Carbon dioxide protects simulated driving performance during severe hypoxia.

PURPOSE: We sought to determine the effect of acute severe hypoxia, with and without concurrent manipulation of carbon dioxide (CO2), on complex real-world psychomotor task performance. METHODS: Twenty-one participants completed a 10-min simulated driving task while breathing room air (normoxia) or hypoxic air (PETO2 = 45 mmHg) under poikilocapnic, isocapnic, and hypercapnic conditions (PETCO2 = not manipulated, clamped at baseline, and clamped at baseline + 10 mmHg, respectively). Driving performance was assessed using a fixed-base motor vehicle simulator. Oxygenation in the frontal cortex was measured using functional near-infrared spectroscopy. RESULTS: Speed limit exceedances were greater during the poikilocapnic than normoxic, hypercapnic, and isocapnic conditions (mean exceedances: 8, 4, 5, and 7, respectively; all p ≤ 0.05 vs poikilocapnic hypoxia). Vehicle speed was greater in the poikilocapnic than normoxic and hypercapnic conditions (mean difference: 0.35 km h-1 and 0.67 km h-1, respectively). All hypoxic conditions similarly decreased cerebral oxyhaemoglobin and increased deoxyhaemoglobin, compared to normoxic baseline, while total hemoglobin remained unchanged. CONCLUSIONS: These findings demonstrate that supplemental CO2 can confer a neuroprotective effect by offsetting impairments in complex psychomotor task performance evoked by severe poikilocapnic hypoxia; however, differences in performance are unlikely to be linked to measurable differences in cerebral oxygenation.

The association of psychosocial risk factors for mental health with a brain marker altered by inflammation: A translocator protein (TSPO) PET imaging study.

Psychiatric disorders associated with psychosocial risk factors, including depression and psychosis, have been shown to demonstrate increased microglia activity. Whilst preclinical studies indicate that psychosocial stress leads to increased levels of microglia in the frontal cortex, no study has yet been performed in humans. This study aimed at investigating whether psychosocial risk factors for depression and/or psychosis would be associated with alterations in a brain marker expressed by microglia, the translocator specific protein (TSPO) in humans. We used [11C]-PBR28 Positron Emission Tomography on healthy subjects exposed to childhood and adulthood psychosocial risk factors (high-risk group, N = 12) and age- and sex-matched healthy controls not exposed to childhood and adulthood psychosocial risk factors (low-risk group, N = 12). The [11C]-PBR28 volume of distribution (VT) and Distribution Volume Ratio (DVR) were measured in the total gray matter, and frontal, parietal, temporal, occipital lobes. Levels of childhood trauma, anxiety and depression were measured using respectively the Childhood Trauma Questionnaire, State-anxiety questionnaire and Beck Depression Inventory. Compared to the low-risk group, the high-risk group did not exhibit significant differences in the mean [11C]-PBR28 VT (F(1,20) = 1.619, p = 0.218) or DVR (F(1,22) = 0.952, p = 0.340) on any region. There were no significant correlations between the [11C]-PBR28 VT and DVRs in total gray matter and frontal lobe and measures of childhood trauma, anxiety and depression. Psychosocial risk factors for depression and/or psychosis are unlikely to be associated with alterations in [11C]-PBR28 binding, indicating that alterations in TSPO expression reported in these disorders is unlikely to be caused by psychosocial risk factors alone.

The methodology of TSPO imaging with positron emission tomography.

The 18-kDA translocator protein (TSPO) is consistently elevated in activated microglia of the central nervous system (CNS) in response to a variety of insults as well as neurodegenerative and psychiatric conditions. It is therefore a target of interest for molecular strategies aimed at imaging neuroinflammation in vivo. For more than 20 years, positron emission tomography (PET) has allowed the imaging of TSPO density in brain using [(11)C]-(R)-PK11195, a radiolabelled-specific antagonist of the TSPO that has demonstrated microglial activation in a large number pathological cohorts. The significant clinical interest in brain immunity as a primary or comorbid factor in illness has sparked great interest in the TSPO as a biomarker and a surprising number of second generation TSPO radiotracers have been developed aimed at improving the quality of TSPO imaging through novel radioligands with higher affinity. However, such major investment has not yet resulted in the expected improvement in image quality. We here review the main methodological aspects of TSPO PET imaging with particular attention to TSPO genetics, cellular heterogeneity of TSPO in brain tissue and TSPO distribution in blood and plasma that need to be considered in the quantification of PET data to avoid spurious results as well as ineffective development and use of these radiotracers.

Neurological deficits caused by tissue hypoxia in neuroinflammatory disease.

OBJECTIVE: To explore the presence and consequences of tissue hypoxia in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). METHODS: EAE was induced in Dark Agouti rats by immunization with recombinant myelin oligodendrocyte glycoprotein and adjuvant. Tissue hypoxia was assessed in vivo using 2 independent methods: an immunohistochemical probe administered intravenously, and insertion of a physical, oxygen-sensitive probe into the spinal cord. Indirect markers of tissue hypoxia (eg, expression of hypoxia-inducible factor-1α [HIF-1α], vessel diameter, and number of vessels) were also assessed. The effects of brief (1 hour) and continued (7 days) normobaric oxygen treatment on function were evaluated in conjunction with other treatments, namely administration of a mitochondrially targeted antioxidant (MitoQ) and inhibition of inducible nitric oxide synthase (1400W). RESULTS: Observed neurological deficits were quantitatively, temporally, and spatially correlated with spinal white and gray matter hypoxia. The tissue expression of HIF-1α also correlated with loss of function. Spinal microvessels became enlarged during the hypoxic period, and their number increased at relapse. Notably, oxygen administration significantly restored function within 1 hour, with improvement persisting at least 1 week with continuous oxygen treatment. MitoQ and 1400W also caused a small but significant improvement. INTERPRETATION: We present chemical, physical, immunohistochemical, and therapeutic evidence that functional deficits caused by neuroinflammation can arise from tissue hypoxia, consistent with an energy crisis in inflamed central nervous system tissue. The neurological deficit was closely correlated with spinal white and gray matter hypoxia. This realization may indicate new avenues for therapy of neuroinflammatory diseases such as MS.

Major ionic compositions of fine particulate matter in an animal feeding operation facility and its vicinity.

Animal feeding operations (AFOs) produce particulate matter (PM) and gaseous pollutants. Investigation of the chemical composition of PM2.5 inside and in the local vicinity of AFOs can help to understand the impact of the AFO emissions on ambient secondary PM formation. This study was conducted on a commercial egg production farm in North Carolina. Samples of PM2.5 were collected from five stations, with one located in an egg production house and the otherfour located in the vicinity ofthe farm alongfour wind directions. The major ions of NH4+, Na+, K+, SO4(2-), Cl-, and NO3- were analyzed using ion chromatography (IC). In the house, the mostly abundant ions were SO4(2-), Cl-, and K+. At ambient stations, SO4(2-), and NH4+ were the two most abundant ions. In the house, NH4+, SO4(2-), and NO3- accounted for only 10% of the PM2.5 mass; at ambient locations, NH4+, SO4(2-), and NO3- accounted for 36-41% of the PM2.5 mass. In the house, NH4+ had small seasonal variations indicating that gas- phase NH3. was not the only major force driving its gas-particle partitioning. At the ambient stations, NH4+ had the highest concentrations in summer In the house, K+, Na+, and Cl- were highly correlated with each other In ambient locations, SO4(2-) and NH4+ had a strong correlation, whereas in the house, SO4(2-) and NH4+ had a very weak correlation. Ambient temperature and solar radiation were positively correlated with NH4+ and SO4(2-). This study suggests that secondary PM formation inside the animal house was not an important source of PM2.5. In the vicinity, NH3 emissions had greater impact on PM2.5 formation.

The effect of acute normobaric hyperoxia on cognition: A systematic review, meta-analysis and meta-regression.

This systematic review, meta-analysis and meta-regression examined the effect of acute normobaric hyperoxic breathing on cognition in healthy humans. 23 studies were included providing 76 effect estimates (EE). Hyperoxic breathing improved memory accuracy (22 EEs; g = 0.34) and speed (9 EEs; g = 0.59), attention accuracy (7 EEs; g = 0.59) and speed (7 EEs; g = 0.51), reaction speed (8 EEs; g = 0.82), crystallised intelligence (7 EEs; g = 0.73), executive function (6 EEs; g = 0.88) and information processing (10 EEs; g = 0.62). However, the overall quality of evidence was low (average Rosendal score of 47%) and there was a large range of study heterogeneity, with prediction intervals often crossing 0; therefore, reducing the reliability of the magnitude of these favourable effects. Oxygen percentage, 100% compared with 22-99% oxygen, temporal position of administration to task performance, and study quality did not influence the overall weighted mean effects for most cognitive domains. Altogether, despite beneficial results, further high quality research is required prior to recommending hyperoxic breathing to enhance cognition.

Recovery from acute hypoxia: A systematic review of cognitive and physiological responses during the 'hypoxia hangover'.

Recovery of cognitive and physiological responses following a hypoxic exposure may not be considered in various operational and research settings. Understanding recovery profiles and influential factors can guide post-hypoxia restrictions to reduce the risk of further cognitive and physiological deterioration, and the potential for incidents and accidents. We systematically evaluated the available evidence on recovery of cognitive and basic physiological responses following an acute hypoxic exposure to improve understanding of the performance and safety implications, and to inform post-hypoxia restrictions. This systematic review summarises 30 studies that document the recovery of either a cognitive or physiological index from an acute hypoxic exposure. Titles and abstracts from PubMed (MEDLINE) and Scopus were searched from inception to July 2022, of which 22 full text articles were considered eligible. An additional 8 articles from other sources were identified and also considered eligible. The overall quality of evidence was moderate (average Rosendal score, 58%) and there was a large range of hypoxic exposures. Heart rate, peripheral blood haemoglobin-oxygen saturation and heart rate variability typically normalised within seconds-to-minutes following return to normoxia or hyperoxia. Whereas, cognitive performance, blood pressure, cerebral tissue oxygenation, ventilation and electroencephalogram indices could persist for minutes-to-hours following a hypoxic exposure, and one study suggested regional cerebral tissue oxygenation requires up to 24 hours to recover. Full recovery of most cognitive and physiological indices, however, appear much sooner and typically within ~2-4 hours. Based on these findings, there is evidence to support a 'hypoxia hangover' and a need to implement restrictions following acute hypoxic exposures. The severity and duration of these restrictions is unclear but should consider the population, subsequent requirement for safety-critical tasks and hypoxic exposure.

Cocoa flavanols protect cognitive function, cerebral oxygenation, and mental fatigue during severe hypoxia.

We tested the hypothesis that ingestion of cocoa flavanols would improve cognition during acute hypoxia equivalent to 5,500 m altitude (partial pressure of end-tidal oxygen = 45 mmHg). Using placebo-controlled double-blind trials, 12 participants ingested 15 mg·kg-1 of cocoa flavanols 90 min before completing cognitive tasks during normoxia and either poikilocapnic or isocapnic hypoxia (partial pressure of end-tidal carbon dioxide uncontrolled or maintained at the baseline value, respectively). Cerebral oxygenation was measured using functional near-infrared spectroscopy. Overall cognition was impaired by poikilocapnic hypoxia (main effect of hypoxia, P = 0.008). Cocoa flavanols improved a measure of overall cognitive performance by 4% compared with placebo (effect of flavanols, P = 0.033) during hypoxia, indicating a change in performance from "low average" to "average." The hypoxia-induced decrease in cerebral oxygenation was two-fold greater with placebo than with cocoa flavanols (effect of flavanols, P = 0.005). Subjective fatigue was increased by 900% with placebo compared with flavanols during poikilocapnic hypoxia (effect of flavanols, P = 0.004). Overall cognition was impaired by isocapnic hypoxia (effect of hypoxia, P = 0.001) but was not improved by cocoa flavanols (mean improvement = 1%; effect of flavanols, P = 0.72). Reaction time was impaired by 8% with flavanols during normoxia and further impaired by 11% during isocapnic hypoxia (effect of flavanols, P = 0.01). Our findings are the first to show that flavanol-mediated improvements in cognition and mood during normoxia persist during severe oxygen deprivation, conferring a neuroprotective effect.NEW & NOTEWORTHY We show for the first time that cocoa flavanols exert a neuroprotective effect during severe hypoxia. Following acute cocoa flavanol ingestion, we observed improvements in cognition, cerebral oxygenation, and subjective fatigue during normoxia and severe poikilocapnic hypoxia. Cocoa flavanols did not improve cognition during severe isocapnic hypoxia, suggesting a possible interaction with carbon dioxide.

Cerebral haemodynamics during simulated driving: Changes in workload are detectable with functional near infrared spectroscopy.

Motor vehicle operation is a complicated task and substantial cognitive resources are required for safe driving. Experimental paradigms examining cognitive workload using driving simulators often introduce secondary tasks, such as mathematical exercises, or utilise simulated in-vehicle information systems. The effects of manipulating the demands of the primary driving task have not been examined in detail using advanced neuroimaging techniques. This study used a manipulation of the simulated driving environment to test the impact of increased driving complexity on brain activity. Fifteen participants drove in two scenarios reflecting common driving environments differing in the amount of vehicular traffic, frequency of intersections, number of buildings, and speed limit restrictions. Functional near infrared spectroscopy was used to quantify changes in cortical activity; fifty-five optodes were placed over the prefrontal and occipital cortices, commonly assessed areas during driving. Compared to baseline, both scenarios increased oxyhaemoglobin in the bilateral prefrontal cortex and cerebral blood volume in the right prefrontal cortex (all p ≤ 0.05). Deoxyhaemoglobin decreased at the bilateral aspects of the prefrontal cortex but overall tended to increase in the medial aspect during both scenarios (both p ≤ 0.05). Cerebral oxygen exchange significantly declined at the lateral aspects of the prefrontal cortex, with a small but significant increase seen in the medial aspect (both p < 0.05). There were no significant differences for oxyhaemoglobin, deoxyhaemoglobin, or cerebral blood volume (all p > 0.05). This study demonstrates that functional near infrared spectroscopy is capable of detecting changes in cortical activity elicited by simulated driving tasks but may be less sensitive to variations in driving workload aggregated over a longer duration.

Preclinical Evaluation of TSPO and MAO-B PET Radiotracers in an LPS Model of Neuroinflammation.

Discovery of novel PET radiotracers targeting neuroinflammation (microglia and astrocytes) is actively pursued. Employing a lipopolysaccharide (LPS) rat model, this longitudinal study evaluated the translocator protein 18-kDa radiotracer [18F]FEPPA (primarily microglia) and monoamine oxidase B radiotracers [11C]L-deprenyl and [11C]SL25.1188 (astrocytes preferred). Increased [18F]FEPPA binding peaked at 1 week in LPS-injected striatum whereas increased lazabemide-sensitive [11C]L-deprenyl binding developed later. No increase in radiotracer uptake was observed for [11C]SL25.1188. The unilateral intrastriatal LPS rat model may serve as a useful tool for benchmarking PET tracers targeted toward distinct phases of neuroinflammatory reactions involving both microglia and astrocytes.

Synthesis, in vitro and in vivo evaluation of 11C-O-methylated arylpiperazines as potential serotonin 1A (5-HT1A) receptor antagonist radiotracers.

BACKGROUND: Serotonin 1A (5-HT1A) receptors are implicated in the pathogenesis of several psychiatric and neurodegenerative disorders motivating the development of suitable radiotracers for in vivo positron emission tomography (PET) neuroimaging. The gold standard PET imaging agent for this target is [carbonyl-11C]WAY-100635, labeled via a technically challenging multi-step reaction that has limited its widespread use. While several antagonist and agonist-based PET radiotracers for 5-HT 1A receptors have been developed, their clinical translation has been hindered by methodological challenges and/or and non-specific binding. As a result, there is continued interest in the development of new and more selective 5-HT1A PET tracers having a relatively easier and reliable radiosynthesis process for routine production and with favorable metabolism to facilitate tracer-kinetic modeling. The purpose of the current study was to develop and characterize a radioligand with suitable characteristics for imaging 5-HT1A receptors in the brain. The current study reports the in vitro characterization and radiosyntheses of three candidate 5-HT1A receptor antagonists, DF-100 (1), DF-300 (2) and DF-400 (3), to explore their suitability as potential PET radiotracers. RESULTS: Syntheses of 1-3 and corresponding precursors for radiolabeling were achieved from isonicotinic, picolinic acid or picolino nitrile. In vitro binding studies demonstrated nanomolar affinity of the compounds for 5-HT1A receptors. Binding of 1-3 for other biogenic amines, neurotransmitter receptors, and transporters was negligible with the exception of moderate affinities for α1-adrenergic receptors (4-6-fold less potent than that for 5-HT1A receptor). Radioligands [11C]1-3 were efficiently prepared by 11C-O-methylation of the corresponding phenolic precursor in non-decay corrected radiochemical yields of 7-11% with > 99% chemical and radiochemical purities. Dynamic PET studies in rats demonstrated negligible brain uptake of [11C]1 and [11C]2. In contrast, significant brain uptake of [11C]3 was observed with an early peak SUV of 4-5. However, [11C]3 displayed significant off-target binding attributed to α1-adrenergic receptors based on regional distribution (thalamus>hippocampus) and blocking studies. CONCLUSION: Despite efficient radiolabeling, results from PET imaging experiments limit the application of [11C]3 for in vivo quantification of 5-HT1A receptors. Nevertheless, derivatives of compound 3 may provide a scaffold for alternative PET radiotracers with improved selectivity for 5-HT 1A receptors or α1-adrenergic receptors.

Spatial and temporal variations of PM2.5 mass closure and inorganic PM2.5 in the Southeastern U.S.

Fine particulate matter (i.e., PM2.5) has gained extensive attention owing to its adverse effects. The impacts of PM2.5 may vary in time and space due to the spatiotemporal variations of PM2.5 number size distribution and chemical compositions. This research analyzed the latest PM2.5 chemical compositions measurements with an aim to better understand the dynamic changes of PM2.5 in response to emission reductions due to the new regulations. The particulate measurements from the Southeastern Aerosol Research and Characterization (SEARCH) network between 2001 and 2016 were analyzed for the spatiotemporal variations of PM2.5 and inorganic PM2.5 (iPM2.5 = SO42- + NH4+ + NO3-) chemical compositions in the Southeastern United States (U.S.). It was discovered that PM2.5 and iPM2.5 mass concentrations exhibited significant downward trends in 2001-2016. Both PM2.5 and iPM2.5 mass concentrations were higher at urban and inland sites than rural/suburban and coastal sites. The higher iPM2.5 concentrations at agricultural sites were attributed to the influences of ammonia (NH3) emissions from animal feeding operations (AFOs). The iPM2.5 was the dominant contributor to PM2.5 in 2001-2016 at the coastal sites, whereas organic carbon matter (OCM) was the major contributor to PM2.5 after 2011 at the inland sites. Our data analysis suggests that significant decrease of PM2.5 concentrations is attributed to the reductions in nitrogen oxides (NOx) and sulfur dioxide (SO2) emissions in 2001-2016. Findings from this research provide insights into the development of effective PM2.5 control strategies and assessment of air pollutants exposure.

A Unified Framework for Plasma Data Modeling in Dynamic Positron Emission Tomography Studies.

OBJECTIVE: Full quantification of dynamic positron emission tomography (PET) data requires the knowledge of tracer concentration in the arterial plasma. However, its accurate measurement is challenging due to the presence of radiolabeled metabolites and measurement noise. Mathematical models are fitted to the plasma data for both radiometabolite correction and data denoising. However, the models used are generally not physiologically informed and not consistently applied across studies even when quantifying the kinetics of the same radiotracer, introducing methodological variability affecting the results interpretation. The aim of this study was to develop and validate a unified framework for the arterial data modeling to achieve an accurate and fully automated description of the plasma tracer kinetics. METHODS: The proposed pipeline employs basis pursuit techniques for estimating both radiometabolites and parent concentration models from the raw plasma measurements, allowing the resulting algorithm to be both robust and flexible to the different quality of data available. The pipeline was tested on four PET tracers ([11C]PBR28, [11C]MePPEP, [11C]WAY-100635, and [11C]PIB) with continuous and discrete blood sampling. RESULTS: Compared to the standard procedure, the pipeline provided similar fit of the parent fraction but yielded a better description of the total plasma radioactivity, which in turn allowed a more accurate fit of the tissue PET data. CONCLUSION: The new method showed superior fits compared to the standard pipeline, for both continuous and discrete arterial sampling protocol, yielding to better description of PET data. SIGNIFICANCE: The proposed pipeline has the potential to standardize the blood data modeling in dynamic PET studies given its robustness, flexibility and easiness of use.

Generalization of endothelial modelling of TSPO PET imaging: Considerations on tracer affinities.

The 18 kDa translocator protein (TSPO) is a marker of microglia activation and the main target of positron emission tomography (PET) ligands for neuroinflammation. Previous works showed that accounting for TSPO endothelial binding improves PET quantification for [11C]PBR28, [18F]DPA714 and [11C]-R-PK11195. It is still unclear, however, whether the vascular signal is tracer-dependent. This work aims to explore the relationship between the TSPO vascular and tissue components for PET tracers with varying affinity, also assessing the impact of affinity towards the differentiability amongst kinetics and the ensuing ligand amenability to cluster analysis for the extraction of a reference region. First, we applied the compartmental model accounting for vascular binding to [11C]-R-PK11195 data from six healthy subjects. Then, we compared the [11C]-R-PK11195 vascular binding estimates with previously published values for [18F]DPA714 and [11C]PBR28. Finally, we determined the suitability for reference region extraction by calculating the angle between grey and white matter kinetics. Our results showed that endothelial binding is common to all TSPO tracers and proportional to their affinity. By consequence, grey and white matter kinetics were most similar for the radioligand with the highest affinity (i.e. [11C]PBR28), hence poorly suited for the extraction of a reference region using supervised clustering.

Theta burst stimulation-induced inhibition of dorsolateral prefrontal cortex reveals hemispheric asymmetry in striatal dopamine release during a set-shifting task: a TMS-[(11)C]raclopride PET study.

The prefrontostriatal network is considered to play a key role in executive functions. Previous neuroimaging studies have shown that executive processes tested with card-sorting tasks requiring planning and set-shifting [e.g. Montreal-card-sorting-task (MCST)] may engage the dorsolateral prefrontal cortex (DLPFC) while inducing dopamine release in the striatum. However, functional imaging studies can only provide neuronal correlates of cognitive performance and cannot establish a causal relation between observed brain activity and task performance. In order to investigate the contribution of the DLPFC during set-shifting and its effect on the striatal dopaminergic system, we applied continuous theta burst stimulation (cTBS) to left and right DLPFC. Our aim was to transiently disrupt its function and to measure MCST performance and striatal dopamine release during [(11)C]raclopride PET. A significant hemispheric asymmetry was observed. cTBS of the left DLPFC impaired MCST performance and dopamine release in the ipsilateral caudate-anterior putamen and contralateral caudate nucleus, as compared to cTBS of the vertex (control). These effects appeared to be limited only to left DLPFC stimulation while right DLPFC stimulation did not influence task performance or [(11)C]raclopride binding potential in the striatum. This is the first study showing that cTBS, by disrupting left prefrontal function, may indirectly affect striatal dopamine neurotransmission during performance of executive tasks. This cTBS-induced regional prefrontal effect and modulation of the frontostriatal network may be important for understanding the contribution of hemisphere laterality and its neural bases with regard to executive functions, as well as for revealing the neurochemical substrate underlying cognitive deficits.

A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis.

BACKGROUND: Calcific aortic stenosis has many characteristics in common with atherosclerosis, including hypercholesterolemia. We hypothesized that intensive lipid-lowering therapy would halt the progression of calcific aortic stenosis or induce its regression. METHODS: In this double-blind, placebo-controlled trial, patients with calcific aortic stenosis were randomly assigned to receive either 80 mg of atorvastatin daily or a matched placebo. Aortic-valve stenosis and calcification were assessed with the use of Doppler echocardiography and helical computed tomography, respectively. The primary end points were change in aortic-jet velocity and aortic-valve calcium score. RESULTS: Seventy-seven patients were assigned to atorvastatin and 78 to placebo, with a median follow-up of 25 months (range, 7 to 36). Serum low-density lipoprotein cholesterol concentrations remained at 130+/-30 mg per deciliter in the placebo group and fell to 63+/-23 mg per deciliter in the atorvastatin group (P<0.001). Increases in aortic-jet velocity were 0.199+/-0.210 m per second per year in the atorvastatin group and 0.203+/-0.208 m per second per year in the placebo group (P=0.95; adjusted mean difference, 0.002; 95 percent confidence interval, -0.066 to 0.070 m per second per year). Progression in valvular calcification was 22.3+/-21.0 percent per year in the atorvastatin group, and 21.7+/-19.8 percent per year in the placebo group (P=0.93; ratio of post-treatment aortic-valve calcium score, 0.998; 95 percent confidence interval, 0.947 to 1.050). CONCLUSIONS: Intensive lipid-lowering therapy does not halt the progression of calcific aortic stenosis or induce its regression. This study cannot exclude a small reduction in the rate of disease progression or a significant reduction in major clinical end points. Long-term, large-scale, randomized, controlled trials are needed to establish the role of statin therapy in patients with calcific aortic stenosis.

Vascular B1 kinin receptors in patients with congestive heart failure.

Animal models suggest a vasomotor role for the B1 kinin receptor in cardiovascular disease states. In patients with heart failure treated with angiotensin-converting enzyme inhibition (ACEi), or combined B1/B2 receptor antagonism, but not B2 receptor antagonism alone, causes vasoconstriction. However, B1 agonism has no effect on vasomotor or fibrinolytic function. Findings from transgenic animals lacking the B2 receptor suggest that these conflicting data may be explained by cross-talk between B1 and B2 receptors. We hypothesized that B1 stimulation causes vasodilatation and tissue plasminogen activator release in the human forearm when B2 receptor signaling is inhibited. Forearm blood flow was measured in 16 patients with heart failure receiving ACEi. In double-blinded crossover studies, intrabrachial Lys-[Leu8]-des-Arg9-bradykinin (B1 antagonist), lys-des-Arg9-bradykinin (B1 agonist), bradykinin (B2 agonist), and sodium nitroprusside (endothelium-independent vasodilator) were infused alone or with HOE-140 (B2 antagonist). HOE-140 did not affect basal vascular tone or t-PA release, but it abolished bradykinin-induced vasodilatation and t-PA release (P < 0.0001). Blood flow and t-PA release were unaffected by B1 agonism or antagonism in the presence and absence HOE-140. Our findings do not support a role for crosstalk between the B1 and B2 kinin receptors in the human peripheral circulation.

The effects of haloperidol on microglial morphology and translocator protein levels: An in vivo study in rats using an automated cell evaluation pipeline.

BACKGROUND: Altered microglial markers and morphology have been demonstrated in patients with schizophrenia in post-mortem and in vivo studies. However, it is unclear if changes are due to antipsychotic treatment. AIMS: Here we aimed to determine whether antipsychotic medication affects microglia in vivo. METHODS: To investigate this we administered two clinically relevant doses (0.05 mg n=12 and 2.5 mg n=7 slow-release pellets, placebo n=20) of haloperidol, over 2 weeks, to male Sprague Dawley rats to determine the effect on microglial cell density and morphology (area occupied by processes and microglial cell area). We developed an analysis pipeline for the automated assessment of microglial cells and used lipopolysaccharide (LPS) treatment ( n=13) as a positive control for analysis. We also investigated the effects of haloperidol ( n=9) or placebo ( n=10) on the expression of the translocator protein 18 kDa (TSPO) using autoradiography with [3H]PBR28, a TSPO ligand used in human positron emission tomography (PET) studies. RESULTS: Here we demonstrated that haloperidol at either dose does not alter microglial measures compared with placebo control animals ( p > 0.05). Similarly there was no difference in [3H]PBR28 binding between placebo and haloperidol tissue ( p > 0.05). In contrast, LPS was associated with greater cell density ( p = 0.04) and larger cell size ( p = 0.01). CONCLUSION: These findings suggest that haloperidol does not affect microglial cell density, morphology or TSPO expression, indicating that clinical study alterations are likely not the consequence of antipsychotic treatment. The automated cell evaluation pipeline was able to detect changes in microglial morphology induced by LPS and is made freely available for future use.

Brain TSPO imaging and gray matter volume in schizophrenia patients and in people at ultra high risk of psychosis: An [11C]PBR28 study.

Patients with schizophrenia show whole brain and cortical gray matter (GM) volume reductions which are progressive early in their illness. Microglia, the resident immune cells in the CNS, phagocytose neurons and synapses. Some post mortem and in vivo studies in schizophrenia show evidence for elevated microglial activation compared to matched controls. However, it is currently unclear how these results relate to changes in cortical structure. METHODS: Fourteen patients with schizophrenia and 14 ultra high risk for psychosis (UHR) subjects alongside two groups of age and genotype matched healthy controls received [11C]PBR28 PET scans to index TSPO expression, a marker of microglial activation and a 3T MRI scan. We investigated the relationship between the volume changes of cortical regions and microglial activation in cortical GM (as indexed by [11C]PBR28 distribution volume ratio (DVR). RESULTS: The total cortical GM volume was significantly lower in SCZ than the controls [mean (SD)/cm3: SCZ=448.83 (39.2) and controls=499.6 (59.2) (p=0.02) but not in UHR (mean (SD)=503.06 (57.9) and controls=524.46 (45.3) p=0.3). Regression model fitted the total cortical GM DVR values with the cortical regional volumes in SCZ (r=0.81; p<0.001) and in UHR (r=0.63; p=0.02). We found a significant negative correlation between the TSPO signal and total cortical GM volume in SCZ with the highest absolute correlation coefficient in the right superior-parietal cortex (r=-0.72; p=0.006). CONCLUSIONS: These findings suggest that microglial activity is related to the altered cortical volume seen in schizophrenia. Longitudinal investigations are required to determine whether microglial activation leads to cortical gray matter loss.