in Higgsstrahlung (e+e- -> ZH) and WW-fusion (e+e- -> Hnunu), resulting in precise measurements of the production cross sections, the Higgs total decay width Gamma_H, and model-independent determinations of the Higgs couplings. Operation at sqrt(s) > 1 TeV provides high-statistics samples of Higgs bosons produced through WW-fusion, enabling tight constraints on the Higgs boson couplings. Studies of the rarer processes e+e- -> ttH and e+e- -> HHnunu allow measurements of the top Yukawa coupling and the Higgs boson self-coupling. This paper presents detailed studies of the precision achievable with Higgs measurements at CLIC and describes the interpretation of these measurements in a global fit.The Compact Linear Collider (CLIC) is an option for a future ${\mathrm{e}^{+}}{\mathrm{e}^{-}}$ collider operating at centre-of-mass energies up to $3\,\text {TeV}$ , providing sensitivity to a wide range of new physics phenomena and precision physics measurements at the energy frontier. This paper is the first comprehensive presentation of the Higgs physics reach of CLIC operating at three energy stages: $\sqrt{s} = 350\,\text {GeV}$ , 1.4 and $3\,\text {TeV}$ . The initial stage of operation allows the study of Higgs boson production in Higgsstrahlung ( ${\mathrm{e}^{+}}{\mathrm{e}^{-}} \rightarrow {\mathrm{Z}} {\mathrm{H}}$ ) and ${\mathrm{W}} {\mathrm{W}}$ -fusion ( ${\mathrm{e}^{+}}{\mathrm{e}^{-}} \rightarrow {\mathrm{H}} {{\nu }}_{\!\mathrm{e}} {\bar{{\nu }}}_{\!\mathrm{e}}$ ), resulting in precise measurements of the production cross sections, the Higgs total decay width $\varGamma _{{\mathrm{H}}}$ , and model-independent determinations of the Higgs couplings. Operation at $\sqrt{s} > 1\,\text {TeV}$ provides high-statistics samples of Higgs bosons produced through ${\mathrm{W}} {\mathrm{W}}$ -fusion, enabling tight constraints on the Higgs boson couplings. Studies of the rarer processes ${\mathrm{e}^{+}}{\mathrm{e}^{-}} \rightarrow \mathrm{t} {\bar{\mathrm{t}}} {\mathrm{H}}$ and ${\mathrm{e}^{+}}{\mathrm{e}^{-}} \rightarrow {\mathrm{H}} {\mathrm{H}} {{\nu }}_{\!\mathrm{e}} {\bar{{\nu }}}_{\!\mathrm{e}}$ allow measurements of the top Yukawa coupling and the Higgs boson self-coupling. This paper presents detailed studies of the precision achievable with Higgs measurements at CLIC and describes the interpretation of these measurements in a global fit

Mortality of emergency abdominal surgery in high-, middle- and low-income countries

Background: Surgical mortality data are collected routinely in high-income countries, yet virtually no low- or middle-income countries have outcome surveillance in place. The aim was prospectively to collect worldwide mortality data following emergency abdominal surgery, comparing findings across countries with a low, middle or high Human Development Index (HDI). Methods: This was a prospective, multicentre, cohort study. Self-selected hospitals performing emergency surgery submitted prespecified data for consecutive patients from at least one 2-week interval during July to December 2014. Postoperative mortality was analysed by hierarchical multivariable logistic regression. Results: Data were obtained for 10 745 patients from 357 centres in 58 countries; 6538 were from high-, 2889 from middle- and 1318 from low-HDI settings. The overall mortality rate was 1⋅6 per cent at 24 h (high 1⋅1 per cent, middle 1⋅9 per cent, low 3⋅4 per cent; P < 0⋅001), increasing to 5⋅4 per cent by 30 days (high 4⋅5 per cent, middle 6⋅0 per cent, low 8⋅6 per cent; P < 0⋅001). Of the 578 patients who died, 404 (69⋅9 per cent) did so between 24 h and 30 days following surgery (high 74⋅2 per cent, middle 68⋅8 per cent, low 60⋅5 per cent). After adjustment, 30-day mortality remained higher in middle-income (odds ratio (OR) 2⋅78, 95 per cent c.i. 1⋅84 to 4⋅20) and low-income (OR 2⋅97, 1⋅84 to 4⋅81) countries. Surgical safety checklist use was less frequent in low- and middle-income countries, but when used was associated with reduced mortality at 30 days. Conclusion: Mortality is three times higher in low- compared with high-HDI countries even when adjusted for prognostic factors. Patient safety factors may have an important role. Registration number: NCT02179112 (http://www.clinicaltrials.gov)

Optical coherence tomography as a biomarker of neurodegeneration in multiple sclerosis: A review.

Neurodegeneration is one the most important pathological factors which contributes to permanent disability in multiple sclerosis (MS). Optical coherence tomography (OCT) measurements of macular ganglion cell layer (mGCL) and retinal nerve fiber layer (RNFL) have been proposed as biomarkers of axonal damage in MS. The aim of this review is to describe the most relevant findings regarding OCT and axonal damage in MS. We have selected studies that describe retina impairment in MS patients, and those which quantitatively assess the relationship between OCT and physical disability, cognitive impairment and relationship between OCT and magnetic resonance imaging (MRI). Results show that there is a relationship between the degree of retinal layers reduction and physical or cognitive disability and degenerative changes in MRI

Solar imaging capabilities of the Brazilian decimetric array

En colaboración con la Universidad Federal de São Carlos, el Instituto Nacional de Pesquisas y la Universidad Federal de Santa María se hacen esfuerzos para desarrollar una tomograrfía solar utilizando imágenes solares obtenidas en varias longitudes de onda en distintos observatorios, en particular se utilizan imágenes de radio, con el objetivo de predecir la ocurrencia de perturbaciones solares y relacionarlas con efectos solar terrestres y de clima espacial. Se sugiere que la emisión decimétrica ocurre cerca de las regiones solares donde son aceleradas partículas o la energía de la ráfaga solar se libera. Sin embargo, aún no ha sido construido ningún radioheliógrafo con suficiente resolución espacial y temporal que opere en longitudes de onda decimétricas; debido a esto se hacen esfuerzos multi institucionales y multinacionales para desarrollar un radioheliógrafo solar decimétrico en forma de T. En este trabajo describimos las capacidades para formar imágenes de un heliógrafo solar de banda ancha en forma de T que opera entre 1.2 y 1.7 GHz que es capaz de obtener imágenes del disco solar con una resolución de 100 ms y una resolución angular de aproximadamente 4 minutos de arco. Con el desarrollo futuro del equipo se espera obtener una resolución angular de 18 x 24 segundos de arco que será comparable a las imágenes de rayos X que se obtuvieron con el satélite YOHKOH y las imágenes de radio del radioheliógrafo milimétrico de Nobeyama. doi: https://doi.org/10.22201/igeof.00167169p.2000.39.1.31

Modafinil Effects on Middle-Frequency Oscillatory Power During Rule Selection in Schizophrenia

Control-related cognitive processes such as rule selection are associated with cortical oscillations in the theta, alpha and, beta ranges, and modulated by catecholamine neurotransmission. Thus, a potential strategy for improving cognitive control deficits in schizophrenia would be to use pro-catecholamine pharmacological agents to augment these control-related oscillations. In a double-blind, placebo-controlled (within-subjects) study, we tested the effects of adjunctive single-dose modafinil 200 mg on rule-related 4–30 Hz oscillations in 23 stable schizophrenia patients, using EEG during cognitive control task performance. EEG data underwent time-frequency decomposition with Morlet wavelets to determine the power of 4–30 Hz oscillations. Modafinil (relative to placebo) enhanced oscillatory power associated with high-control rule selection in theta, alpha, and beta ranges, with modest effects during rule maintenance. Modafinil treatment in schizophrenia augments middle-frequency cortical oscillatory power associated with rule selection, and may subserve diverse subcomponent processes in proactive cognitive control

Sustained Modafinil Treatment Effects on Control-Related Gamma Oscillatory Power in Schizophrenia

Control-related cognitive processes such as rule selection and maintenance are associated with cortical oscillations in the gamma range, and modulated by catecholamine neurotransmission. Control-related gamma power is impaired in schizophrenia, and an understudied treatment target. It remains unknown whether pro-catecholamine pharmacological agents augment control-related gamma oscillations in schizophrenia. We tested the effects of 4-week fixed-dose daily adjunctive modafinil (MOD) 200 mg, in a randomized double-blind, placebo-controlled, parallel-groups design. Twenty-seven stable schizophrenia patients performed a cognitive control task during EEG, at baseline and after 4 weeks of treatment. EEG data underwent time-frequency decomposition with Morlet wavelets to determine power of 4–80 Hz oscillations. The modafinil group (n=14), relative to placebo group (n=13), exhibited enhanced oscillatory power associated with high-control rule selection in the gamma range after treatment, with additional effects during rule maintenance in gamma and sub-gamma ranges. MOD-treated patients who exhibited improved task performance with treatment also showed greater treatment-related delay period gamma compared with MOD-treated patients without improved performance. This is the first evidence in schizophrenia of augmentation of cognition-related gamma oscillations by an FDA-approved agent with therapeutic potential. Gamma oscillations represent a novel treatment target in this disorder, and modulation of catecholamine signaling may represent a viable strategy at this target

Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C

Context: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. Objective: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. Design: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. Setting: This was a multicenter retrospective study using information collected from 3 predominant centers. Patients: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. Main Outcome Measures: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. Results: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. Conclusions: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder. © 2020 The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society