Cortisol After "Ecstasy" Ingestion Brvar, M; Kozelj, G; Osredkar, J ...
Journal of toxicology. Clinical toxicology,
06/2004, Letnik:
42, Številka:
4
Journal Article
Ecstasy (3,4 methyldioxymethamphetamine, MDMA) is a recreational drug. The volunteer studies did not give a clear answer to the dynamic of cortisol after MDMA poisoning. We report a case of ...intentional MDMA ingestion in which we obtained serial measurements of serum cortisol and MDMA levels.
The in vivo imaging probe 11C-PIB (Pittsburgh Compound B, N-methyl11C2-(4′-methylaminophenyl-6-hydroxybenzathiazole) is under evaluation as a key imaging tool in Alzheimer's disease (AD) and to date ...has been assumed to bind with high affinity and specificity to the amyloid structures associated with classical plaques (CPs), one of the pathological hallmarks of the disease. However, no studies have systematically investigated PIB binding to human neuropathological brain specimens at the tracer concentrations achieved during in vivo imaging scans. Using a combination of autoradiography and histochemical techniques, we demonstrate that PIB, in addition to binding CPs clearly delineates diffuse plaques and cerebrovascular amyloid angiopathy (CAA). The interaction of PIB with CAA was not fully displaceable and this may be linked to the apolipoprotein E-ε4 allele. PIB was also found to label neurofibrillary tangles, although the overall intensity of this binding was markedly lower than that associated with the amyloid-beta (Aβ) pathology. The data provide a molecular explanation for PIB's limited specificity in diagnosing and monitoring disease progression in AD and instead indicate that the ligand is primarily a non-specific marker of Aβ-peptide related cerebral amyloidosis.
Aims
To test the effect of the dipeptidyl peptidase‐4 inhibitor saxagliptin on adipose tissue inflammation and microvascular function, and whole‐body postprandial endothelial function.
Methods
A ...randomized, double‐blind, placebo‐controlled, parallel study was conducted between June 2013 and November 2016 in 44 overweight or obese people without diabetes (saxagliptin, n=28; placebo, n=16). Subcutaneous abdominal adipose tissue biopsies, a 4‐h fat‐enriched meal test and peripheral arterial tonometry for measurement of endothelial function were performed at baseline and after 6 weeks of treatment with saxagliptin (5 mg/day) or matching placebo.
Results
Forty participants were analysed (saxagliptin, n=26; placebo, n=14). Secretion of interleukin‐8 from adipose tissue explants was reduced after saxagliptin (median fold‐change from baseline: 0.8 saxagliptin vs 3.3 placebo; P=0.02). Adipose tissue expression of thioredoxin‐inhibitory protein (TxNIP) was lower after saxagliptin (0.75 vs 1.0; P=0.02), while there were no significant differences in adipose tissue secretion of interleukin‐1b, interleukin‐6 or macrophage chemoattractant protein 1 (MCP‐1), adipose tissue macrophage content, adipose tissue mRNA levels of mcp1, cd36, cd68, il6, il8, txnip and adpq, and activation of adipose tissue inflammatory pathways extracellular signal‐regulated kinase, c‐Jun N‐terminal kinase (JNK) and nuclear factor‐κB (NF‐ κB) or insulin‐induced vasodilation of adipose tissue arterioles. Postprandial plasma glucose was slightly lower (by an estimated 0.3 mmol/l; P=0.01), while postprandial insulin, triglyceride levels and endothelial function were unchanged after saxagliptin.
Conclusions
The effect of saxagliptin on adipose tissue inflammation was relatively modest, with many inflammatory markers unchanged. We also found no evidence that saxagliptin therapy improved adipose tissue arteriole vasodilation or postprandial endothelial function.
What's new?
Preclinical evidence indicates a pro‐inflammatory effect of adipose tissue dipeptidyl peptidase‐4 (DPP‐4), which may be alleviated by DPP‐4 inhibitors.
The present study found only a modest effect of the DPP‐4 inhibitor saxagliptin on multiple measures of adipose tissue inflammation and microvascular function.
The mild effects of saxagliptin on adipose tissue inflammation and microvascular function, fasting or postprandial plasma lipid profile and endothelial function may correspond to the largely neutral effect of saxagliptin and other DPP‐4 inhibitors on cardiovascular events in recent cardiovascular outcome trials.
Purpose
We compared the effects of hypobaric and normobaric hypoxia on select cardio-respiratory responses, oxidative stress and acute mountain sickness (AMS) severity in prematurely born ...individuals, known to exhibit blunted hypoxic ventilatory response.
Methods
Sixteen prematurely born but otherwise healthy males underwent two 8-h hypoxic exposures under: (1) hypobaric hypoxic HH; terrestrial altitude 3840 m; P
i
O
2
:90.2 (0.5) mmHg; BP: 478 (2) mmHg and (2) normobaric hypoxic NH; P
i
O
2
:90.6 (0.9) mmHg; F
i
O
2
:0.142 (0.001) condition. Resting values of capillary oxyhemoglobin saturation (SpO
2
), heart rate (HR) and blood pressure were measured before and every 2 h during the exposures. Ventilatory responses and middle cerebral artery blood flow velocity (MCAv) were assessed at rest and during submaximal cycling before and at 4 and 8 h. Plasmatic levels of selected oxidative stress and antioxidant markers and AMS symptoms were also determined at these time points.
Results
HH resulted in significantly lower resting (
P
= 0.010) and exercise (
P
= 0.004) SpO
2
as compared to NH with no significant differences in the ventilatory parameters, HR or blood pressure. No significant differences between conditions were found in resting or exercising MCAv and measured oxidative stress markers. Significantly lower values of ferric-reducing antioxidant power (
P
= 0.037) were observed during HH as opposed to NH. AMS severity was higher at 8 h compared to baseline (
P
= 0.002) with no significant differences between conditions.
Conclusion
These data suggest that, in prematurely born adults, 8-h exposure to hypobaric, as opposed to normobaric hypoxia, provokes greater reductions in systemic oxygenation and antioxidant capacity. Further studies investigating prolonged hypobaric exposures in this population are warranted.
Registration
NCT02780908 (ClinicalTrials.gov).
In recent years, several studies have addressed the issue of prenatal exposure to methylmercury (MeHg); however, few have actually analysed MeHg blood concentrations. Our study population included ...mothers and their new-borns from Slovenia (central region; N = 584) and Croatia (coastal region; N = 234). We have measurements of total Hg (THg) and MeHg in maternal hair, maternal peripheral blood, and cord blood. Cord blood Hg concentrations were low to moderate (median THg = 1.84 ng/g and MeHg = 1.69 ng/g). The proportion of THg as MeHg (%MeHg) in maternal and cord blood varied between 4% and 100% (coefficient of variation, CV = 32%) and between 8% and 100% (CV = 20%), respectively. Our data shows that variability of %MeHg was higher at lower blood THg levels. Concentrations of MeHg in maternal blood and cord blood were highly correlated (Rs = 0.943), in the case of inorganic Hg correlation was significant but weaker (Rs = 0.198). MeHg levels in maternal blood and cord blood were positively associated with seafood intake, maternal age, and negatively associated with pre-pregnancy BMI. Additionally, MeHg in maternal blood was positively associated with plasma selenium levels, and cord blood MeHg was negatively associated with parity. The results of multiple linear regression models showed that speciation analysis provides more defined estimation of prenatal exposure in association modelling. Associations between Hg exposure and cognitive performance of children (assessed using Bayley Scales of Infant and Toddler development) adjusted for maternal or child Apolipoprotein E genotypes showed higher model R2 and lower p-values when adjusted for MeHg compared to THg. This study demonstrates that Hg speciation improves the association between exposure and possible negative health effects.
•The variability of % Hg as MeHg substantially increases with lower levels of THg.•MeHg better predicts factors that affect blood concentrations of Hg.•Hg speciation improved models associating Hg exposure and neurodevelopment.
•Interstitial lung water accumulation at altitude might precede high-altitude pulmonary oedema development.•We studied independent effects of hypobaria on interstitial lung water accumulation ...following hypoxic exercise in prematurely born adults.•Short, moderate-intensity exercise provokes a significant increase in the interstitial lung water accumulation after 8 h of exposure to terrestrial but not simulated altitude.
We aimed to gauge the interstitial lung water accumulation following moderate-intensity exercise under normobaric and hypobaric hypoxic conditions in a group of preterm born but otherwise healthy young adults.
Sixteen pre-term-born individuals (age = 21±2yrs.; gestational age = 29±3wk.; birth weight = 1160±273 g) underwent two 8 -h hypoxic/altitude exposures in a cross-over manner: 1) Normobaric hypoxic exposure (NH; FIO2 = 0.142±0.001; PIO2 = 90.6±0.9 mmHg) 2) Hypobaric hypoxic exposure (HH; terrestrial high-altitude 3840 m; PIO2 = 90.2±0.5 mmHg). Interstitial lung water was assessed via quantification of B-Lines (using lung ultrasound) before (normoxia) and after 4-h and 8-h of respective exposures. At each time point, B-Lines were quantified before (Pre) and immediately after (Post) a 6-min moderate-intensity exercise.
The baseline B-lines count were comparable between both conditions (P = 0.191). A higher B-lines count was noted at Pre-H4 in HH versus NH (P = 0.0420). At Post-H8 B-lines score was significantly higher in HH (4.6 ± 1.6) than in NH (3.1 ± 1.4; P = 0.0073). Furthermore, at this time point, a significantly higher number of individuals with B-line scores ≥5 was observed in HH (n = 7) than in NH (n = 3; P = 0.0420).
These findings suggest that short moderate-intensity exercise provokes a significant increase in the interstitial lung water accumulation after 8 h of exposure to terrestrial but not simulated altitude (≈3840 m) in prematurely born adults. Further work is needed to elucidate the exact mechanisms of (moderate-intensity) exercise-induced interstitial lung water accumulation in this population and directly compare the obtained data to full-term born adults.
Pre-term birth is associated with numerous cardio-respiratory sequelae in children. Whether these impairments impact the responses to exercise in normoxia or hypoxia remains to be established. ...Fourteen prematurely-born (PREM) (Mean ± SD; gestational age 29 ± 2 weeks; age 9.5 ± 0.3 years), and 15 full-term children (CONT) (gestational age 39 ± 1 weeks; age 9.7 ± 0.9 years), underwent incremental exercise tests to exhaustion in normoxia (FiO
= 20.9%) and normobaric hypoxia (FiO
= 13.2%) on a cycle ergometer. Cardio-respiratory variables were measured throughout. Peak power output was higher in normoxia than hypoxia (103 ± 17 vs. 77 ± 18 W;
< 0.001), with no difference between CONT and PREM (94 ± 23 vs. 86 ± 19 W;
= 0.154). VO
peak was higher in normoxia than hypoxia in CONT (50.8 ± 7.2 vs. 43.8 ± 9.9 mL·kg
·min
;
< 0.001) but not in PREM (48.1 ± 7.5 vs. 45.0 ± 6.8 mL·kg
·min
;
= 0.137; interaction
= 0.044). Higher peak heart rate (187 ± 11 vs. 180 ± 10 bpm;
= 0.005) and lower stroke volume (72 ± 13 vs. 77 ± 14 mL;
= 0.004) were observed in normoxia
hypoxia in CONT, with no such differences in PREM (
= 0.218 and >0.999, respectively). In conclusion, premature birth does not appear to exacerbate the negative effect of hypoxia on exercise capacity in children. Further research is warranted to identify whether prematurity elicits a protective effect, and to clarify the potential underlying mechanisms.
Key points
High altitude‐induced hypoxia in humans evokes a pattern of breathing known as periodic breathing (PB), in which the regular oscillations corresponding to rhythmic expiration and ...inspiration are modulated by slow periodic oscillations.
The phase coherence between instantaneous heart rate and respiration is shown to increase significantly at the frequency of periodic breathing during acute and sustained normobaric and hypobaric hypoxia.
It is also shown that polymorphism in specific genes, NOTCH4 and CAT, is significantly correlated with this coherence, and thus with the incidence of PB.
Differences in phase shifts between blood flow signals and respiratory and PB oscillations clearly demonstrate contrasting origins of the mechanisms underlying normal respiration and PB.
These novel findings provide a better understanding of both the genetic and the physiological mechanisms responsible for respiratory control during hypoxia at altitude, by linking genetic factors with cardiovascular dynamics, as evaluated by phase coherence.
Periodic breathing (PB) occurs in most humans at high altitudes and is characterised by low‐frequency periodic alternation between hyperventilation and apnoea. In hypoxia‐induced PB the dynamics and coherence between heart rate and respiration and their relationship to underlying genetic factors is still poorly understood. The aim of this study was to investigate, through novel usage of time–frequency analysis methods, the dynamics of hypoxia‐induced PB in healthy individuals genotyped for a selection of antioxidative and neurodevelopmental genes. Breathing, ECG and microvascular blood flow were simultaneously monitored for 30 min in 22 healthy males. The same measurements were repeated under normoxic and hypoxic (normobaric (NH) and hypobaric (HH)) conditions, at real and simulated altitudes of up to 3800 m. Wavelet phase coherence and phase difference around the frequency of breathing (approximately 0.3 Hz) and around the frequency of PB (approximately 0.06 Hz) were evaluated. Subjects were genotyped for common functional polymorphisms in antioxidative and neurodevelopmental genes. During hypoxia, PB resulted in increased cardiorespiratory coherence at the PB frequency. This coherence was significantly higher in subjects with NOTCH4 polymorphism, and significantly lower in those with CAT polymorphism (HH only). Study of the phase shifts clearly indicates that the physiological mechanism of PB is different from that of the normal respiratory cycle. The results illustrate the power of time‐evolving oscillatory analysis content in obtaining important insight into high altitude physiology. In particular, it provides further evidence for a genetic predisposition to PB and may partly explain the heterogeneity in the hypoxic response.
Key points
High altitude‐induced hypoxia in humans evokes a pattern of breathing known as periodic breathing (PB), in which the regular oscillations corresponding to rhythmic expiration and inspiration are modulated by slow periodic oscillations.
The phase coherence between instantaneous heart rate and respiration is shown to increase significantly at the frequency of periodic breathing during acute and sustained normobaric and hypobaric hypoxia.
It is also shown that polymorphism in specific genes, NOTCH4 and CAT, is significantly correlated with this coherence, and thus with the incidence of PB.
Differences in phase shifts between blood flow signals and respiratory and PB oscillations clearly demonstrate contrasting origins of the mechanisms underlying normal respiration and PB.
These novel findings provide a better understanding of both the genetic and the physiological mechanisms responsible for respiratory control during hypoxia at altitude, by linking genetic factors with cardiovascular dynamics, as evaluated by phase coherence.
In 80% of patients, major life stressors precede onset of autoimmune diseases, including rheumatoid arthritis (RA) linking stress pathway activation to disease onset. We examined the contribution of ...high sympathetic nervous system activity to RA onset using the adjuvant-induced (AA) arthritis model in Lewis rats. Rats were immunized with complete Freund’s adjuvant to induce AA. From day (D)12 (disease onset) through D28, rats were treated with vehicle or 2 mg/kg/day moxonidine, an imidazoline receptor-1 agonist that acts centrally to reduce SNS tone. Disease outcome was assessed using dorsoplantar widths and X-ray analysis. Cytokines critical for inflammation and CD4+ Th cell development (interleukin (IL)-1 β , IL-10, tumor necrosis factor (TNF)- α , IL-6, IL-2, IL-4, IFN- γ , and tumor growth factor (TGF)- β ) were assessed in spleen, draining lymph node (DLN) and peripheral blood mononuclear cells (PBMCs) by enzyme-linked immunoassays. Treatment with moxonidine dramatically prevented hind foot inflammation and joint destruction in AA compared with vehicle treatment. In DLN cells, moxonidine treatment had no effect on cytokine production. In contrast, moxonidine treatment significantly reduced IL-1 β , IL-2, IL-4 and IFN- γ in PBMCs. Drug treatment decreased splenocyte production of TGF- β and IFN- γ by ∼ 50% and ∼ 30%, respectively. Lowering SNS tone effectively reduced clinical signs of disease and altered production of cytokines involved in inflammation and shifting the balance between auto-reactive CD4+Th cells and T regulatory cells in directions expected to limit disease activity.
SATB2
-associated syndrome (SAS) is an autosomal dominant neurogenetic multisystemic disorder. We describe two individuals with global developmental delay and hypotonia who underwent an extensive ...evaluation to rule out an underlying mitochondrial disorder before their eventual diagnosis of SAS. Although the strict application of the clinical mitochondrial disease score only led to the designation of “possible” mitochondrial disorder for these two individuals, other documented abnormalities included nonspecific neuroimaging findings on magnetic resonance imaging and magnetic resonance spectroscopy, decreased complex I activity on muscle biopsy for patient 2, and variation in the size and relative proportion of types of muscle fibers in the muscle biopsies that were aligned with mitochondrial diseases. SAS should be in the differential diagnoses of mitochondrial disorders, and broad-spectrum diagnostic tests such as exome sequencing need to be considered early in the evaluation process of undiagnosed neurodevelopmental disorders.
PDF
