Trends in prevalence, awareness, treatment and control of hypertension in the Republic of Seychelles (African region) between 1989 and 2013 [Poster]

Background: Few data exist on secular trends of high blood pressure (HBP) detection and control in low and middle income countries, particularly in the African region. This study examines trends of HBP over 25 years based on 4 independent population surveys. In the Seychelles, heath care is free to all inhabitants within a national health system, inclusive all HBP medications. Previous studies have shown a transition from traditional to cardiometabolic cardiovascular risk factors in Seychelles. Age adjusted cardiovascular disease mortality rates is high but decreasing over the last two decades.

Influence of CYP2D6 activity on pre-emptive analgesia by the N-methyl-D-aspartate antagonist dextromethorphan in a randomized controlled trial of acute pain.

BACKGROUND: There is some evidence that dextromethorphan (DM) is effective as a pre-emptive analgesic agent.  DM is mainly metabolized to dextrorphan (DOR) by CYP2D6 whose activity can be inhibited by pharmacologic intervention. OBJECTIVES: To investigate the efficacy of DM as a pre-emptive analgesic agent and describe the population pharmacokinetics in the presence of normal and poor CYP2D6 metabolism in acute post-operative pain. STUDY DESIGN: Double blind, randomized, placebo-controlled trial SETTING: Post-surgical analgesic consumption after knee ligament surgery, a setting of acute pain. METHODS: Forty patients were randomized to a single oral dose of 50 mg quinidine or placebo, administered 12 hours before 50 mg DM. Patients were genotyped for the major CYP2D6 and ABCB1 variants and phenotyped for CYP2D6 using urine DM/DOR metabolic ratios and blood samples for population pharmacokinetic modeling. RESULTS: Quinidine was effective in inhibiting CYP2D6 activity, with 2-fold reduction of DM to DOR biotransformation clearance, prolonged DM half-life, and increased DM systemic availability. Patients in the quinidine group required significantly less often NSAIDs than patients in the placebo group (35.3% vs. 75.0%, P = 0.022). The odds ratio for NSAID consumption in the placebo vs. quinidine group was 5.5 (95% confidence interval (CI) 1.3 - 22.7) at 48 hours after surgery. LIMITATIONS: While this study shows an impact of DM on pre-emptive analgesia and is mechanistically interesting, the findings need to be confirmed in larger trials. CONCLUSION: CYP2D6 inhibition by quinidine influenced the pre-emptive analgesic effectiveness of DM confirming that CYP2D6 phenotypic switch increases the neuromodulatory effect of oral dextromethorphan.

Combined report on the institutions under the control of the Iowa Department of Corrections for the five years ended June 30, 2007

Combined report on the institutions under the control of the Iowa Department of Corrections for the five years ended June 30, 2007

Combined report on the institutions under the control of the Iowa Department of Human Services for the five years ended June 30, 2007

Combined report on the institutions under the control of the Iowa Department of Human Services for the five years ended June 30, 2007

Neural control of vascular reactions: impact of emotion and attention.

This study investigated the neural regions involved in blood pressure reactions to negative stimuli and their possible modulation by attention. Twenty-four healthy human subjects (11 females; age = 24.75 ± 2.49 years) participated in an affective perceptual load task that manipulated attention to negative/neutral distractor pictures. fMRI data were collected simultaneously with continuous recording of peripheral arterial blood pressure. A parametric modulation analysis examined the impact of attention and emotion on the relation between neural activation and blood pressure reactivity during the task. When attention was available for processing the distractor pictures, negative pictures resulted in behavioral interference, neural activation in brain regions previously related to emotion, a transient decrease of blood pressure, and a positive correlation between blood pressure response and activation in a network including prefrontal and parietal regions, the amygdala, caudate, and mid-brain. These effects were modulated by attention; behavioral and neural responses to highly negative distractor pictures (compared with neutral pictures) were smaller or diminished, as was the negative blood pressure response when the central task involved high perceptual load. Furthermore, comparing high and low load revealed enhanced activation in frontoparietal regions implicated in attention control. Our results fit theories emphasizing the role of attention in the control of behavioral and neural reactions to irrelevant emotional distracting information. Our findings furthermore extend the function of attention to the control of autonomous reactions associated with negative emotions by showing altered blood pressure reactions to emotional stimuli, the latter being of potential clinical relevance.

Impact of physical activity on energy balance, food intake and choice in normal weight and obese children in the setting of acute social stress: a randomized controlled trial.

BACKGROUND: Psychological stress negatively influences food intake and food choices, thereby contributing to the development of childhood obesity. Physical activity can also moderate eating behavior and influence calorie intake. However, it is unknown if acute physical activity influences food intake and overall energy balance after acute stress exposure in children. We therefore investigated the impact of acute physical activity on overall energy balance (food intake minus energy expenditure), food intake, and choice in the setting of acute social stress in normal weight (NW) and overweight/obese (OW/OB) children as well as the impact of psychological risk factors. METHOD: After receiving written consent from their parents, 26 NW (BMI < 90(th) percentile) and 24 7-to 11-year-old OW (n = 5)/OB (n = 19, BMI ≥ 90(th) percentile) children were randomly allocated using computer-generated numbers (1:1, after stratification for weight status) to acute moderate physical or to sedentary activity for 30 min. Afterwards, all children were exposed to an acute social stressor. Children and their parents completed self-report questionnaires. At the end of the stressor, children were allowed to eat freely from a range of 12 different foods (6 sweet/6 salty; each of low/high caloric density). Energy balance, food intake/choice and obesity-related psychological risk factors were assessed. RESULTS: Lower overall energy balance (p = 0.019) and a decreased choice of low density salty foods (p < 0.001) in NW children compared with OW/OB children was found after acute moderate physical activity but not sedentary activity. Independent of their allocation, OW/OB children ate more high density salty foods (104 kcal (34 to 173), p = 0.004) following stress. They scored higher on impulsive behavior (p = 0.005), restrained eating (p < 0.001) and parental corporal punishment (p = 0.03), but these psychological factors were not related to stress-induced food intake/choice. Positive parenting tended to be related to lower intake of sweet high density food (-132 kcal, -277 to 2, p = 0.054). CONCLUSIONS: In the setting of stress, acute moderate physical activity can address energy balance in children, a benefit which is especially pronounced in the OW/OB. Positive parenting may act as a protective factor preventing stress-induced eating of comfort food. TRIAL REGISTRATION: clinicaltrials.gov NCT01693926 The study was a pilot study of a project funded by the Swiss National Science Foundation (CRSII3_147673).

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Ubiquitylation and control of renal na+ balance and blood pressure.

Ubiquitylation is crucial for regulating numerous cellular functions. In the kidney, ubiquitylation regulates the epithelial Na(+) channel ENaC. The importance of this process is highlighted in Liddle's syndrome, where mutations interfere with ENaC ubiquitylation, resulting in constitutive Na(+) reabsorption and hypertension. There is emerging evidence that NCC, involved in hypertensive diseases, is also regulated by ubiquitylation. Here, we discuss the current knowledge and recent findings in this field.

Counteraction of HLA-C-mediated immune control of HIV-1 by Nef.

A host genetic variant (-35C/T) correlates with increased human leukocyte antigen C (HLA-C) expression and improved control of HIV-1. HLA-C-mediated immunity may be particularly protective because HIV-1 is unable to remove HLA-C from the cell surface, whereas it can avoid HLA-A- and HLA-B-mediated immunity by Nef-mediated down-modulation. However, some individuals with the protective -35CC genotype exhibit high viral loads. Here, we investigated whether the ability of HIV-1 to replicate efficiently in the "protective" high-HLA-C-expression host environment correlates with specific functional properties of Nef. We found that high set point viral loads (sVLs) were not associated with the emergence of Nef variants that had acquired the ability to down-modulate HLA-C or were more effective in removing HLA-A and HLA-B from the cell surface. However, in individuals with the protective -35CC genotype we found a significant association between sVLs and the efficiency of Nef-mediated enhancement of virion infectivity and modulation of CD4, CD28, and the major histocompatibility complex class II (MHC-II)-associated invariant chain (Ii), while this was not observed in subjects with the -35TT genotype. Since the latter Nef functions all influence the stimulation of CD4(+) T helper cells by antigen-presenting cells, they may cooperate to affect both the activation status of infected T cells and the generation of an antiviral cytotoxic T-lymphocyte (CTL) response. In comparison, different levels of viremia in individuals with the common -35TT genotype were not associated with differences in Nef function but with differences in HLA-C mRNA expression levels. Thus, while high HLA-C expression may generally facilitate control of HIV-1, Nef may counteract HLA-C-mediated immune control in some individuals indirectly, by manipulating T-cell function and MHC-II antigen presentation.

Combined report on the institutions under the control of the Iowa Department of Human Services for the year ended June 30, 2008

Combined report on the institutions under the control of the Iowa Department of Human Services for the year ended June 30, 2008

Multifactorial ERβ and NOTCH1 control of squamous differentiation and cancer.

Downmodulation or loss-of-function mutations of the gene encoding NOTCH1 are associated with dysfunctional squamous cell differentiation and development of squamous cell carcinoma (SCC) in skin and internal organs. While NOTCH1 receptor activation has been well characterized, little is known about how NOTCH1 gene transcription is regulated. Using bioinformatics and functional screening approaches, we identified several regulators of the NOTCH1 gene in keratinocytes, with the transcription factors DLX5 and EGR3 and estrogen receptor β (ERβ) directly controlling its expression in differentiation. DLX5 and ERG3 are required for RNA polymerase II (PolII) recruitment to the NOTCH1 locus, while ERβ controls NOTCH1 transcription through RNA PolII pause release. Expression of several identified NOTCH1 regulators, including ERβ, is frequently compromised in skin, head and neck, and lung SCCs and SCC-derived cell lines. Furthermore, a keratinocyte ERβ-dependent program of gene expression is subverted in SCCs from various body sites, and there are consistent differences in mutation and gene-expression signatures of head and neck and lung SCCs in female versus male patients. Experimentally increased ERβ expression or treatment with ERβ agonists inhibited proliferation of SCC cells and promoted NOTCH1 expression and squamous differentiation both in vitro and in mouse xenotransplants. Our data identify a link between transcriptional control of NOTCH1 expression and the estrogen response in keratinocytes, with implications for differentiation therapy of squamous cancer.

Combined report on the institutions under the control of the Iowa Department of Corrections for the year ended June 30, 2008

Combined report on the institutions under the control of the Iowa Department of Corrections for the year ended June 30, 2008

Common genetic variation and the control of HIV-1 in humans.

To extend the understanding of host genetic determinants of HIV-1 control, we performed a genome-wide association study in a cohort of 2,554 infected Caucasian subjects. The study was powered to detect common genetic variants explaining down to 1.3% of the variability in viral load at set point. We provide overwhelming confirmation of three associations previously reported in a genome-wide study and show further independent effects of both common and rare variants in the Major Histocompatibility Complex region (MHC). We also examined the polymorphisms reported in previous candidate gene studies and fail to support a role for any variant outside of the MHC or the chemokine receptor cluster on chromosome 3. In addition, we evaluated functional variants, copy-number polymorphisms, epistatic interactions, and biological pathways. This study thus represents a comprehensive assessment of common human genetic variation in HIV-1 control in Caucasians.

HLA-C cell surface expression and control of HIV/AIDS correlate with a variant upstream of HLA-C.

A variant 35 kb upstream of the HLA-C gene (-35C/T) was previously shown to associate with HLA-C mRNA expression level and steady-state plasma HIV RNA levels. We genotyped this variant in 1,698 patients of European ancestry with HIV. Individuals with known seroconversion dates were used for disease progression analysis and those with longitudinal viral load data were used for viral load analysis. We further tested cell surface expression of HLA-C in normal donors using an HLA-C-specific antibody. We show that the -35C allele is a proxy for high HLA-C cell surface expression, and that individuals with high-expressing HLA-C alleles progress more slowly to AIDS and control viremia significantly better than individuals with low HLA-C expressing alleles. These data strongly implicate high HLA-C expression levels in more effective control of HIV-1, potentially through better antigen presentation to cytotoxic T lymphocytes or recognition and killing of infected cells by natural killer cells.