Sucrose activates human taste pathways differently from artificial sweetener

Animal models suggest that sucrose activates taste afferents differently than non-caloric sweeteners. Little information exists how artificial sweeteners engage central taste pathways in the human brain. We assessed sucrose and sucralose taste pleasantness across a concentration gradient in 12 healthy control women and applied 10% sucrose and matched sucralose during functional magnet resonance imaging. The results indicate that (1) both sucrose and sucralose activate functionally connected primary taste pathways; (2) taste pleasantness predicts left insula response; (3) sucrose elicits a stronger brain response in the anterior insula, frontal operculum, striatum and anterior cingulate, compared to sucralose; (4) only sucrose, but not sucralose, stimulation engages dopaminergic midbrain areas in relation to the behavioral pleasantness response. Thus, brain response distinguishes the caloric from the non-caloric sweetener, although the conscious mind could not. This could have important implications on how effective artificial sweeteners are in their ability to substitute sugar intake

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials

An Extended Amygdala Path with Implications for Early Life Stress

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Neurobiology and Anatomy, 2014.Early life stress (ELS) carries an increased risk for the development of anxiety disorders. The goal of this thesis was to examine gene expression profiles in a novel circuit through the primate amygdala implicated in persistent anxiety, and to determine how ELS may alter gene expression in this path. The amygdala may exert effects on anxiety behaviors through inputs to the lateral bed nucleus of the stria terminalis (BSTL). In Aim 1, I used tracing techniques and found that a unique region of the amygdala, the paralaminar nucleus (PL), projects to the BSTL in primates. This suggests a novel path by which the amygdala can influence anxiety responses. In primates, including humans, the adult PL contains a population of immature appearing cells, suggesting capabilities for neural growth not seen in other amygdala regions. Because the PL projects to the BSTL (Aim 1), developmental changes in PL immature appearing cells may be important in BSTL regulation. In Aim 2, I used laser capture and microarray to examine whether the infant PL is enriched in genes involved in neuronal maturation. Stress in early life can alter the developmental trajectory of maturing cells in the amygdala overall, resulting in precocious myelination, altered dendritic arborization and changes in the expression of synaptic plasticity genes. Altered neuronal maturation may be one mechanism through which ELS may alter PL structure and function, with consequences for downstream effector sites including the BSTL. In Aim 3, I used similar molecular techniques to determine whether ELS alters the expression of genes involved in neuronal maturation in the PL of stressed infant monkeys compared to controls. Results of our gene expression studies confirm and extend previous data: cells in the PL have an increased expression of specific genes involved in neuronal maturation relative to an amygdala nucleus lacking immature appearing cells (Aim 2). Moreover, exposure to ELS decreases the expression of genes involved in neuronal maturation (Aim 3). In conclusion, ELS may affect neural development in the PL, which may ultimately alter circuitry that influences anxious behavioral responding through output channels such as the BSTL

Changes in exploratory behavior and cell proliferation in the amygdala following repeated variable stress in male rats : focus on adolescence

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Neurobiology and Anatomy, 2014.Adolescence is a developmental stage characterized by changes in exploratory behavior and neural organization. The amygdala, a key structure in the temporal lobe, is important for mediating exploratory behaviors, and continues to undergo plastic changes during adolescence. Stressful events can cause long-lasting changes in both exploratory behavior and brain development, suggesting that the adolescent amygdala may be affected. In these studies I examined whether a repeated variable stress (RVS) in male rats influenced exploratory behavior and a unique form of amygdala plasticity-- cellular proliferation-- focusing on adolescent animals. In Aim 1, I compared the effects of RVS exposure in adolescent and adult rats on exploratory behavior six weeks later. Exploratory behavior in a novel anxiogenic, but not an anxiolytic, environment was significantly decreased in both age groups. In Aim 2, I quantified the number of dividing cells in the amygdala of adolescent and adult animals, assayed using bromodeoxyuridine (BrdU) and immunocytochemical expression of neural markers. Normal adolescent rats showed 4-5 times more dividing cells in the amygdala than young adult animals. BrdU pulse-chase studies indicated that at least a portion of cells divide locally in the adolescent amygdala, leaving open the possibility that dividing cells are also migrating in. Further characterization with neural markers showed that BrdU-labeled cells do not show the developmental profile of typical neuronal precursors. Finally, in Aim 3, I determined how RVS, which significantly altered exploratory behavior (Aim 1), influences cell proliferation/survival in the adolescent amygdala. Adolescent rats were administered RVS, injected with BrdU, and sacrificed either 24 hours or 10 days later. In stressed animals, the number of BrdU-positive cells significantly decreased 10 days post-BrdU (12 days post-RVS), but did not change 24 hours post-BrdU (2 days post-RVS). This suggests that RVS exerts effects over a delayed time course, possibly through apoptosis or cell cycle arrest. In sum, RVS exposure decreases exploratory behavior in a novel anxiogenic environment and has delayed consequences for the number of dividing cell in the adolescent amygdala. RVS-induced behavioral changes may correlate with cell proliferation reduction, suggesting a potential anatomical link between amygdala plasticity and future behavior in anxiogenic environments

Defining Limbic Subsystems: Examining a Functional Reward Network and Cortico-Amygdala-Striatal Anatomic Circuits

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Neurobiology and Anatomy, 2012.The limbic system was conceived as a set of cortical and subcortical neural regions responsible for emotional processing. Since ‘limbic system’ was coined by Paul MacLean, this concept has been criticized for its nonspecificity, yet remains highly influential for affective neuroscience. This doctoral thesis studied the functional and structural relationships between limbic structures by inspecting: 1.) a functional incentive processing network, and; 2.) anatomic cortico-amygdala-striatal circuits. Experiment 1 used functional magnetic resonance imaging (fMRI) to examine the effective connectivity of an a priori designated network composed of the nucleus accumbens, anterior insula, and medial thalamus during incentive anticipation in healthy human adults and adolescents. Results demonstrated that the best-fit model involved all possible anatomic connections across the three regions, and that, across the whole task, the thalamus and insula significantly influenced the nucleus accumbens. The network was used similarly during loss and gain anticipation, and between adults and adolescents. In Experiment 2, the prefrontal and insula cortical inputs, and striatal outputs, of amygdala subregions were charted following the placement of bidirectional tracers in the macaque amygdala. Results demonstrated three main cortico-amygdala-striatal circuits that were organized according to degree of cortical laminar differentiation, and associated striatal outputs to, and beyond, the rostral ventral striatum. These circuits were layered in a hierarchical fashion in the amygdala such that the ventral amygdala hosted only one or two of these circuits, while the dorsal amygdala hosted all three circuits. These experiments provide further detail on the ‘system’ of the limbic system, and additionally give definition to subsystems of the limbic system. While the ‘limbic system’ as a whole may be vaguely defined, further research on limbic subsystems may reveal the combination of influences responsible for specific emotional processes