ABSTRACT
Dynamic brain immune function in individuals with posttraumatic stress disorder is rarely studied, despite evidence of peripheral immune dysfunction. Positron emission tomography brain imaging using the radiotracer [11C]PBR28 was used to measure the 18-kDa translocator protein (TSPO), a microglial marker, at baseline and 3 h after administration of lipopolysaccharide (LPS), a potent immune activator. Data were acquired in 15 individuals with PTSD and 15 age-matched controls. The PTSD group exhibited a significantly lower magnitude LPS-induced increase in TSPO availability in an a priori prefrontal-limbic circuit compared to controls. Greater anhedonic symptoms in the PTSD group were associated with a more suppressed neuroimmune response. In addition, while a reduced granulocyte-macrophage colony-stimulating factor response to LPS was observed in the PTSD group, other measured cytokine responses and self-reported sickness symptoms did not differ between groups; these findings highlight group differences in central-peripheral immune system relationships. The results of this study provide evidence of a suppressed microglia-mediated neuroimmune response to a direct immune system insult in individuals with PTSD that is associated with the severity of symptoms. They also provide further support to an emerging literature challenging traditional concepts of microglial and immune function in psychiatric disease.
Subject(s)
Anhedonia , Microglia , Positron-Emission Tomography , Receptors, GABA , Stress Disorders, Post-Traumatic , Stress Disorders, Post-Traumatic/immunology , Stress Disorders, Post-Traumatic/diagnostic imaging , Stress Disorders, Post-Traumatic/metabolism , Humans , Microglia/immunology , Microglia/metabolism , Male , Adult , Positron-Emission Tomography/methods , Female , Receptors, GABA/metabolism , Lipopolysaccharides , Middle Aged , Neuroimmunomodulation/physiology , Brain/diagnostic imaging , Brain/immunology , Brain/metabolismABSTRACT
PURPOSE: To determine baseline patient characteristics that predict the need for glaucoma surgery or blindness in eyes with neovascular glaucoma (NVG) despite intravitreal antivascular endothelial growth factor therapy. METHODS: This is a retrospective cohort study of patients with NVG who had not previously received glaucoma surgery and were treated with intravitreal antivascular endothelial growth factor injections at the time of diagnosis, from September 8, 2011, to May 8, 2020, at a large, retina subspecialty practice. RESULTS: Of 301 newly presenting NVG eyes, 31% required glaucoma surgery and 20% progressed to no light perception vision despite treatment. Patients with intraocular pressure >35 mmHg ( P < 0.001), two or more topical glaucoma medications ( P = 0.003), worse than 20/100 vision ( P = 0.024), proliferative diabetic retinopathy ( P = 0.001), eye pain or discomfort ( P = 0.010), and new patient status ( P = 0.015) at the time of NVG diagnosis were at a higher risk of glaucoma surgery or blindness regardless of antivascular endothelial growth factor therapy. The effect of panretinal photocoagulation was not statistically significant in a subgroup analysis of patients without media opacity ( P = 0.199). CONCLUSION: Several baseline characteristics at the time of presentation to a retina specialist with NVG seem to portend a higher risk of uncontrolled glaucoma despite the use of antivascular endothelial growth factor therapy. Prompt referral of these patients to a glaucoma specialist should be strongly considered.
Subject(s)
Glaucoma, Neovascular , Glaucoma , Humans , Bevacizumab/therapeutic use , Glaucoma, Neovascular/drug therapy , Glaucoma, Neovascular/etiology , Angiogenesis Inhibitors , Endothelial Growth Factors , Vascular Endothelial Growth Factor A , Retrospective Studies , Retina , Intraocular Pressure , Intravitreal Injections , Blindness/etiology , Risk FactorsABSTRACT
BACKGROUND: There are more than 7,800 people living with human immunodeficiency virus (HIV) in Victoria, Australia. Crucial in maximising the individual and population level benefits from antiretroviral therapy (ART) is understanding how to achieve patient retention in care and the factors that drive it. This study was an expansion of a 2015 assessment of HIV-care retention in Victoria, which sought out to determine whether the inclusion of a broader range of HIV-healthcare sites would yield more accurate estimates of retention in HIV-care. We aimed to improve our understanding of HIV-care retention in Victoria, Australia, identify people living with HIV (PLHIV) with unknown outcomes, and attempt to re-engage PLHIV in care. METHODS: A network of 15 HIV-care sites was established in Victoria, Australia across diverse care settings which ranged from low-caseload rural sites to high-caseload metropolitan GP clinics and hospitals. Individuals who had an HIV viral load (VL) performed in both calendar years of 2016 and 2017 were classified as retained in care. Individuals with a VL test in 2016 but not in 2017 were considered to potentially have unknown outcomes as they may have been receiving care elsewhere, have disengaged from care or died. For this group, an intervention of cross-referencing partially de-identified data between healthcare sites, and contact tracing individuals who still had unknown outcomes was performed. RESULTS: For 5223 individuals considered to be retained in care across 15 healthcare sites in the study period, 49 had unconfirmed transfers of care to an alternative provider and 79 had unknown outcomes. After the intervention, the number of unconfirmed care transfers was reduced to 17 and unknown outcomes reduced to 51. These changes were largely attributed to people being reclassified as confirmed transfers of care. Retention in care estimates that did not include the patient outcome of confirmed transfer of care ranged from 76.2 to 95.8% and did not alter with the intervention. However, retention in care estimates which considered confirmed transfers and those that re-entered care at a new site as retained in care significantly increased across five of the sites with estimates ranging from 80.9 to 98.3% pre-intervention to 83.3-100% post-intervention. Individuals whose outcomes remained unknown post-intervention were more often men who have sex with men (MSM) when compared to other categories (person who injects drugs (PWID), combined PWID/MSM, men who identify as heterosexual or unknown) (74.5% vs. 53.5%, [p = 0.06]) and receiving ART at their last HIV-care visit (84.3% vs. 67.8% [p = 0.09]). CONCLUSION: This study confirmed high retention in HIV-care and low numbers of people disengaged from HIV-care in Victoria. This was demonstrated across a larger number of sites with varying models of care than a prior assessment in 2015. These data align with national and state targets aiming for 95% of PLHIV retained in HIV-care.
Subject(s)
HIV Infections , Retention in Care , Sexual and Gender Minorities , Substance Abuse, Intravenous , Male , Humans , HIV Infections/drug therapy , HIV Infections/epidemiology , Homosexuality, MaleABSTRACT
Exercise performance is variable and often impaired in patients with repaired tetralogy of Fallot (rTOF). We sought to identify factors associated with exercise performance by comparing high to low performers on cardiopulmonary exercise testing (CPET) in patients with rTOF. We conducted a cross-sectional study of subjects presenting for CPET who underwent echocardiograms at rest and peak exercise. Patients with pacemakers and arrhythmias were excluded. Right ventricular (RV) global longitudinal strain was used as a measure of systolic function. Pulmonary insufficiency (PI) was assessed with the diastolic systolic ratio and the diastolic systolic time-velocity integral ratio by Doppler interrogation of the pulmonary artery. CPET measures included percent-predicted maximum [Formula: see text][Formula: see text], percent-predicted maximum work and oxygen pulse. High versus low performers were identified as those achieving [Formula: see text] of at least 80% or falling below, respectively. Differences in echocardiographic parameters from rest to peak exercise were examined using mixed-effects regression models. Compared to the low performers (n = 17), high performers (n = 12) were younger (12.8 ± 3.3 years vs. 18.3 ± 4.8 years), had normal chronotropic response (peak heart rate > 185 bpm) with greater heart rate reserve and superior physical working capacity. High performers also had a greater reduction in PI at peak exercise, despite greater PI severity at rest. Oxygen pulse was comparable between groups. For both groups, there was no association of PI severity and RV systolic function at rest with exercise parameters. There was no group difference in the magnitude of change in RV strain and diastolic parameters from rest to peak exercise. Chronotropic response to exercise appears to be an important parameter with which to assess exercise performance in rTOF. Chronotropic health should be taken into consideration in this population, particularly given that RV function and PI severity at rest were not associated with exercise performance.
Subject(s)
Exercise Test/methods , Exercise/physiology , Tetralogy of Fallot/physiopathology , Ventricular Function, Right , Adolescent , Age Factors , Child , Cross-Sectional Studies , Echocardiography , Echocardiography, Stress , Female , Humans , Male , Prospective Studies , Pulmonary Valve Insufficiency/physiopathology , Tetralogy of Fallot/surgery , Ultrasonography, Doppler , Young AdultABSTRACT
We aimed to characterize changes in binding of (-)-[18 F]Flubatine to α4 ß2 *-nicotinic acetylcholine receptors (α4 ß2 *-nAChRs) during a tobacco cigarette smoking challenge. Displacement of (-)-[18 F]Flubatine throughout the brain was quantified as change in (-)-[18 F]Flubatine distribution volume (VT ), with particular emphasis on regions with low VT . Three tobacco smokers were imaged with positron emission tomography (PET) during a 210 min bolus-plus-constant infusion of (-)-[18 F]Flubatine. A tobacco cigarette was smoked in the PET scanner â¼125 min after the start of (-)-[18 F]Flubatine injection. Equilibrium analysis was used to estimate VT at baseline (90-120 min) and after cigarette challenge (180-210 min), at the time of greatest receptor occupancy by nicotine. Smoking reduced VT by 21 ± 9% (average ±SD) in corpus callosum, 17 ± 9% in frontal cortex, 36 ± 11% in cerebellum, and 22 ± 10% in putamen. The finding of displaceable (-)-[18 F]Flubatine binding throughout the brain is an important consideration for reference region-based quantification approaches with this tracer. We observed displacement of (-)-[18 F]Flubatine binding to α4 ß2 *-nicotinic acetylcholine receptors in corpus callosum by a tobacco cigarette challenge. We conclude that reference region approaches utilizing corpus callosum should first perform careful characterization of displaceable (-)-[18 F]Flubatine binding and nondisplaceable kinetics in this putative reference region.
Subject(s)
Benzamides , Brain/diagnostic imaging , Brain/metabolism , Bridged Bicyclo Compounds, Heterocyclic , Positron-Emission Tomography , Radiopharmaceuticals , Receptors, Nicotinic/metabolism , Adult , Benzamides/pharmacokinetics , Brain/drug effects , Brain Mapping , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Female , Humans , Male , Middle Aged , Nicotine/administration & dosage , Nicotine/pharmacokinetics , Nicotinic Agonists/administration & dosage , Nicotinic Agonists/pharmacokinetics , Protein Binding , Radiopharmaceuticals/pharmacokinetics , Smoking/metabolismABSTRACT
The objective of this study is to compare quality of life (QOL) in patients with mild pulmonary insufficiency (PI) after Tetralogy of Fallot (TOF) repair or after balloon dilation for isolated valvar pulmonary stenosis (VPS). A cross-sectional study of patients with TOF (n = 12) and VPS (n = 19), ages 8-18 years, who underwent cardiac magnetic resonance (CMR) and cardiopulmonary exercise test (CPET) was conducted. Patients with genetic syndromes were excluded. The groups were matched by severity and duration of PI using propensity scores. PI was greater than mild if the regurgitant fraction by CMR was >20%. Health status and QOL assessment included Child Health Questionnaire Child Self-Report (CHQ-CF87), Child Health Questionnaire Parent Report (CHQ-PF50), and Pediatric Cardiac QOL Instrument (parent and patient). QOL scores were compared between groups. Due to propensity matching, the groups had, at worst, mild PI and normal right ventricular ejection fraction on CMR. Parental perception of QOL was significantly worse in TOF as compared to VPS in the domains of general perception of health (P = 0.03), physical functioning (PF; P = 0.004), and family cohesion (P = 0.048). There were no differences in self-reported QOL between groups. There was no association between QOL and right ventricular function on CMR or percent-predicted maximal oxygen consumption on CPET in both groups. Parent-perceived QOL, in the domains of general health perception, PF, and family cohesion, is significantly reduced in patients with TOF with mild residual disease suggesting that the psychosocial impact of congenital heart disease may be significant even with successful repair and satisfactory medical status.
Subject(s)
Cardiac Surgical Procedures/adverse effects , Pulmonary Valve Insufficiency/psychology , Pulmonary Valve Stenosis/psychology , Quality of Life/psychology , Tetralogy of Fallot/surgery , Adolescent , Cardiac Surgical Procedures/methods , Child , Cross-Sectional Studies , Exercise Test , Female , Health Status , Heart/physiopathology , Humans , Magnetic Resonance Imaging, Cine , Male , Oxygen Consumption , Propensity Score , Pulmonary Valve Insufficiency/physiopathology , Pulmonary Valve Insufficiency/surgery , Pulmonary Valve Stenosis/surgery , Self Report , Surveys and Questionnaires , Tetralogy of Fallot/psychology , Ventricular Function, RightABSTRACT
Right ventricular function is a crucial determinant of long-term outcomes of children with heart disease. Quantification of right ventricular systolic and diastolic performance by echocardiography is of paramount importance, given the prevalence of children with heart disease, particularly those with involvement of the right heart, such as single or systemic right ventricles, tetralogy of Fallot, and pulmonary arterial hypertension. Identification of poor right ventricular performance can provide an opportunity to intervene. In this review, we will go through the different systolic and diastolic indices, as well as their application in practice. Quantification of right ventricular function is possible and should be routinely performed using a combination of different measures, taking into account each disease state. Quantification is extremely useful for individual patient follow-up. Laboratories should continue to strive to optimise reproducibility through quality improvement and quality assurance efforts in addition to investing in technology and training for new, promising techniques, such as three-dimensional echocardiography.
Subject(s)
Echocardiography, Doppler, Color/methods , Echocardiography, Three-Dimensional/methods , Heart Ventricles/diagnostic imaging , Tricuspid Valve/diagnostic imaging , Ventricular Dysfunction, Right/diagnostic imaging , Ventricular Function, Right , Child , Diastole , Echocardiography/methods , Humans , Hypertension, Pulmonary/diagnostic imaging , Myocardial Contraction , Reproducibility of Results , Systole , Tetralogy of Fallot/diagnostic imagingABSTRACT
Background: Stress is a potent activator of the hypothalamic-pituitary-adrenal (HPA) axis, initiating the release of glucocorticoid hormones, such as cortisol. Alcohol consumption can lead to HPA axis dysfunction, including altered cortisol levels. Until recently, research has only been able to examine peripheral cortisol associated with alcohol use disorder (AUD) in humans. We used positron emission tomography (PET) brain imaging with the radiotracer [18F]AS2471907 to measure 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), a cortisol-regenerating enzyme, in people with AUD compared to healthy controls. Methods: We imaged 9 individuals with moderate to severe AUD (5 men, 4 women; mean age = 38 years) and 12 healthy controls (8 men, 4 women; mean age = 29 years). Participants received 93.5 ± 15.6 MBq of the 11ß-HSD1 inhibitor radiotracer [18F]AS2471907 as a bolus injection and were imaged for 150-180 min on the High-Resolution Research Tomograph. 11ß-HSD1 availability was quantified by [18F]AS2471907 volume of distribution (VT; mL/cm3). A priori regions of interest included amygdala, anterior cingulate cortex (ACC), hippocampus, ventromedial PFC (vmPFC) and caudate. Results: Individuals with AUD consumed 52.4 drinks/week with 5.8 drinking days/week. Healthy controls consumed 2.8 drinks/week with 1.3 drinking days/week. Preliminary findings suggest that [18F]AS2471907 VT was higher in amygdala, ACC, hippocampus, vmPFC, and caudate of those with AUD compared to healthy controls (p < 0.05). In AUD, vmPFC [18F]AS2471907 VT was associated with drinks per week (r = 0.81, p = 0.01) and quantity per drinking episode (r = 0.75, p = 0.02). Conclusions: This is the first in vivo examination of 11ß-HSD1 availability in individuals with AUD. Our data suggest higher brain availability of the cortisol-regenerating enzyme 11ß-HSD1 in people with AUD (vs. controls), and that higher vmPFC 11ß-HSD1 availability is related to greater alcohol consumption. Thus, in addition to the literature suggesting that people with AUD have elevated peripheral cortisol, our findings suggest there may also be heightened central HPA activity. These findings set the foundation for future hypotheses on mechanisms related to HPA axis function in this population.
ABSTRACT
Background: Cerebral air embolism is a rare cause of acute ischemic stroke that is becoming increasingly well-described in the literature. However, the mechanism and severity of this type of injury can vary, with ischemia typically emerging early in the course of care. To the best of our knowledge, delayed ischemia in this setting has not yet been described. Case Description: A stroke code was called for an unresponsive, hospitalized, 75-year-old man. A computerized tomography (CT) scan of the head revealed air within the right greater than left hemispheric cortical veins with loss of sulcation, concerning for developing ischemia, and CT angiography revealed absent opacification of the distal cortical vessels in the right anterior cerebral artery and middle cerebral artery territories. Magnetic resonance imaging (MRI) of the brain was obtained 5.75 h after the patient's last known well-showed small areas of subtle cortical diffusion restriction. Follow-up CT head within 24 h showed near-complete resolution of the air emboli after treatment with 100% fraction of inspired oxygen on mechanical ventilation. Subsequent MRI, performed 4 days after the initial event, showed extensive cortical diffusion restriction and cerebral edema crossing vascular territories. Conclusion: This case highlights that cerebral air emboli can cause delayed ischemia that may not be appreciated on initial imaging. As such, affected patients may require intensive neurocritical care management, close neurologic monitoring, and repeat imaging irrespective of initial radiographic findings.
ABSTRACT
The maturation of retinal ganglion cell (RGC) axon projections in the dorsal lateral geniculate nucleus (dLGN) and the superior colliculus (SC) relies on both molecular and activity-dependent mechanisms. Despite the increasing popularity of the mouse as a mammalian visual system model, little is known in this species about the normal development of individual RGC axon arbors or the role of activity in this process. We used a novel in vivo single RGC labeling technique to quantitatively characterize the elaboration and refinement of RGC axon arbors in the dLGN and SC in wild-type (WT) and ß2-nicotinic acetylcholine receptors mutant (ß2(-/-)) mice, which have perturbed retinal waves, during the developmental period when eye-specific lamination and retinotopic refinement occurs. Our results suggest that eye-specific segregation and retinotopic refinement in WT mice are not the result of refinement of richly exuberant arbors but rather the elaboration of arbors prepositioned in the proper location combined with the elimination of inappropriately targeted sparse branches. We found that retinocollicular arbors mature â¼1 week earlier than retinogeniculate arbors, although RGC axons reach the dLGN and SC at roughly the same age. We also observed striking differences between contralateral and ipsilateral RGC axon arbors in the SC but not in the LGN. These data suggest a strong influence of target specific cues during arbor maturation. In ß2(-/-) mice, we found that retinofugal single axon arbors are well ramified but enlarged, particularly in the SC, indicating that activity-dependent visual map development occurs through the refinement of individual RGC arbors.
Subject(s)
Axons/physiology , Receptors, Nicotinic/deficiency , Retina/growth & development , Retinal Ganglion Cells/physiology , Superior Colliculi/growth & development , Visual Pathways/growth & development , Animals , Animals, Newborn , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptors, Nicotinic/biosynthesis , Receptors, Nicotinic/genetics , Retina/cytology , Retina/metabolism , Retinal Ganglion Cells/cytology , Retinal Ganglion Cells/metabolism , Superior Colliculi/cytology , Superior Colliculi/metabolism , Visual Pathways/cytology , Visual Pathways/metabolismABSTRACT
Diastolic dysfunction after repair for Tetralogy of Fallot (TOF) is associated with adverse long-term outcomes. Right atrial (RA) mechanics as a proxy of right ventricular (RV) diastolic function in the early post-operative period after surgical repair for TOF has not been reported. We sought to evaluate RA and RV strain prior to hospital discharge after TOF repair and to identify important patient factors associated with strain using a machine learning method. Single center retrospective cohort study of TOF patients undergoing surgical repair, with analysis of RA and RV strain from pre-and post-operative echocardiograms. RA function was assessed by the peak RA strain, systolic RA strain rate, early diastolic RA strain rate and RA emptying fraction. RV systolic function was measured by global longitudinal strain. Pre- and post-operative values were compared using Wilcoxon rank sum test. Gradient boosted machine (GBM) models were used to identify the most important predictors of post-operative strain. In total, 153 patients were enrolled, median age at TOF repair 3.5 months (25th-75th percentile: 2.2- 5.2), mostly male (67%), and White (64.1%). From pre-to post-operative period, there was significant worsening in all RA parameters and in RV strain. GBM models identified patient, anatomic, and surgical factors that were strong predictors of post-operative RA and RV strain. These factors included pulmonary valve and branch pulmonary artery Z scores, birth weight, gestational age and age at surgery, pre-operative RV fractional area change and oxygen saturation, type of outflow tract repair, duration of cardiopulmonary bypass, and early post-operative partial arterial pressure of oxygen. There is significant worsening in RA and RV strain early after TOF repair, indicating early alteration in diastolic and systolic function after surgery. Several patient and operative factors influence post-operative RV function. Most of the factors described are not readily modifiable, however they may inform pre-operative risk-stratification. The clinical application of RA strain and the prognostic implication of these early changes merit further study.
Subject(s)
Atrial Appendage , Tetralogy of Fallot , Humans , Male , Infant , Female , Atrial Function, Right , Retrospective Studies , Tetralogy of Fallot/diagnostic imaging , Tetralogy of Fallot/surgery , Predictive Value of TestsABSTRACT
Stab wounds produced by serrated blades are generally indistinguishable from stab wounds produced by non-serrated blades, except when visible tool mark striations are left on severed cartilage. Using a pig-skin experimental model, we explored the possibility that similar striations may be left in skin. Stabs into pig skin were made using a straight spine coarsely serrated blade (121), a drop point finely serrated blade (20), a clip point irregular coarsely serrated blade (20), a drop point coarsely serrated blade (15), and as controls 2 non-serrated blades (40). Tool mark striations could be seen on the skin wall of the stab canal in all stabs made using serrated blades but in none with non-serrated blades.The striation pattern, reflecting the class characteristics of the serrated blade, was the same as that described in cartilage but less well defined. Fixation of the specimen with Carnoy's solution best preserved visible striations, and fixation with formaldehyde after staining with 5% Neutral Red was also satisfactory. Casting with vinyl polysiloxane dental impression material greatly facilitated photo-documentation. Applying the technique to homicidal stabbings may help identify stab wounds produced with serrated blades.
Subject(s)
Skin/injuries , Skin/pathology , Weapons , Wounds, Stab/pathology , Animals , Dental Impression Materials , Fixatives , Forensic Pathology , Models, Animal , Photography , Staining and Labeling , SwineABSTRACT
BACKGROUNDInvestigations of stress dysregulation in posttraumatic stress disorder (PTSD) have focused on peripheral cortisol, but none have examined cortisol in the human brain. This study used positron emission tomography (PET) to image 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), a cortisol-producing enzyme, as a putative brain cortisol marker in PTSD.METHODSSixteen individuals with PTSD and 17 healthy, trauma-exposed controls (TCs) underwent PET imaging with [18F]AS2471907, a radioligand for 11ß-HSD1.RESULTSPrefrontal-limbic 11ß-HSD1 availability, estimated as [18F]AS2471907 volume of distribution (VT), was significantly higher in the PTSD group compared with the TC group (ß = 1.16, P = 0.0057). Lower prefrontal-limbic 11ß-HSD1 availability was related to greater overall PTSD severity (R2 = 0.27, P = 0.038) in the PTSD group. 11ß-HSD1 availability was not related to plasma cortisol levels (R2 = 0.026, P = 0.37). In a PTSD subset (n = 10), higher 11ß-HSD1 availability was associated with higher availability of translocator protein (TSPO), a microglial marker (ß = 4.40, P = 0.039).CONCLUSIONHigher brain cortisol-producing 11ß-HSD1 in the PTSD group may represent a resilience-promoting neuroadaptation resulting in lower PTSD symptoms. Along with preliminary associations between 11ß-HSD1 and TSPO, corroborating previous evidence of immune suppression in PTSD, these findings collectively challenge previous hypotheses of the deleterious effects of both excessive brain glucocorticoid and brain immune signaling in PTSD.FUNDINGBrain and Behavior Research Foundation Independent Investigator Grant, National Institute of Mental Health grants F30MH116607 and R01MH110674, the Veterans Affairs National Center for PTSD, the Gustavus and Louise Pfeiffer Foundation Fellowship, Clinical and Translational Science Awards grant UL1 TR000142 from the NIH National Center for Advancing Translational Science.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Brain/diagnostic imaging , Hydrocortisone/biosynthesis , Positron-Emission Tomography/methods , Stress Disorders, Post-Traumatic/diagnostic imaging , Triazoles/metabolism , Adult , Brain/metabolism , Female , Humans , Male , Middle Aged , Severity of Illness Index , Stress Disorders, Post-Traumatic/metabolismABSTRACT
11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) catalyzes enzymatic conversion of cortisone into the stress hormone cortisol. This first-in-human brain imaging study characterizes the kinetic modeling and test-retest reproducibility of [18F]AS2471907, a novel PET radiotracer for 11ß-HSD1. Eight individuals underwent one 180-min (n = 4) or two 240-min (n = 4) [18F]AS2471907 PET brain scans (12 total) acquired on the high-resolution research tomograph (HRRT) scanner with arterial blood sampling. Imaging data were modeled with 1-tissue (1T) and 2-tissue (2T) compartment models and with multilinear analysis (MA1) to estimate [18F]AS2471907 availability (VT). [18F]AS2471907 demonstrated high, heterogeneous uptake throughout the brain. Of the compartment models, 2T best described [18F]AS2471907 data. Estimates of VT were highly correlated between 2T and MA1 (t* = 30 min) with MA1 yielding VT values ranging from 3.2 ± 1.0 mL/cm3 in the caudate to 15.7 ± 4.2 mL/cm3 in the occipital cortex. The median absolute test-retest variability of 16 ± 5% and high intraclass correlation coefficient (ICC) values of 0.67-0.97 across regions indicate fair test-retest reliability but large intersubject variability. VT estimates using 180 min were within 10% of estimates using full acquisition time. In summary, [18F]AS2471907 exhibits reasonable kinetic properties for imaging 11ß-HSD1 in human brain.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Brain/diagnostic imaging , Molecular Imaging/methods , Positron-Emission Tomography/methods , Radiopharmaceuticals/pharmacokinetics , Triazoles/pharmacokinetics , Adult , Brain/enzymology , Female , Fluorine Radioisotopes , Humans , Hydrocortisone/blood , Kinetics , Male , Models, Biological , Radiopharmaceuticals/blood , Tissue Distribution , Triazoles/bloodABSTRACT
CONTEXT: Cortisol, a glucocorticoid steroid stress hormone, is primarily responsible for stimulating gluconeogenesis in the liver and promoting adipocyte differentiation and maturation. Prolonged excess cortisol leads to visceral adiposity, insulin resistance, hyperglycemia, memory dysfunction, cognitive impairment, and more severe Alzheimer's disease phenotypes. The intracellular enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) catalyzes the conversion of inactive cortisone to active cortisol; yet the amount of 11ß-HSD1 in the brain has not been quantified directly in vivo. OBJECTIVE: We analyzed positron emission tomography (PET) scans with an 11ß-HSD1 inhibitor radioligand in twenty-eight individuals (23 M/5F): 10 lean, 13 overweight, and 5 obese individuals. Each individual underwent PET imaging on the high-resolution research tomograph PET scanner after injection of 11C-AS2471907 (n = 17) or 18F-AS2471907 (n = 11). Injected activity and mass doses were 246 ± 130 MBq and 0.036 ± 0.039 µg, respectively, for 11C-AS2471907, and 92 ± 15 MBq and 0.001 ± 0.001 µg for 18F-AS2471907. Correlations of mean whole brain and regional distribution volume (VT) with body mass index (BMI) and age were performed with a linear regression model. RESULTS: Significant correlations of whole brain mean VT with BMI and age (VT = 15.23-0.63 × BMI + 0.27 × Age, p = 0.001) were revealed. Age-adjusted mean whole brain VT values were significantly lower in obese individuals. Post hoc region specific analyses revealed significantly reduced mean VT values in the thalamus (lean vs. overweight and lean vs. obese individuals). Caudate, hypothalamus, parietal lobe, and putamen also showed lower VT value in obese vs. lean individuals. A significant age-associated increase of 2.7 mL/cm3 per decade was seen in BMI-corrected mean whole brain VT values. CONCLUSIONS: In vivo PET imaging demonstrated, for the first time, correlation of higher BMI (obesity) with lower levels of the enzyme 11ß-HSD1 in the brain and correlation of increased 11ß-HSD1 levels in the brain with advancing age.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Aging/metabolism , Body Mass Index , Brain/diagnostic imaging , Brain/enzymology , Positron-Emission Tomography , Adult , Age Factors , Female , Humans , Male , Organ SpecificityABSTRACT
Despite well-known peripheral immune activation in posttraumatic stress disorder (PTSD), there are no studies of brain immunologic regulation in individuals with PTSD. [11C]PBR28 Positron Emission Tomography brain imaging of the 18-kDa translocator protein (TSPO), a microglial biomarker, was conducted in 23 individuals with PTSD and 26 healthy individuals-with or without trauma exposure. Prefrontal-limbic TSPO availability in the PTSD group was negatively associated with PTSD symptom severity and was significantly lower than in controls. Higher C-reactive protein levels were also associated with lower prefrontal-limbic TSPO availability and PTSD severity. An independent postmortem study found no differential gene expression in 22 PTSD vs. 22 controls, but showed lower relative expression of TSPO and microglia-associated genes TNFRSF14 and TSPOAP1 in a female PTSD subgroup. These findings suggest that peripheral immune activation in PTSD is associated with deficient brain microglial activation, challenging prevailing hypotheses positing neuroimmune activation as central to stress-related pathophysiology.
Subject(s)
Brain/immunology , Microglia/immunology , Stress Disorders, Post-Traumatic/immunology , Acetamides/administration & dosage , Adaptor Proteins, Signal Transducing/metabolism , Adult , Brain/diagnostic imaging , Brain/pathology , Case-Control Studies , Female , Gene Expression Profiling , Healthy Volunteers , Humans , Male , Microglia/pathology , Middle Aged , Positron-Emission Tomography/methods , Pyridines/administration & dosage , Radiopharmaceuticals/administration & dosage , Receptors, GABA/immunology , Receptors, GABA/metabolism , Receptors, Tumor Necrosis Factor, Member 14/metabolism , Sex Factors , Stress Disorders, Post-Traumatic/diagnostic imaging , Stress Disorders, Post-Traumatic/pathology , Young AdultABSTRACT
BACKGROUND: Pulmonary insufficiency (PI) and right ventricular (RV) dysfunction are long-term complications in patients with repaired tetralogy of Fallot (rTOF). The aim of this study was to investigate RV contractile reserve and changes in PI that occur during exercise in patients with rTOF and the associations of these changes with exercise performance using stress echocardiography. METHODS: Subjects with rTOF (n = 32) and healthy control subjects (n = 10) were prospectively enrolled and underwent rest and peak exercise echocardiography during standard cardiopulmonary exercise test protocol on a cycle ergometer or treadmill. RV contractile reserve was defined as the change in RV global longitudinal strain from rest to peak exercise. PI was assessed with the diastolic-to-systolic time-velocity integral ratio and diastolic/systolic velocity ratio from pulmonary artery Doppler interrogation. Exercise measures included heart rate reserve, percentage predicted maximum oxygen consumption, percentage predicted maximum work, and oxygen pulse. RESULTS: RV contractile reserve was impaired in patients with rTOF compared with control subjects, with a significant drop in the absolute value of RV global longitudinal strain from 17% (range, 8%-27%) at rest to 13% (range, 5%-28%) at peak exercise. Similarly, PI decreased at peak exercise, with decreases in diastolic-to-systolic time-velocity integral and diastolic/systolic velocity ratios. Reduction in PI was directly associated with percentage predicted maximum oxygen consumption, percentage predicted maximum work, and greater oxygen pulse. Heart rate reserve was directly associated with percentage predicted maximum oxygen consumption and percentage predicted maximum work. RV contractile reserve was not associated with any exercise parameters. CONCLUSIONS: Patients with rTOF have an abnormal myocardial response to exercise with impaired RV contractile reserve compared with control subjects. Heart rate reserve and reduction in PI at peak exercise are associated with better exercise performance and appear to be significant contributors to exercise performance in rTOF. Measures to improve chronotropic health in rTOF should be explored.
Subject(s)
Cardiac Surgical Procedures , Echocardiography, Stress/methods , Exercise/physiology , Myocardial Contraction/physiology , Tetralogy of Fallot/physiopathology , Ventricular Dysfunction, Right/physiopathology , Ventricular Function, Right/physiology , Adolescent , Child , Cross-Sectional Studies , Exercise Test , Female , Follow-Up Studies , Heart Ventricles/diagnostic imaging , Heart Ventricles/physiopathology , Humans , Male , Postoperative Period , Prospective Studies , Tetralogy of Fallot/complications , Tetralogy of Fallot/surgery , Ventricular Dysfunction, Right/diagnosis , Ventricular Dysfunction, Right/etiologyABSTRACT
BACKGROUND: Some patients receive long-term or life-long antibiotics for suppression of infections deemed otherwise incurable. Little is known about the consequences of this strategy. We aimed to explore patients' attitudes towards and knowledge concerning prolonged antibiotic therapy. METHODS: A cross-sectional cohort pilot study of outpatients on long-term antibiotics was performed. Surveys were conducted at our healthcare network in Victoria, Australia between April and December 2015. Microbiological screening for multi-resistant organisms (MRO) was also performed. RESULTS: Heterogeneity was noted in the prescribed antibiotics and documented indications, with rifampicin and fusidic acid for suppression of prosthetic joint infection the most common regimen and indication. 41% (12/29) of participants reported side-effects attributed to their antibiotics, but 72% (21/29) still declared complete adherence to their prescribed regimen. 76% (22/29) of participants stated that they would cease their long-term antibiotics based on medical advice. 19/29 (66%) participants consented to microbiological screening and 4 were found to be colonised with MROs. They had spent more days as an inpatient in the preceding 12 months than the screened participants who were not colonised. CONCLUSION: Participants in this study had a good understanding of their infection and the indications for their long-term antibiotic therapy, and were adherent to this therapy despite many experiencing side-effects attributed to their antibiotics. Patients who are prescribed life-long antibiotics can be carriers of multi-resistant organisms, but both the drivers of this resistance, and the broader impact of colonisation with MRO in this population is unclear.
Subject(s)
Anti-Bacterial Agents/adverse effects , Health Knowledge, Attitudes, Practice , Patients/psychology , Adult , Aged , Aged, 80 and over , Anti-Bacterial Agents/therapeutic use , Bacterial Infections/drug therapy , Cohort Studies , Cross-Sectional Studies , Drug Resistance, Bacterial , Female , Humans , Male , Middle Aged , Pilot Projects , Surveys and Questionnaires , Time FactorsABSTRACT
Objective: We sought to determine how sex and dexrazoxane therapy influence cardiac remodelling in children with sarcoma receiving high-dose doxorubicin. Methods: In a retrospective cohort of 85 children with sarcoma receiving high-dose doxorubicin, echocardiography measures prior to, early after (within 6 months of doxorubicin completion) and 1 - 2 years after doxorubicin completion were quantified. At each follow-up visit, multivariable, propensity-adjusted linear regression models evaluated dexrazoxane's effects on changes in left ventricular (LV) shortening fraction (SF), structure, strain and wall stress for subgroups divided by sex. Likelihood ratio tests assessed the interaction between sex and dexrazoxane in determining these changes. Results: Early after doxorubicin completion, males not treated with dexrazoxane (n = 15) developed increased cavity size and diminished circumferential strain; females (n = 8) developed diminished SF and strain indices, and increased cavity size and wall stress. With dexrazoxane, males (n = 33) demonstrated less deterioration in circumferential strain by 3.4% (95% CI 0.01 to 6.8), and females (n = 29) demonstrated less reduction in SF by 5.7% (95% CI 2.1 to 9.3), and had mitigation of increases in cavity size and wall stress. In interaction analyses, females had greater protection with dexrazoxane with regard to SF (p = 0.019) and cavity size in diastole (p = 0.002) and systole (p ≤ 0.001). These findings largely persisted 1 - 2 years after doxorubicin therapy. Conclusions: Early, sustained alterations in LV structure and function occur in children with sarcoma after high-dose doxorubicin, with adverse changes and protective effects of dexrazoxane more pronounced in females as compared with males. Dexrazoxane may have sex-specific cardioprotective effects.