Requirements for efficient correction of ΔF508 CFTR revealed by analyses of evolved sequences.

Misfolding of ΔF508 cystic fibrosis (CF) transmembrane conductance regulator (CFTR) underlies pathology in most CF patients. F508 resides in the first nucleotide-binding domain (NBD1) of CFTR near a predicted interface with the fourth intracellular loop (ICL4). Efforts to identify small molecules that restore function by correcting the folding defect have revealed an apparent efficacy ceiling. To understand the mechanistic basis of this obstacle, positions statistically coupled to 508, in evolved sequences, were identified and assessed for their impact on both NBD1 and CFTR folding. The results indicate that both NBD1 folding and interaction with ICL4 are altered by the ΔF508 mutation and that correction of either individual process is only partially effective. By contrast, combination of mutations that counteract both defects restores ΔF508 maturation and function to wild-type levels. These results provide a mechanistic rationale for the limited efficacy of extant corrector compounds and suggest approaches for identifying compounds that correct both defective steps.

Connectome architecture shapes large-scale cortical alterations in schizophrenia: a worldwide ENIGMA study.

Schizophrenia is a prototypical network disorder with widespread brain-morphological alterations, yet it remains unclear whether these distributed alterations robustly reflect the underlying network layout. We tested whether large-scale structural alterations in schizophrenia relate to normative structural and functional connectome architecture, and systematically evaluated robustness and generalizability of these network-level alterations. Leveraging anatomical MRI scans from 2439 adults with schizophrenia and 2867 healthy controls from 26 ENIGMA sites and normative data from the Human Connectome Project (n = 207), we evaluated structural alterations of schizophrenia against two network susceptibility models: (i) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; (ii) epicenter mapping, which identifies regions whose typical connectivity profile most closely resembles the disease-related morphological alterations. To assess generalizability and specificity, we contextualized the influence of site, disease stages, and individual clinical factors and compared network associations of schizophrenia with that found in affective disorders. Our findings show schizophrenia-related cortical thinning is spatially associated with functional and structural hubs, suggesting that highly interconnected regions are more vulnerable to morphological alterations. Predominantly temporo-paralimbic and frontal regions emerged as epicenters with connectivity profiles linked to schizophrenia's alteration patterns. Findings were robust across sites, disease stages, and related to individual symptoms. Moreover, transdiagnostic comparisons revealed overlapping epicenters in schizophrenia and bipolar, but not major depressive disorder, suggestive of a pathophysiological continuity within the schizophrenia-bipolar-spectrum. In sum, cortical alterations over the course of schizophrenia robustly follow brain network architecture, emphasizing marked hub susceptibility and temporo-frontal epicenters at both the level of the group and the individual. Subtle variations of epicenters across disease stages suggest interacting pathological processes, while associations with patient-specific symptoms support additional inter-individual variability of hub vulnerability and epicenters in schizophrenia. Our work outlines potential pathways to better understand macroscale structural alterations, and inter- individual variability in schizophrenia.

Impact of weight adjusted high frequency low tidal volume ventilation and atrial pacing in lesion metrics in high-power short-duration ablation: Results of a pilot study.

INTRODUCTION: Lesion size index (LSI) was introduced with the use of Tacticath™ and as a surrogate of lesion quality. The metric used to achieve the predetermined values involves combined information of contact force (CF), power and radiofrequency time. Rapid atrial pacing (RAP) and high-frequency low-tidal volume ventilation (HFLTV) independently or in combination improve catheter stability and CF and quality of lesions. Data of the impact of body weight adjusted HFLTV ventilation strategy associated with RAP in the lesion metrics still lacking. The study aimed to compare the results of high-power short-duration (HPSD) atrial fibrillation ablation using simultaneous weight adjusted HFLTV and RAP and standard ventilation (SV) protocol. METHODS: Prospective, nonrandomized study with 136 patients undergoing de novo ablation divided into two groups; 70 in RAP (100 ppm) + HFLTV with 4 mL/kg of tidal volume and 25 breaths/min (group A) and 66 patients with SV in intrinsic sinus rhythm (group B). Ablation using 50 W, CF of 5-10 g/10-20 g and 40 mL/minute flow rate on the posterior and anterior left atrial wall, respectively. RESULTS: No procedure-related complications. Group A: Mean LSI points 70 ± 16.5, mean total lower LSI 3.4 ± 0.5, mean total higher LSI 8.2 ± 0.4 and mean total LSI 5.6 ± 0.6. Anterior and posterior wall mean total LSI was 6.0 ± 0.4 and 4.2 ± 0.3, respectively. Mean local impedance drop (LID) points were 118.8 ± 28.4, mean LID index (%) 12.9 ± 1.5, and mean LID < 12% points 55.9 ± 23.8. Anterior and posterior wall mean total LID index were 13.6 ± 2.0 and 11.9 ± 1.7, respectively. Recurrence in 11 (15.7%) patients. Group B: Mean LSI points 56 ± 2.7, mean total lower LSI 2.9 ± 0.7, mean total higher LSI 6.9 ± 0.9, and mean total LSI 4.8 ± 0.8. Anterior and posterior wall mean total LSI was 5.1 ± 0.3 and 3.5 ± 0.5, respectively. Mean LID points were 111.4 ± 21.5, mean LID index (%) 11.4 ± 1.2, and mean LID < 12% points 54.9 ± 25.2. Anterior and posterior wall mean total LID index were 11.8 ± 1.9 and 10.3 ± 1.7, respectively. Recurrence in 14 (21.2%) patients. Mean follow up was 15.2 ± 4.4 months. CONCLUSION: Weight adjusted HFLTV ventilation with RAP HPSD ablation produced lower recurrence rate and better LSI and LID parameters in comparison to SV and intrinsic sinus rhythm.

Chagas Cardiomyopathy and Myocardial Sympathetic Denervation.

PURPOSE OF REVIEW: More than a century since its discovery, the pathogenesis of Chagas heart disease (CHD) remains incompletely understood. The role of derangements in the autonomic control of the heart in triggering malignant arrhythmia before the appearance of contractile ventricular impairment was reviewed. RECENT FINDINGS: Although previous investigations had demonstrated the anatomical and functional consequences of parasympathetic dysautonomia upon the heart rate control, only recently, coronary microvascular disturbances and sympathetic denervation at the ventricular level have been reported in patients and experimental models of CHD, exploring with nuclear medicine methods their impact on the progression of myocardial dysfunction and cardiac arrhythmias. More important than parasympathetic impaired sinus node regulation, recent evidence indicates that myocardial sympathetic denervation associated with coronary microvascular derangements is causally related to myocardial injury and arrhythmia in CHD. Additionally, 123I-MIBG imaging is a promising tool for risk stratification of progression of ventricular dysfunction and sudden death.

Autologous stem cell transplantation improves cardiopulmonary exercise testing outcomes in systemic sclerosis patients.

OBJECTIVES: Autologous haematopoietic stem cell transplantation (AHSCT) is a disease-modifying treatment for patients with severe SSc. Here, we aimed at assessing cardiopulmonary function outcomes of SSc patients after AHSCT. METHODS: Twenty-seven SSc adult patients treated with AHSCT were included in this retrospective study. Most had the diffuse cutaneous subset (93%) and pulmonary involvement (85%). Before and 12 months after AHSCT, patients underwent cardiopulmonary exercise testing, transthoracic echocardiography, pulmonary function test with diffusing capacity for carbon monoxide (DLCO), 6-min walk test (6MWT) and quality of life evaluations. RESULTS: After AHSCT, the peak VO2 increased from 954 to 1029 ml/min (P = 0.02), the percentage of predicted peak VO2 increased from 48.9 to 53.5 m (P = 0.01), and the distance measured by the 6MWT increased from 445 to 502 m (P = 0.01), compared with baseline. Improvements in peak VO2 correlated positively with improvements in 6MWT distance, and negatively with a decrease in resting heart rate. At baseline, patients with DLCO >70% had higher peak VO2 values than those with DLCO <70% (P = 0.04), but after AHSCT all patients showed improved VO2 values, regardless of baseline DLCO levels. Increases in VO2 levels after AHSCT positively correlated with increases in the physical component scores of the Short Form-36 quality of life questionnaire (r = 0.70; P = 0.0003). CONCLUSION: AHSCT improves the aerobic capacity of SSc patients probably reflecting combined increments in lungs, skeletal muscle and cardiac function.

Prevalence of cognitive impairments and strengths in the early course of psychosis and depression.

BACKGROUND: Studies investigating cognitive impairments in psychosis and depression have typically compared the average performance of the clinical group against healthy controls (HC), and do not report on the actual prevalence of cognitive impairments or strengths within these clinical groups. This information is essential so that clinical services can provide adequate resources to supporting cognitive functioning. Thus, we investigated this prevalence in individuals in the early course of psychosis or depression. METHODS: A comprehensive cognitive test battery comprising 12 tests was completed by 1286 individuals aged 15-41 (mean age 25.07, s.d. 5.88) from the PRONIA study at baseline: HC (N = 454), clinical high risk for psychosis (CHR; N = 270), recent-onset depression (ROD; N = 267), and recent-onset psychosis (ROP; N = 295). Z-scores were calculated to estimate the prevalence of moderate or severe deficits or strengths (>2 s.d. or 1-2 s.d. below or above HC, respectively) for each cognitive test. RESULTS: Impairment in at least two cognitive tests was as follows: ROP (88.3% moderately, 45.1% severely impaired), CHR (71.2% moderately, 22.4% severely impaired), ROD (61.6% moderately, 16.2% severely impaired). Across clinical groups, impairments were most prevalent in tests of working memory, processing speed, and verbal learning. Above average performance (>1 s.d.) in at least two tests was present for 40.5% ROD, 36.1% CHR, 16.1% ROP, and was >2 SDs in 1.8% ROD, 1.4% CHR, and 0% ROP. CONCLUSIONS: These findings suggest that interventions should be tailored to the individual, with working memory, processing speed, and verbal learning likely to be important transdiagnostic targets.

Effect of short-term, high-dose probiotic supplementation on cognition, related brain functions and BDNF in patients with depression: a secondary analysis of a randomized controlled trial.

BACKGROUND: In major depressive disorder (MDD), cognitive dysfunctions strongly contribute to functional impairments but are barely addressed in current therapies. Novel treatment strategies addressing cognitive symptoms in depression are needed. As the gut microbiota-brain axis is linked to depression and cognition, we investigated the effect of a 4-week high-dose probiotic supplementation on cognitive symptoms in depression. METHODS: This randomized controlled trial included 60 patients with MDD, of whom 43 entered modified intention-to-treat analysis. A probiotic supplement or indistinguishable placebo containing maltose was administered over 31 days in addition to treatment as usual for depression. Participant scores on the Verbal Learning Memory Test (VLMT), Corsi Block Tapping Test, and both Trail Making Test versions as well as brain-derived neurotrophic factor levels were assessed at 3 different time points: before, immediately after and 4 weeks after intervention. Additionally, brain activation changes during working memory processing were investigated before and immediately after intervention. RESULTS: We found a significantly improved immediate recall in the VLMT in the probiotic group immediately after intervention, and a trend for a time × group interaction considering all time points. Furthermore, we found a time × group interaction in hippocampus activation during working memory processing, revealing a remediated hippocampus function in the probiotic group. Other measures did not reveal significant changes. LIMITATIONS: The modest sample size resulting from our exclusion of low-compliant cases should be considered. CONCLUSION: Additional probiotic supplementation enhances verbal episodic memory and affects neural mechanisms underlying impaired cognition in MDD. The present findings support the importance of the gut microbiota-brain axis in MDD and emphasize the potential of microbiota-related regimens to treat cognitive symptoms in depression. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov identifier NCT02957591.

Anesthetic management for lower extremity vascular bypass procedures: The impact of general or regional anesthesia on clinical outcomes.

PURPOSE: Postoperative complications after major surgery, especially vascular procedures, are associated with a significant increase in costs and mortality. Previous studies evaluating general anesthesia versus regional or neuraxial anesthesia for infrainguinal bypass have produced conflicting results. The main aim of the present study is to review current evidence on the application of regional or general anesthesia in patients undergoing infrainguinal bypass surgery and its potential favorable effects on postoperative outcomes. CONTENTS: Patients undergoing vascular surgery often have multiple comorbidities, and it is important to outline both benefits and risks of regional anesthesia techniques. Neuraxial anesthesia in vascular surgery allows overall avoidance of general anesthesia and does provide short-term benefits beyond analgesia. Previous observational studies suggest that neuraxial anesthesia for lower limb revascularization may reduce morbidity and length of stay. However, evidence of long-term benefits is lacking in most procedures and further work is still warranted. CONCLUSIONS: Neuraxial anesthesia is usually an effective anesthesia technique for infrainguinal bypass surgery. Elderly patients and those with underlying respiratory problems may display some benefit from neuraxial anesthesia. Further evaluation within institutions should be performed to identify which patients would most benefit from regional techniques. Notably, systemic antithrombotic and anticoagulation therapy is common among this population and may affect anesthetic choices.

Cerebrospinal fluid purinomics as a biomarker approach to predict outcome after severe traumatic brain injury.

Severe traumatic brain injury (TBI) is associated with high rates of mortality and long-term disability linked to neurochemical abnormalities. Although purine derivatives play important roles in TBI pathogenesis in preclinical models, little is known about potential changes in purine levels and their implications in human TBI. We assessed cerebrospinal fluid (CSF) levels of purines in severe TBI patients as potential biomarkers that predict mortality and long-term dysfunction. This was a cross-sectional study performed in 17 severe TBI patients (Glasgow Coma Scale <8) and 51 controls. Two to 4 h after admission to ICU, patients were submitted to ventricular drainage and CSF collection for quantification of adenine and guanine purine derivatives by HPLC. TBI patients' survival was followed up to 3 days from admission. A neurofunctional assessment was performed through the modified Rankin Scale (mRS) 2 years after ICU admission. Purine levels were compared between control and TBI patients, and between surviving and non-surviving patients. Relative to controls, TBI patients presented increased CSF levels of GDP, guanosine, adenosine, inosine, hypoxanthine, and xanthine. Further, GTP, GDP, IMP, and xanthine levels were different between surviving and non-surviving patients. Among the purines, guanosine was associated with improved mRS (p = 0.042; r = -0.506). Remarkably, GTP displayed predictive value (AUC = 0.841, p = 0.024) for discriminating survival versus non-survival patients up to 3 days from admission. These results support TBI-specific purine signatures, suggesting GTP as a promising biomarker of mortality and guanosine as an indicator of long-term functional disability.

Association of left ventricular abnormalities with incident cerebrovascular events and sources of thromboembolism in patients with chronic Chagas cardiomyopathy.

BACKGROUND: Although Chagas cardiomyopathy is related to thromboembolic stroke, data on risk factors for cerebrovascular events in Chagas disease is limited. Thus, we assessed the relationship between left ventricular (LV) impairment and cerebrovascular events and sources of thromboembolism in patients with Chagas cardiomyopathy. METHODS: This retrospective cohort included patients with chronic Chagas cardiomyopathy who underwent cardiovascular magnetic resonance (CMR). CMR was performed with a 1.5 T scanner to provide LV volumes, mass, ejection fraction (LVEF), and myocardial fibrosis. The primary outcome was a composite of incident ischemic cerebrovascular events (stroke or transient ischemic attack-TIA) and potential thromboembolic sources (atrial fibrillation (AF), atrial flutter, or intracavitary thrombus) during the follow-up. RESULTS: A total of 113 patients were included. Median age was 56 years (IQR: 45-67), and 58 (51%) were women. The median LVEF was 53% (IQR: 41-62). LV aneurysms and LV fibrosis were present in 38 (34%) and 76 (67%) individuals, respectively. The median follow-up time was 6.9 years, with 29 events: 11 cerebrovascular events, 16 had AF or atrial flutter, and two had LV apical thrombosis. In the multivariable model, only lower LVEF remained significantly associated with the outcomes (HR: 0.96, 95% CI: 0.93-0.99). Patients with reduced LVEF lower than 40% had a much higher risk of cerebrovascular events and thromboembolic sources (HR: 3.16 95% CI: 1.38-7.25) than those with normal LVEF. The combined incidence rate of the combined events in chronic Chagas cardiomyopathy patients with reduced LVEF was 13.9 new cases per 100 persons-year. CONCLUSIONS: LV systolic dysfunction is an independent predictor of adverse cerebrovascular events and potential sources of thromboembolism in patients with chronic Chagas cardiomyopathy.

Heart rate variability as a biomarker in patients with Chronic Chagas Cardiomyopathy with or without concomitant digestive involvement and its relationship with the Rassi score.

BACKGROUND: Dysautonomia plays an ancillary role in the pathogenesis of Chronic Chagas Cardiomyopathy (CCC), but is the key factor causing digestive organic involvement. We investigated the ability of heart rate variability (HRV) for death risk stratification in CCC and compared alterations of HRV in patients with isolated CCC and in those with the mixed form (CCC + digestive involvement). Thirty-one patients with CCC were classified into three risk groups (low, intermediate and high) according to their Rassi score. A single-lead ECG was recorded for a period of 10-20 min, RR series were generated and 31 HRV indices were calculated. The HRV was compared among the three risk groups and regarding the associated digestive involvement. Four machine learning models were created to predict the risk class of patients. RESULTS: Phase entropy is decreased and the percentage of inflection points is increased in patients from the high-, compared to the low-risk group. Fourteen patients had the mixed form, showing decreased triangular interpolation of the RR histogram and absolute power at the low-frequency band. The best predictive risk model was obtained by the support vector machine algorithm (overall F1-score of 0.61). CONCLUSIONS: The mixed form of Chagas' disease showed a decrease in the slow HRV components. The worst prognosis in CCC is associated with increased heart rate fragmentation. The combination of HRV indices enhanced the accuracy of risk stratification. In patients with the mixed form of Chagas disease, a higher degree of sympathetic autonomic denervation may be associated with parasympathetic impairment.

Comparison of outcomes with low-power long duration versus high-power short duration of ablation: the role of the acute change in sinus rhythm after the ablation as a predictor of long-term success.

Different results are described after atrial fibrillation ablation and multiple predictors of recurrence are well established. Evaluate and analyze if heart rate increase (HRI) during a first atrial fibrillation (AF) ablation with low-power long-duration (LPLD) and subsequently with high-power short-duration (HPSD) can impact. Retrospectively analyzed 340 consecutive patients (pts) undergoing first AF ablation. There were 158 pts in LPLD group: 113 (71.5%) paroxysmal AF with ablation with a power of 30/20 w, on anterior and posterior left atrial (LA) wall, respectively, and contact force of 10-30g for 30 s. There were 182 pts in HPSD group: 106 (58.2%) paroxysmal AF, who underwent ablation with 45/50 w, contact force of 8-15g/10-20g and 35 mL/min flow rate on anterior and posterior left atrial wall, respectively. Median follow-up was 32 ± 16 months. Success was observed in 94 (59.5%) patients in LPLD and 152 (83.5%) in HPSD, in LPLD group we documented a median HRI of 4.3 bpm (8%), compared to preablation heart rate, while a higher HRI in HPSD group of HRI 13.5 bpm (27.2%) was noted. Heart rate increase was associated with a higher success rate in both ablation techniques and independently showed an important impact on the success rate after AF ablation. HPSD compared to LPLD showed a higher proportion of HRI and also demonstrated a superiority in maintaining sinus rhythm at a long-term follow-up.

Electrocardiogram abnormalities in chronic Chagas cardiomyopathy correlate with scar mass and left ventricular dysfunction as assessed by cardiac magnetic resonance imaging.

Electrocardiographic (ECG) abnormalities are frequently identified in Chronic Chagas cardiomyopathy (CCC) patients and advanced abnormalities are related to a worse prognosis. Cardiac Magnetic Resonance (CMR) can precisely assess ventricular systolic dysfunction and quantify myocardial fibrosis (MF), both identified as prognostic factors. We sought to investigate if ECG abnormalities in CCC patients were associated with more severe myocardial involvement as evaluated by CMR. METHODS: CCC patients with 12­lead ECG and CMR closely obtained were included. ECG analysis evaluated rhythm, presence, and type of intraventricular conduction disturbances (IVCD) and, ventricular premature beats (VPB). CMR short-axis cine and late gadolinium enhancement images were evaluated to obtain left and right ventricular ejection fractions and MF mass, respectively. Statistical significance was set in 5%. RESULTS: 194 CCC patients (98 women, 56 ± 14 years) were evaluated, and no IVCD was detected in 71. The most common IVCD was the association of right bundle branch block and left anterior fascicular block (RBBB+LAFB) in 58 patients, followed by isolated RBBB in 34, isolated LAFB in 17, and left bundle branch block (LBBB) in 14 patients. Of patients with no IVCD, 63% had MF and the burden of fibrosis (no IVCD - 7.4 ± 8.6%; RBBB - 6.6 ± 6.5%; p = 1.00), as well as left ventricular ejection fraction (LVEF) (no IVCD - 52 ± 14%; RBBB - 55 ± 10%; p = 1.00) were similar to patients with isolated RBBB. Left conduction system impairment was associated with lower LVEF (LAFB - 39 ± 15%; RBBB+LAFB- 41 ± 15%; and LBBB - 35 ± 15%; p < 0.001) and more MF (RBBB+LAFB - 12.2 ± 10.4%; LBBB - 10.6 ± 7.5%; and LAFB - 12.0 ± 7.0%; p < 0.001). The univariable model showed that the presence of MF was related to RBBB+LAFB (OR 5.0; p = 0.001) and VPB (OR 6.3; p = 0.014). After adjustment for age, gender, and different risk factors in a multivariable model, the same findings were still significantly related to CMR myocardial fibrosis (RBBB+LAFB OR 5.0; p = 0.002 / VPB OR 6.9; p = 0.015). CONCLUSIONS: ECG without IVCD does not exclude serious cardiac abnormalities in CCC, and isolated RBBB seems to have a benign course. The presence of VPB and left branch conduction impairment, especially LAFB associated with RBBB, indicate a more severe cardiac involvement.

Allopurinol for fibromyalgia pain in adults: A randomized controlled trial.

BACKGROUND: Allopurinol is a potent inhibitor of the enzyme xanthine oxidase used in the treatment of hyperuricemia and gout. Because it is well known that purines exert multiple affects on pain transmission, we hypothesized that the inhibition of xanthine oxidase by allopurinol could be a valid strategy to treat pain in humans. This study aimed to compare the analgesic efficacy of oral allopurinol versus placebo as an adjuvant therapy in patients displaying fibromyalgia. METHODS: This randomized, double-blinded, placebo-controlled study included 60 women with the diagnosis of fibromyalgia. Patients were randomly assigned to receive either oral allopurinol 300 mg (n = 31) or placebo (n = 29) twice daily during 30 days. The patients were submitted to evaluation for pain sensitivity, anxiety, depression, and functional status before treatment, and 15 and 30 days thereafter. RESULTS: Oral administration of allopurinol 300 mg twice daily was ineffective in improving pain scores measured by several tools up to 30 days of treatment (P > 0.05). Additionally, no significant effects of allopurinol over anxiety, depressive symptoms, and functional status of fibromyalgia patients were observed in the present study. CONCLUSIONS: Although previous findings indicated that allopurinol could present intrinsic analgesic effects in both animals and humans, this study showed no benefit of the use of oral allopurinol as an adjuvant strategy during 30 days in women displaying fibromyalgia. However, considering previous promising results, new prospective studies are still valid to further investigate allopurinol and more selective purine derivatives in the management of pain syndromes.

Ketamine Affects Prediction Errors about Statistical Regularities: A Computational Single-Trial Analysis of the Mismatch Negativity.

The auditory mismatch negativity (MMN) is significantly reduced in schizophrenia. Notably, a similar MMN reduction can be achieved with NMDA receptor (NMDAR) antagonists. Both phenomena have been interpreted as reflecting an impairment of predictive coding or, more generally, the "Bayesian brain" notion that the brain continuously updates a hierarchical model to infer the causes of its sensory inputs. Specifically, neurobiological interpretations of predictive coding view perceptual inference as an NMDAR-dependent process of minimizing hierarchical precision-weighted prediction errors (PEs), and disturbances of this putative process play a key role in hierarchical Bayesian theories of schizophrenia. Here, we provide empirical evidence for this theory, demonstrating the existence of multiple, hierarchically related PEs in a "roving MMN" paradigm. We applied a hierarchical Bayesian model to single-trial EEG data from healthy human volunteers of either sex who received the NMDAR antagonist S-ketamine in a placebo-controlled, double-blind, within-subject fashion. Using an unrestricted analysis of the entire time-sensor space, our trial-by-trial analysis indicated that low-level PEs (about stimulus transitions) are expressed early (102-207 ms poststimulus), while high-level PEs (about transition probability) are reflected by later components (152-199 and 215-277 ms) of single-trial responses. Furthermore, we find that ketamine significantly diminished the expression of high-level PE responses, implying that NMDAR antagonism disrupts the inference on abstract statistical regularities. Our findings suggest that NMDAR dysfunction impairs hierarchical Bayesian inference about the world's statistical structure. Beyond the relevance of this finding for schizophrenia, our results illustrate the potential of computational single-trial analyses for assessing potential pathophysiological mechanisms.

Brain volume changes after long-term injectable opioid treatment: A longitudinal voxel-based morphometry study.

Clinical research has demonstrated the efficacy of injectable opioid treatment for long-term, treatment-refractory opioid-dependent patients. It has been hypothesized that compulsive drug use is particularly associated with neuroplasticity changes in the networks corresponding to withdrawal/negative affect and preoccupation/anticipation rather than binge/intoxication. However, as yet, no study has investigated the effect of long-term opioid treatment on key regions within these networks. Magnetic resonance imaging (MRI) was used to assess brain volumes changes during long-term (approximately 9 years) injectable opioid agonist treatment with diacetylmorphine (DAM) in 22 patients with opioid use disorder. Voxel-based morphometry was applied to detect volumetric changes within the networks of binge/intoxication (ventral/dorsal striatum, globus pallidus and thalamus), withdrawal/negative affect (amygdala and ventral striatum) and preoccupation/anticipation (hippocampus, orbitofrontal and anterior cingulate cortex). The relationships between significant volume changes and features of opioid use disorder were tested using Pearson correlation. Long-term opioid agonist treatment was associated with the enlargement of the right caudate nucleus, which was related to the duration of opioid use disorder. In contrast, reduced volume in the right amygdala, anterior cingulate cortex and orbitofrontal cortex were found that were related to opioid dose, onset of opioid consumption and state anxiety. These findings suggest that long-term opioid agonist treatment is related to structural changes in key brain regions underlying binge/intoxication, withdrawal/negative affect and preoccupation/anticipation, suggesting sustained interaction between these systems.

Allopurinol attenuates postoperative pain and modulates the purinergic system in patients undergoing abdominal hysterectomy: a randomized controlled trial.

PURPOSE: Allopurinol is a potent inhibitor of the enzyme xanthine oxidase used primarily in the treatment of hyperuricemia and gout. The aim of this study was to compare the analgesic efficacy of preanesthetic allopurinol versus placebo on postoperative pain and anxiety in patients undergoing abdominal hysterectomy. METHODS: This is a prospective, double-blinded, placebo-controlled, randomized clinical trial. We investigated 54 patients scheduled to undergo elective abdominal hysterectomy. Patients were randomly assigned to receive either oral allopurinol 300 mg (n = 27) or placebo (n = 27) the night before and 1 h before surgery. Patients were submitted to evaluation of pain and anxiety before the treatment, for 24 h postoperatively, 30 and 90 days after surgery. Cerebrospinal fluid was collected at the time of the spinal anesthesia to perform the measurement of the central levels of purines. RESULTS: Preoperative administration of allopurinol was effective in reducing postoperative pain 2 h after surgery. Allopurinol caused a reduction of approximately 40% in pain scores measured by the visual analogue pain scale after surgery (p < 0.05). No differences were found between groups in anxiety scores after surgery. There was a significant change in the cerebrospinal fluid concentrations of xanthine and uric acid before surgery (p < 0.01). CONCLUSION: This study showed a short-term benefit of the use of allopurinol as a preanesthetic medication since it was related to a reduction on pain scores 2 h after surgery. The purinergic system is a potential target for new analgesic drugs. New studies investigating more selective purine derivatives in the management of pain should be performed. TRIAL NUMBER REGISTRATION: Brazilian Registry of Clinical Trials-ReBEC #RBR-9pw58p.

An overlapping pattern of cerebral cortical thinning is associated with both positive symptoms and aggression in schizophrenia via the ENIGMA consortium.

BACKGROUND: Positive symptoms are a useful predictor of aggression in schizophrenia. Although a similar pattern of abnormal brain structures related to both positive symptoms and aggression has been reported, this observation has not yet been confirmed in a single sample. METHOD: To study the association between positive symptoms and aggression in schizophrenia on a neurobiological level, a prospective meta-analytic approach was employed to analyze harmonized structural neuroimaging data from 10 research centers worldwide. We analyzed brain MRI scans from 902 individuals with a primary diagnosis of schizophrenia and 952 healthy controls. RESULTS: The result identified a widespread cortical thickness reduction in schizophrenia compared to their controls. Two separate meta-regression analyses revealed that a common pattern of reduced cortical gray matter thickness within the left lateral temporal lobe and right midcingulate cortex was significantly associated with both positive symptoms and aggression. CONCLUSION: These findings suggested that positive symptoms such as formal thought disorder and auditory misperception, combined with cognitive impairments reflecting difficulties in deploying an adaptive control toward perceived threats, could escalate the likelihood of aggression in schizophrenia.

Relationship between microvascular changes, autonomic denervation, and myocardial fibrosis in Chagas cardiomyopathy: Evaluation by MRI and SPECT imaging.

BACKGROUND: The relationship between microvasculopathy, autonomic denervation, and myocardial fibrosis, in Chagas cardiomyopathy is incompletely understood. The aim of this study was to explore the relative extent and anatomic distribution of myocardial hypoperfusion, autonomic denervation, and myocardial scarring using Single-Photon Emission Computerized Tomography (SPECT) imaging and Magnetic Resonance Imaging (MRI). METHODS: Thirteen patients with Chagas disease all had Iodine-123-metaiodobenzylguanidine (MIBG) SPECT, 99mTc-Sestamibi (MIBI) rest-stress SPECT, and gadolinium late enhancement MRI imaging within a 2-month interval. The anatomic location and extent of denervation, of stress-induced hypoperfusion and fibrosis, were assessed through image co-registration and quantification of abnormal tissue areas as a percent of total myocardium. RESULTS: The results showed a strong general anatomic concordance between areas of hypoperfusion, denervation, and fibrosis, suggesting that the three abnormal features may be correlated. Myocardial denervation was anatomically and quantitatively closely associated areas of stress hypoperfusion. CONCLUSION: Combined myocardial analysis of the extent and location of autonomic denervation, hypoperfusion, and scarring may allow for better understanding of the pathophysiology of Chagas cardiomyopathy. Autonomic myocardial denervation may be a more sensitive marker of cardiac involvement in Chagas Disease than finding by other imaging modalities.

S100B protein and neuron-specific enolase as predictors of postoperative cognitive dysfunction in aged dogs: a case-control study.

OBJECTIVE: Postoperative cognitive dysfunction (POCD) may be related to brain injury. S100B protein and neuron-specific enolase (NSE) have been investigated as potential biochemical markers of neural cell injury in animals and humans. This study aimed to investigate the association between POCD, brain injury and serum concentrations of S100B and NSE after periodontal surgery in aged dogs. STUDY DESIGN: Prospective observational animal study. ANIMALS: A total of 24 male and female dogs undergoing periodontal surgery. METHODS: Dogs were separated into two groups based on age: control group, 10 dogs ≤ 8 years and aged group, 14 dogs > 8 years. Cognitive function was measured preoperatively and on the seventh postoperative day using the Canine Cognitive Dysfunction Rating scale and the Age-Related Cognitive and Affective Disorders scale. S100B protein and NSE serum concentrations were measured before and immediately after the surgery. RESULTS: POCD was not observed after surgery in the present study. Serum concentrations of S100B and NSE were increased postoperatively in the control group but not in the aged group (p = 0.04 and 0.03, respectively). Preoperative S100B serum concentrations were significantly higher in the aged group (p = 0.01). CONCLUSIONS: There was no association between POCD and high concentrations of S100B and NSE in dogs. However, increased postoperative serum concentrations of S100B and NSE were found in the control group after surgery, an effect that may indicate neural damage. CLINICAL RELEVANCE: The results suggest that anesthesia and oral surgery are associated with higher postoperative serum concentrations of S100B and NSE in dogs ≤ 8 years old, which may indicate neural damage. Serum concentrations of S100B were elevated in aged dogs before anesthesia, a finding that might be related to chronic preoperative brain damage.