Synapses do not facilitate prion-like transfer of alpha-synuclein: a quantitative study in reconstructed unidirectional neural networks.

Alpha-synuclein (aSyn) aggregation spreads between cells and underlies the progression of neuronal lesions in the brain of patients with synucleinopathies such as Parkinson's diseases. The mechanisms of cell-to-cell propagation of aggregates, which dictate how aggregation progresses at the network level, remain poorly understood. Notably, while prion and prion-like spreading is often simplistically envisioned as a "domino-like" spreading scenario where connected neurons sequentially propagate protein aggregation to each other, the reality is likely to be more nuanced. Here, we demonstrate that the spreading of preformed aSyn aggregates is a limited process that occurs through molecular sieving of large aSyn seeds. We further show that this process is not facilitated by synaptic connections. This was achieved through the development and characterization of a new microfluidic platform that allows reconstruction of binary fully oriented neuronal networks in vitro with no unwanted backward connections, and through the careful quantification of fluorescent aSyn aggregates spreading between neurons. While this allowed us for the first time to extract quantitative data of protein seeds dissemination along neural pathways, our data suggest that prion-like dissemination of proteinopathic seeding aggregates occurs very progressively and leads to highly compartmentalized pattern of protein seeding in neural networks.

Apathy in a high prevalence population of moderate to severe traumatic brain injury: An investigation in Vietnam.

OBJECTIVE: The reduction of goal-directed behavior, termed apathy, is a pervasive and debilitating syndrome after traumatic brain injury (TBI). However, understanding of apathy as a multifaceted construct is limited, especially in Southeast Asian nations. This study aimed to investigate the severity, insight, and psychosocial influences of apathy in executive, emotional, and initiation dimensions in Vietnam-a country with high prevalence of TBI. METHOD: One hundred and eleven Vietnamese participants (61 individuals with moderate to severe TBI and 50 healthy controls) and their informants completed the self-rated and informant-rated Dimensional Apathy Scale (DAS) for the assessment of executive, emotional, and initiation apathy severity. Insight of apathy was calculated by subtracting DAS self-ratings from informant ratings. Additionally, carers completed measures assessing psychosocial factors of overall family health and overprotective behavior, while participants rated their own self-efficacy. RESULTS: Our results showed greater informant-rated apathy for all three dimensions in individuals with TBI relative to controls. However, while people with TBI had greater self-rated initiation apathy, they regarded their executive apathy as lower and their emotional apathy as similar compared with controls. Reduced insight in patients was seen for executive and initiation apathy. Across participants, executive apathy was predicted by family functioning and overprotectiveness, emotional apathy was predicted by family functioning, and initiation apathy was predicted by self-efficacy. CONCLUSIONS: These findings support the multidimensional characterizations and socio-cultural considerations of apathy after TBI, which will potentially develop both individual-specific and symptom-specific approaches in clinical practice. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Metabolic flexibility differs by body composition in adults.

BACKGROUND & AIMS: With the rise of global cardiometabolic diseases, it is important to investigate risk factors such as obesity. Metabolic flexibility, the ability to maintain metabolic homeostasis following an acute challenge, can reflect cardiometabolic health. We investigated the association between body composition and the metabolic flexibility following meal consumption in an adult population. METHODS: In this study of 1027 participants (mean age 44.0 y ± SD 4.2 y), we administered a mixed-macronutrient meal challenge. Fasting and 2-h postprandial plasma were assayed for lipids, glycemic, and inflammation biomarkers. We characterized metabolic flexibility through meal-induced biomarker responses (%Δ, the difference between postprandial and fasting concentrations, divided by fasting concentration). We then compared the responses by sex-specific tertiles of body mass index (BMI) and percent body fat. RESULTS: With every unit (kg/m2) increase in BMI, %Δ (95% confidence interval) increased by 0.17% (0.09, 0.26%) for total cholesterol, 0.31% (0.07, 0.54%) for triglycerides, and 0.11% (0.01, 0.20%) for apoA-I, whereas insulin elevation was reduced (-6.30%; -8.41, -4.20%), and the reduction in leptin was attenuated (0.64%; 0.25, 1.05%). With each unit (percent) increase in body fat, we observed similar changes in the %Δ of total cholesterol and leptin but not in triglycerides, apoA-I, or insulin. Glucose response increased by 0.29% (0.06, 0.51%) as body fat increases by one unit. CONCLUSION: Metabolic flexibility, as assessed by biomarker responses to an acute physiological meal challenge, differed by body composition. These findings may help elucidate the pathways through which obesity contributes to cardiometabolic diseases.

Measuring Postprandial Metabolic Flexibility to Assess Metabolic Health and Disease.

Metabolic abnormalities substantially increase the risk of noncommunicable diseases, which are among the leading causes of mortality globally. Mitigating and preventing these adverse consequences remains challenging due to a limited understanding of metabolic health. Metabolic flexibility, a key tenet of metabolic health, encompasses the responsiveness of interrelated pathways to maintain energy homeostasis throughout daily physiologic challenges, such as the response to meal challenges. One critical underlying research gap concerns the measurement of postprandial metabolic flexibility, which remains incompletely understood. We concisely review the methodology for assessment of postprandial metabolic flexibility in recent human studies. We identify 3 commonalities of study design, specifically the nature of the challenge, nature of the response measured, and approach to data analysis. Primary interventions were acute short-term nutrition challenges, including single- and multiple-macronutrient tolerance tests. Postmeal challenge responses were measured via laboratory assays and instrumentation, based on a diverse set of metabolic flexibility indicators [e.g., energy expenditure (whole-body indirect calorimetry), glucose and insulin kinetics, metabolomics, transcriptomics]. Common standard approaches have been diabetes-centric with single-macronutrient challenges (oral-glucose-tolerance test) to characterize the postprandial response based on glucose and insulin metabolism; or broad measurements of energy expenditure with calculated macronutrient oxidation via indirect calorimetry. Recent methodological advances have included the use of multiple-macronutrient meal challenges that are more representative of physiologic meals consumed by free-living humans, combinatorial approaches for assays and instruments, evaluation of other metabolic flexibility indicators via precision health, systems biology, and temporal perspectives. Omics studies have identified potential novel indicators of metabolic flexibility, which provide greater granularity to prior evidence from canonical approaches. In summary, recent findings indicate the potential for an expanded understanding of postprandial metabolic flexibility, based on nonclassical measurements and methodology, which could represent novel dynamic indicators of metabolic diseases.

Postprandial glycemic response differed by early life nutritional exposure in a longitudinal cohort: a single- and multi-biomarker approach.

PURPOSE: Populations malnourished in early life are at increased risk for cardiometabolic diseases. We assessed if improved nutrition predicts cardiometabolic function, as assessed by postprandial biomarker responses. METHODS: Participants had been randomized at the village level to receive one of two nutritional supplements as children. At mean age 44 y (range 37-53 years), we obtained plasma samples before and 2 h after a mixed-component meal challenge. We assayed biomarkers including lipids, glycemic measurements, and inflammatory cytokines. We compared postprandial biomarker responses among those who received the improved nutrition intervention from conception through to their second birthday (the first 1000 days) to those with other exposure status, including those who received the improved nutrition intervention at other ages, and those who received the less nutritious supplement. RESULTS: Among 1027 participants (59.4% female), 22.9% were exposed to improved nutrition in the first 1000 days. Insulin increased the most in response to the meal challenge (over twofold), and non-esterified fatty acids decreased the most (by half). Glucose increased postprandial by 11.4% in the exposed group, compared with 15.7% in the other exposure group (p < 0.05), which remained significant after adjusting for confounders (- 4.7%; 95% confidence interval: - 9.3%, - 0.01%). Responses to the prandial challenges for the other biomarkers did not differ by intervention group (all p > 0.05). CONCLUSION: Early life exposure to improved nutrition was associated with a more favorable postprandial glucose response in this population. We did not observe a difference in overall cardiometabolic responses between the exposure groups.

Protein and gene markers of metabolic dysfunction and inflammation together associate with functional connectivity in reward and motor circuits in depression.

Bidirectional relationships between inflammation and metabolic dysfunction may contribute to the pathophysiology of psychiatric illnesses like depression. Metabolic disturbances drive inflammation, which in turn exacerbate metabolic outcomes including insulin resistance. Both inflammatory (e.g. endotoxin, vaccination) and metabolic challenges (e.g. glucose ingestion) have been shown to affect activity and functional connectivity (FC) in brain regions that subserve reward and motor processing. We previously reported relationships between elevated concentrations of endogenous inflammatory markers including C-reactive protein (CRP) and low corticostriatal FC, which correlated with symptoms of anhedonia and motor slowing in major depression (MD). Herein, we examined whether similar relationships were observed between plasma markers related to glucose metabolism (non-fasting concentrations of glucose, insulin, leptin, adiponectin and resistin) in 42 medically-stable, unmedicated MD outpatients who underwent fMRI. A targeted, hypothesis-driven approach was used to assess FC between seeds in subdivisions of the ventral and dorsal striatum and a region in ventromedial prefrontal cortex (VS-vmPFC), which was previously found to correlate with both inflammation and symptoms of anhedonia and motor slowing. Associations between FC and gene expression signatures were also explored. A composite score of all 5 glucose-related markers (with increasing values reflecting higher concentrations) was negatively correlated with both ventral striatum (VS)-vmPFC (r = -0.33, p < 0.05) and dorsal caudal putamen (dcP)-vmPFC (r = -0.51, p < 0.01) FC, and remained significant after adjusting for covariates including body mass index (p < 0.05). Moreover, an interaction between the glucose-related composite score and CRP was observed for these relationships (F[2,33] = 4.3, p < 0.05) whereby significant correlations between the glucose-related metabolic markers and FC was found only in patients with high plasma CRP (>3 mg/L; r = -0.61 to -0.81, p < 0.05). Insulin and resistin were the individual markers most predictive of VS-vmPFC and dcP-mPFC FC, respectively, and insulin, resistin and CRP clustered together and in association with both LV-vmPFC and dcP-vmPFC in principal component analyses. Exploratory whole blood gene expression analyses also confirmed that gene probes negatively associated with FC were enriched for both inflammatory and metabolic pathways (FDR p < 0.05). These results provide preliminary evidence that inflammation and metabolic dysfunction contribute jointly to deficits in reward and motor circuits in MD. Future studies using fasting samples and longitudinal and interventional approaches are required to further elucidate the respective contributions of inflammation and metabolic dysfunction to circuits and symptoms relevant to motivation and motor activity, which may have treatment implications for patients with psychiatric illnesses like depression.

Leptin partially mediates the association between early-life nutritional supplementation and long-term glycemic status among women in a Guatemalan longitudinal cohort.

BACKGROUND: Early-life exposure to improved nutrition is associated with decreased risk of diabetes but increased risk of obesity. Leptin positively correlates with adiposity and has glucose-lowering effects, thus it may mediate the association of early-life nutrition and long-term glycemic status. OBJECTIVES: We aimed to investigate the role of leptin in the differential association between early-life nutrition and the risks of obesity and diabetes. METHODS: We analyzed data from a Guatemalan cohort who were randomly assigned at the village level to receive nutritional supplements as children. We conducted mediation analysis to examine the role of leptin in the associations of early-life nutrition and adult cardiometabolic outcomes. RESULTS: Among 1112 study participants aged (mean ± SD) 44.1 ± 4.2 y, 60.6% were women. Cardiometabolic conditions were common: 40.2% of women and 19.4% of men were obese, and 53.1% of women and 41.0% of men were hyperglycemic or diabetic. Median (IQR) leptin concentration was 15.2 ng/mL (10.2-17.3 ng/mL) in women and 2.7 ng/mL (1.3-5.3 ng/mL) in men. Leptin was positively correlated with BMI (Spearman's ρ was 0.6 in women, 0.7 in men). Women exposed to improved nutrition in early life had 2.8-ng/mL (95% CI: 0.3, 5.3 ng/mL) higher leptin and tended to have lower fasting glucose (-0.8 mmol/L; -1.8, 0.2 mmol/L, nonsignificant) than unexposed women. There were no significant differences in leptin (-0.7 ng/mL; -2.1, 0.8 ng/mL) or fasting glucose (0.2 mmol/L; -0.5, 0.9 mmol/L) in men exposed to improved nutrition in early life compared with unexposed men. Leptin mediated 34.9% of the pathway between early-life nutrition and fasting glucose in women. The mediation in women was driven by improved pancreatic ß-cell function. We did not observe the mediation effect in men. CONCLUSIONS: Leptin mediated the glucose-lowering effect of early-life nutrition in women but not in men.

Introducing a Supportive Care Team for Advance Directive Education in a Neurological and Neurosurgical Patient Population.

BACKGROUND: Patient-centered care includes delineation of patient treatment values (ie, advance care planning [ACP]). Advance care planning often includes advance directive (AD) completion and is underutilized, particularly among neurology and neurosurgery patients. Implementation of a supportive care team (SCT) in outpatient clinic settings may offer opportunities for AD education and completion. OBJECTIVE: This study assesses the effectiveness of an integrative SCT composed of hospice volunteers and undergraduate quality improvement interns in their efforts to provide ACP education in neurological and neurosurgical outpatient clinics. Assessment includes a description of different types of SCT-patient encounters, as well as patient interest in and completion of ADs after interacting with the SCT. RESULTS: Across the data collection period, 2770 encounters were initiated. The majority of encounters resulted in patient ACP education. Some patients completed ADs during their SCT encounter (3.45%) or after their SCT encounter (10.18%). CONCLUSION: The SCT effectively enhances ACP education in this patient population. The utilization of trained interns to assist with ACP is beneficial and practical in clinic workflow.

What does plasma CRP tell us about peripheral and central inflammation in depression?

Peripheral blood C-reactive protein (CRP) is a biomarker used clinically to measure systemic inflammation and is reproducibly increased in a subset of patients with major depressive disorder (MDD). Furthermore, increased peripheral blood CRP in MDD has been associated with altered reward circuitry and increased brain glutamate in relation with symptoms of anhedonia. Nevertheless, the relationship between peripheral CRP and other peripheral and central markers of inflammation in depressed patients has not been established. Plasma (n = 89) and CSF (n = 73) was collected from medically stable, currently unmedicated adult outpatients with MDD. Associations among plasma and CSF CRP and plasma and CSF inflammatory cytokines (interleukin [IL]-6, tumor necrosis factor [TNF] and IL-1beta) and their soluble receptors/antagonists were examined. Relationships between plasma and CSF inflammatory markers and depressive symptoms including anhedonia and reduced motivation (RM) were also explored. Plasma CRP was correlated with multiple plasma inflammatory markers (all p < 0.05), and a strong correlation was found between plasma and CSF CRP (r = 0.855, p < 0.001). CSF CRP in turn correlated with CSF cytokine receptors/antagonists (all p < 0.05). Principal component analyses revealed clusters of CSF inflammatory markers that were associated with high plasma CRP (>3 mg/L) and correlated with depressive symptom severity. These findings were driven by CSF TNF, which correlated with RM (r = 0.236, p = 0.045), and CSF IL-6 soluble receptor, which correlated with anhedonia (r = 0.301, p = 0.010) in the sample as a whole and particularly females. CRP appears to be a peripheral biomarker that reflects peripheral and central inflammation and seems well-suited for guiding immunotherapies targeting TNF and IL-6 in patients with MDD.

Symptom severity impacts sympathetic dysregulation and inflammation in post-traumatic stress disorder (PTSD).

Post-traumatic stress disorder (PTSD) is associated with a greater risk of incident hypertension and cardiovascular disease. Inflammation, impaired baroreflex sensitivity (BRS) decreased parasympathetic nervous system (PNS) and overactive sympathetic nervous system (SNS) activity are suggested as contributing mechanisms. Increasing severity of PTSD symptoms has been linked to greater cardiovascular risk; however, the impact of PTSD symptom severity on inflammation and autonomic control of blood pressure has not yet been explored. We hypothesized that increasing PTSD symptom severity is linked to higher inflammation, greater SNS activity, lower PNS reactivity and impaired BRS. Seventy Veterans participated in this study: 28 with severe PTSD ((Clinical Administered PTSD Scale (CAPS) > 60; S-PTSD), 16 with moderate PTSD (CAPS ≥ 45 ≤ 60; M-PTSD) and 26 Controls (CAPS < 45; NO-PTSD). We recorded continuous blood pressure (BP), heart rate (HR) via EKG, heart rate variability (HRV) markers reflecting PNS and muscle sympathetic nerve activity (MSNA) at rest, during arterial baroreflex sensitivity (BRS) testing via the modified Oxford technique, and during 3 min of mental stress via mental arithmetic. Blood samples were analyzed for 12 biomarkers of systemic and vascular inflammation. While BP was comparable between severity groups, HR tended to be higher (p = 0.055) in S-PTSD (76 ±â€¯2 beats/min) than in Controls (67 ±â€¯2 beats/min) but comparable to M-PTSD (70 ±â€¯3 beats/min). There were no differences in resting HRV and MSNA between groups; however, cardiovagal BRS was blunted (p = 0.021) in S-PTSD (10 ±â€¯1 ms/mmHg) compared to controls (16 ±â€¯3 ms/mmHg) but comparable to M-PTSD (12 ±â€¯2 ms/mmHg). Veterans in the S-PTSD group had a higher (p < 0.001) combined inflammatory score compared to both M-PTSD and NO-PTSD. Likewise, while mental stress induced similar SNS and cardiovascular responses between the groups, there was a greater reduction in HRV in S-PTSD compared to both M-PTSD and NO-PTSD. In summary, individuals with severe PTSD symptoms have higher inflammation, greater impairment of BRS, a trend towards higher resting HR and exaggerated PNS withdrawal at the onset of mental stress that may contribute to cardiovascular risk in severe PTSD.

Association of Early-Onset Alzheimer Disease With Elevated Low-Density Lipoprotein Cholesterol Levels and Rare Genetic Coding Variants of APOB.

Importance: Early-onset Alzheimer disease (EOAD) is a rare form of Alzheimer disease (AD) with a large genetic basis that is only partially understood. In late-onset AD, elevated circulating cholesterol levels increase AD risk even after adjusting for the apolipoprotein E ε4 (APOE E4) allele, a major genetic factor for AD and elevated cholesterol levels; however, the role of circulating cholesterol levels in EOAD is unclear. Objectives: To investigate the association between circulating cholesterol levels and EOAD and to identify genetic variants underlying this possible association. Design, Setting, and Participants: In this case series, plasma cholesterol levels were directly measured in 267 samples from the AD research centers (ADRCs) of Emory University and University of California, San Francisco, collected from January 21, 2009, through August 21, 2014. The association between cholesterol and EOAD was examined using multiple linear regression. To determine the underlying genetic variants, APOB, APP, PSEN1, and PSEN2 were sequenced in samples from 2125 EOAD cases and controls recruited from 29 ADRCs from January 1, 1984, through December 31, 2015. Data were analyzed from November 23, 2016, through April 10, 2018. Exposures: Clinical diagnosis, age at clinical diagnosis, plasma cholesterol measures (total cholesterol, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol, triglycerides, and apolipoprotein B), and genetic variants in APOE, APP, PSEN1, PSEN2, and APOB. Main Outcomes and Measures: The primary outcome was the association between EOAD and plasma cholesterol measures. The secondary outcome was the association between EOAD and the burden of genetic variants in APOB. Results: Of the 2125 samples that underwent genetic sequencing, 1276 were from women (60.0%) and 654 (30.8%) were from patients with EOAD (mean [SD] ages, 55.6 [4.3] years for cases and 72.0 [9.6] years for controls). APOE E4 explained 10.1% of the variance of EOAD. After controlling for APOE E4, EOAD cases had higher levels of total cholesterol (mean difference [SE], 21.9 [5.2] mg/dL; P = 2.9 × 10-5), LDL-C (mean difference [SE], 22.0 [4.5] mg/dL; P = 1.8 × 10-6), and ApoB (mean difference [SE], 12.0 [2.4] mg/dL; P = 2.0 × 10-6) than controls in 267 frozen samples. Approximately 3% of EOAD cases carried known AD-causing mutations. Gene-based rare variant burden testing in 2066 samples showed that rare APOB coding variants were significantly more abundant in EOAD cases after adjusting for sex, APOE E4, genetic principal components, ADRC center, and batch (effect size, 0.20; P = 4.20 × 10-4). Conclusions and Relevance: Elevated LDL-C levels were associated with higher probability of having EOAD, and EOAD cases were enriched for rare coding variants in APOB, which codes for the major protein of LDL-C. Collectively, these novel findings highlight the important role of LDL-C in EOAD pathogenesis and suggest a direct link of APOB variants to AD risk.

Sympathoexcitation and impaired arterial baroreflex sensitivity are linked to vascular inflammation in individuals with elevated resting blood pressure.

Elevated Resting Blood Pressure (ERBP) in the prehypertensive range is associated with increased risk of hypertension and cardiovascular disease, the mechanisms of which remain unclear. Prior studies have suggested that ERBP may be associated with overactivation and dysregulation of the sympathetic nervous system (SNS). We hypothesized that compared to normotensives (≤120/80 mmHg), ERBP (120/80-139/89 mmHg) has higher SNS activity, impaired arterial baroreflex sensitivity (BRS), and increased vascular inflammation. Twenty-nine participants were studied: 16 otherwise healthy individuals with ERBP (blood pressure (BP) 130 ± 2/85 ± 2 mmHg) and 13 matched normotensive controls (mean BP 114 ± 2/73 ± 2 mmHg). We measured muscle sympathetic nerve activity (MSNA), beat-to-beat BP, and continuous electrocardiogram at rest and during arterial BRS testing via the modified Oxford technique. Blood was analyzed for the following biomarkers of vascular inflammation: lipoprotein-associated phospholipase A2 (Lp-PLA2), E-selectin, and intercellular adhesion molecule 1 (ICAM-1). Resting MSNA burst frequency (22 ± 2 vs. 16 ± 2 bursts/min, P = 0.036) and burst incidence (36 ± 3 vs. 25 ± 3 bursts/100 heart beats, P = 0.025) were higher in ERBP compared to controls. Cardiovagal BRS was blunted in ERBP compared to controls (13 ± 2 vs. 20 ± 3 msec/mmHg, P = 0.032), while there was no difference in sympathetic BRS between groups. Lp-PLA2 (169 ± 8 vs. 142 ± 9 nmol/min/mL, P = 0.020) and E-selectin (6.89 ± 0.6 vs. 4.45 ± 0.51 ng/mL, P = 0.004) were higher in ERBP versus controls. E-selectin (r = 0.501, P = 0.011) and ICAM-1 (r = 0.481, P = 0.015) were positively correlated with MSNA, while E-selectin was negatively correlated with cardiovagal BRS (r = -0.427, P = 0.030). These findings demonstrate that individuals with ERBP have SNS overactivity and impaired arterial BRS that are linked to biomarkers of vascular inflammation.

Glucose and lipid-related biomarkers and the antidepressant response to infliximab in patients with treatment-resistant depression.

The tumor necrosis factor (TNF) antagonist infliximab was previously found to reduce depressive symptoms in patients with treatment-resistant major depression (TRD) who exhibited high baseline inflammation, as reflected by plasma C-reactive protein (CRP) >5 mg/L. Further predictors of antidepressant response to infliximab included differential expression of peripheral blood gene transcripts that were related not only to inflammation but also to glucose and lipid metabolism. To determine whether plasma biomarkers of glucose and lipid metabolism were similarly associated with antidepressant response to infliximab and with relevant gene transcripts, we measured concentrations of glucose, insulin, and protein hormones that regulate glucose homeostasis and metabolism (leptin, resistin, and adiponectin), as well as cholesterols, triglycerides, and non-esterified fatty acids (NEFA), in medically-stable TRD outpatients at baseline and 2 weeks after the first infusion of infliximab (n = 26) or placebo (n = 26). Treatment response was defined as 50% reduction in depressive symptoms at any point during the 12-week trial. We found that baseline cholesterol (total, low-density lipoprotein [LDL], and non-high-density lipoprotein [non-HDL]), triglycerides and NEFA were elevated in patients who exhibited an antidepressant response to infliximab (all p < 0.05) but not placebo (all p > 0.299). HDL and non-HDL cholesterol concentrations also correlated with two lipid-related gene transcripts that were predictive of antidepressant response (r = 0.33 to 0.39, p < 0.05). Although not associated with response to infliximab, resistin correlated with numerous glucose-related transcripts (r = -0.32 to 0.37, p < 0.05) and was higher at 2 weeks post-infusion in patients treated with infliximab compared to placebo (p = 0.028). Concentrations of cholesterol (total, LDL, HDL, non-HDL) were also lower at 2 weeks in patients treated with infliximab compared to placebo, but only in those patients with CRP >5 mg/L at baseline (all p < 0.05). These results are consistent with previous work showing that high inflammation in patients with depression is associated with metabolic alterations, which together predict response to both traditional and experimental antidepressant therapies. Additionally, our findings suggest a causal relationship between increased inflammation and high cholesterol in depression, as a single infusion of infliximab reduced cholesterol in TRD patients with high CRP compared to placebo.

mCME project V.2.0: randomised controlled trial of a revised SMS-based continuing medical education intervention among HIV clinicians in Vietnam.

BACKGROUND: Continuing medical education (CME) is indispensable, but costs are a barrier. We tested the effectiveness of a novel mHealth intervention (mCME V.2.0) promoting CME among Vietnamese HIV clinicians. METHODS: We enrolled HIV clinicians from three provinces near Hanoi. The 6-month intervention consisted of (1) daily short message service multiple-choice quiz questions, (2) daily linked readings, (3) links to online CME courses and (4) feedback messages describing the performance of the participant relative to the group. Control participants had equal access to the online CME courses. Our primary endpoint was utilisation of the online CME courses; secondary endpoints were self-study behaviour, performance on a standardised medical exam and job satisfaction. RESULTS: From 121 total HIV clinicians in the three provinces, 106 (87.6%) enrolled, and 48/53 intervention (90%) and 47/53 control (89%) participants completed the endline evaluations. Compared with controls, intervention participants were more likely to use the CME courses (risk ratio (RR) 2.3, 95% CI 1.4 to 3.8, accounting for 83% of course use (P<0.001)). Intervention participants increased self-study behaviours over controls in terms of use of medical textbooks (P<0.01), consulting with colleagues (P<0.01), searching on the internet (P<0.001), using specialist websites (P=0.02), consulting the Vietnam HIV/AIDS treatment guidelines (P=0.02) and searching the scientific literature (P=0.09). Intervention participants outperformed controls on the exam (+23% vs +12% score gains, P=0.05) and had higher job satisfaction. CONCLUSION: The mCME V.2.0 intervention improved self-study behaviour, medical knowledge and job satisfaction. This approach has potential for expansion in Vietnam and similar settings. TRIAL REGISTRATION NUMBER: NCT02381743.

Baroreflex dysfunction and augmented sympathetic nerve responses during mental stress in veterans with post-traumatic stress disorder.

KEY POINTS: Patients with post-traumatic stress disorder (PTSD) are at a significantly higher risk of developing hypertension and cardiovascular disease. The mechanisms underlying this increased risk are not known. Studies have suggested that PTSD patients have an overactive sympathetic nervous system (SNS) that could contribute to cardiovascular risk; however, sympathetic function has not previously been rigorously evaluated in PTSD patients. Using direct measurements of sympathetic nerve activity and pharmacological manipulation of blood pressure, we show that veterans with PTSD have augmented SNS and haemodynamic reactivity during both combat-related and non-combat related mental stress, impaired sympathetic and cardiovagal baroreflex sensitivity, and increased inflammation. Identifying the mechanisms contributing to increased cardiovascular (CV) risk in PTSD will pave the way for developing interventions to improve sympathetic function and reduce CV risk in these patients. ABSTRACT: Post-traumatic stress disorder (PTSD) is associated with increased cardiovascular (CV) risk. We tested the hypothesis that PTSD patients have augmented sympathetic nervous system (SNS) and haemodynamic reactivity during mental stress, as well as impaired arterial baroreflex sensitivity (BRS). Fourteen otherwise healthy Veterans with combat-related PTSD were compared with 14 matched Controls without PTSD.  Muscle sympathetic nerve activity (MSNA), continuous blood pressure (BP) and electrocardiography were measured at baseline, as well as during two types of mental stress:  combat-related mental stress using virtual reality combat exposure (VRCE) and non-combat related stress using mental arithmetic (MA). A cold pressor test (CPT) was administered for comparison. BRS was tested using pharmacological manipulation of BP via the Modified Oxford technique at rest and during VRCE. Blood samples were analysed for inflammatory biomarkers. Baseline characteristics, MSNA and haemodynamics were similar between the groups. In PTSD vs. Controls, MSNA (+8.2 ± 1.0 vs. +1.2 ± 1.3 bursts min-1 , P < 0.001) and heart rate responses (+3.2 ± 1.1 vs. -2.3 ± 1.0 beats min-1 , P = 0.003) were significantly augmented during VRCE.  Similarly, in PTSD vs. Controls, MSNA (+21.0 ± 2.6 vs. +6.7 ± 1.5 bursts min-1 , P < 0.001) and diastolic BP responses (+6.3 ± 1.0 vs. +3.5 ± 1.0 mmHg, P = 0.011) were significantly augmented during MA but not during CPT (P = not significant). In the PTSD group, sympathetic BRS (-1.2 ± 0.2 vs. -2.0 ± 0.3 burst incidence mmHg-1 , P = 0.026) and cardiovagal BRS (9.5 ± 1.4 vs. 23.6 ± 4.3 ms mmHg-1 , P = 0.008) were significantly blunted at rest. PTSD patients had significantly higher highly sensitive-C-reactive protein levels compared to Controls (2.1 ± 0.4 vs. 1.0 ± 0.3 mg L-1 , P = 0.047). Augmented SNS and haemodynamic responses to mental stress, blunted BRS and inflammation may contribute to an increased CV risk in PTSD.

Metabolism and proteomics of large and small dense LDL in combined hyperlipidemia: effects of rosuvastatin.

Small dense LDL (sdLDL) has been reported to be more atherogenic than large buoyant LDL (lbLDL). We examined the metabolism and protein composition of sdLDL and lbLDL in six subjects with combined hyperlipidemia on placebo and rosuvastatin 40 mg/day. ApoB-100 kinetics in triglyceride-rich lipoproteins (TRLs), lbLDL (density [d] = 1.019-1.044 g/ml), and sdLDL (d = 1.044-1.063 g/ml) were determined in the fed state by using stable isotope tracers, mass spectrometry, and compartmental modeling. Compared with placebo, rosuvastatin decreased LDL cholesterol and apoB-100 levels in TRL, lbLDL, and sdLDL by significantly increasing the fractional catabolic rate of apoB-100 (TRL, +45%; lbLDL, +131%; and sdLDL, +97%), without a change in production. On placebo, 25% of TRL apoB-100 was catabolized directly, 37% was converted to lbLDL, and 38% went directly to sdLDL; rosuvastatin did not alter these distributions. During both phases, sdLDL apoB-100 was catabolized more slowly than lbLDL apoB-100 (P < 0.01). Proteomic analysis indicated that rosuvastatin decreased apoC-III and apoM content within the density range of lbLDL (P < 0.05). In our view, sdLDL is more atherogenic than lbLDL because of its longer plasma residence time, potentially resulting in more particle oxidation, modification, and reduction in size, with increased arterial wall uptake. Rosuvastatin enhances the catabolism of apoB-100 in both lbLDL and sdLDL.

Postprandial Clearance of Oxidized Low-Density Lipoprotein in Patients with Stroke Due to Atherosclerosis.

BACKGROUND: Oxidized low-density lipoprotein (OxLDL) is a contributor to atherosclerosis development. OxLDL formation increases in the postprandial state due to oxidative stress in subjects with coronary artery disease (CAD) and diabetes, but has not been studied in patients with atherosclerotic stroke. We aimed to determine differences in postprandial OxLDL in patients with atherosclerotic stroke compared to stroke from other causes. METHODS: Patients with ischemic stroke but no history of CAD (n = 42) were enrolled and categorized by stroke subtype as extracranial atherosclerosis (EC), n = 12; intracranial atherosclerosis (IC), n = 16; or other cause, n = 14. After fasting overnight, subjects consumed a standardized fat meal. OxLDL levels were measured at t = 0 and t = 4 hours postprandial using enzyme-linked immunosorbent assay. Comparisons between the mean changes in OxLDL between the groups were performed using the analysis of variance procedure. RESULTS: The IC group had the highest mean baseline level of OxLDL and the greatest decline during the postprandial period. There was a trend toward a difference in the mean change in OxLDL between the 3 groups (P = .0553). Subjects with atherosclerotic stroke (EC and IC groups) had higher fasting OxLDL and had a significant decline in OxLDL compared to those with stroke from other causes (P = .0164). CONCLUSIONS: Subjects with stroke due to atherosclerosis, particularly intracranially, demonstrated high fasting OxLDL and a decline in OxLDL during the postprandial period. This decline in OxLDL may indicate an accelerated clearance of OxLDL resulting from meal-induced oxidative stress.

Relationship between risk factor control and vascular events in the SAMMPRIS trial.

OBJECTIVE: The Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) study is the first stroke prevention trial to include protocol-driven intensive management of multiple risk factors. In this prespecified analysis, we aimed to investigate the relationship between risk factor control during follow-up and outcome of patients in the medical arm of SAMMPRIS. METHODS: Data from SAMMPRIS participants in the medical arm (n = 227) were analyzed. Risk factors were recorded at baseline, 30 days, 4 months, and then every 4 months for a mean follow-up of 32 months. For each patient, values for all risk factor measures were averaged and dichotomized as in or out of target. RESULTS: Participants who were out of target for systolic blood pressure and physical activity, as well as those with higher mean low-density lipoprotein cholesterol and non-high-density lipoprotein, were more likely to have a recurrent vascular event (stroke, myocardial infarction, or vascular death) at 3 years compared to those who had good risk factor control. In the multivariable analysis, greater physical activity decreased the likelihood of a recurrent stroke, myocardial infarction, or vascular death (odds ratio 0.6, confidence interval 0.4-0.8). CONCLUSIONS: Raised blood pressure, cholesterol, and physical inactivity should be aggressively treated in patients with intracranial atherosclerosis to prevent future vascular events. Physical activity, which has not received attention in stroke prevention trials, was the strongest predictor of a good outcome in the medical arm in SAMMPRIS. CLINICALTRIALSGOV IDENTIFIER: NCT00576693.

The impact of moderate distance recreational running and ageing on cardiac physiology.

OBJECTIVE: Exercise-induced cardiac dysfunction and corollary biomarker release have been documented following long-distance running events. To what degree these processes occur during shorter distance running events is unknown. METHODS: 72 healthy recreational runners (54% male/46% female) recruited by age (group 1 (18-20 years old, N=19); group 2 (45-50 years old, N=27); group 3 (70-75 years old, N=26)) were studied with echocardiography and biochemical profiling during participation in a 10 km running race. RESULTS: Despite age-dependent baseline differences in ventricular size and diastolic tissue velocities, there were no significant within group or across group decrements in ventricular systolic or diastolic function following race completion. Postrace increases in cardiac troponin-I (cTnI), B-type natriuretic peptide (BNP) and high-sensitivity C-reactive protein (hs-CRP) were common and demonstrated distinct age dependent profiles. Specifically, BNP increases were most pronounced among older runners (group 3Δ: 16±22 pg/mL, p=0.001), hs-CRP increased only among younger runners (group 1Δ: 1.5±2.7 mg/L, p=0.03) and cTnI increased in both younger (group 1Δ: 0.01±0.02 ng/mL, p=0.028) and older (group 3Δ: 0.01±0.01 ng/mL, p=0.007) runners, but not middle aged runners (group 2Δ: 0.00±0.00 ng/mL, p=0.57). CONCLUSIONS: Moderate distance recreational running leads to distinct age-dependent biomarker release but is not associated with cardiac fatigue, a proposed stimulus for pathologic cardiac remodelling that has been observed following longer distance running events.

Plasminogen Activator Inhibitor-1 Predicts Quantity of Hepatic Steatosis Independent of Insulin Resistance and Body Weight.

OBJECTIVE: The aim of the present study was to examine the association between plasminogen activator inhibitor-1 (PAI-1), an acute phase protein strongly associated with cardiovascular disease risk, and adiposity, insulin resistance, and inflammation among overweight and obese children with a wide range of hepatic steatosis. METHODS: Plasma PAI-1 levels were measured in a prospectively recruited cohort of 39 overweight or obese children who underwent comprehensive anthropometric assessment and metabolic measurements. Hepatic steatosis was quantified using magnetic resonance spectroscopy and participants were divided into 3 groups based on whether they had normal hepatic steatosis (<5%), low hepatic steatosis (≥5%-10%), and high hepatic steatosis (>10%). RESULTS: Plasma PAI-1 levels significantly increased across the severity of hepatic steatosis in overweight and obese children, and this association was independent of body mass index z score, visceral fat, insulin resistance, and inflammatory markers (P < 0.05). CONCLUSION: Hepatic steatosis in children is positively associated with circulating levels of PAI-1 independent of body mass index, insulin resistance, and inflammatory markers. Further studies are needed to clarify the potential role of PAI-1 as a therapeutic target in pediatric nonalcoholic fatty liver disease.