The current paradigm for studying hepatitis C virus (HCV) dynamics in patients utilizes a standard viral dynamic model that keeps track of uninfected (target) cells, infected cells, and virus. The model does not account for the dynamics of intracellular viral replication, which is the major target of direct-acting antiviral agents (DAAs). Here we describe and study a recently developed multiscale age-structured model that explicitly considers the potential effects of DAAs on intracellular viral RNA production, degradation, and secretion as virus into the circulation. We show that when therapy significantly blocks both intracellular viral RNA production and virus secretion, the serum viral load decline has three phases, with slopes reflecting the rate of serum viral clearance, the rate of loss of intracellular viral RNA, and the rate of loss of intracellular replication templates and infected cells, respectively. We also derive analytical approximations of the multiscale model and use one of them to analyze data from patients treated for 14 days with the HCV protease inhibitor danoprevir. Analysis suggests that danoprevir significantly blocks intracellular viral production (with mean effectiveness 99.2%), enhances intracellular viral RNA degradation about 5-fold, and moderately inhibits viral secretion (with mean effectiveness 56%). The multiscale model can be used to study viral dynamics in patients treated with other DAAs and explore their mechanisms of action in treatment of hepatitis C.
Chronic infection with hepatitis C virus (HCV) remains an important health-care problem worldwide despite significant progress in the development of HCV therapy since the discovery of the virus in 1989. Current treatment options are focused on direct-acting antiviral agents (DAAs) that target specific steps of the HCV life cycle. Danoprevir, one of the DAAs that inhibit the HCV NS3-4A protease, has induced substantial viral load reductions in patients receiving therapy. We study the viral decline during therapy using a multiscale age-structured model that accounts for the dynamics of intracellular viral replication, and which includes the major steps in the HCV life cycle that are targeted by DAAs. We examine the biological parameters contributing to different phases of the viral decline after treatment initiation. We also explore the mechanisms of action of danoprevir and estimate its treatment effectiveness. The multiscale model provides a theoretical framework for studying virus dynamics in hepatitis C patients treated with other DAAs currently in clinical development, and may help one to optimally combine drugs with complementary modes of action to maximize the HCV cure rate.
To investigate the relationship of cerebrovascular risk factors (CVRFs), endothelial function, carotid artery intima medial thickness (IMT), and neuropsychological performance in a sample of 198 middle-aged and older individuals with major depressive disorder (MDD). Neuropsychological deficits are common among adults with MDD, particularly among those with CVRFs and potentially persons with subclinical vascular disease.
CVRFs were indexed by the Framingham Stroke Risk Profile (FSRP) and serum cholesterol levels obtained by medical history and physical examination. Patients completed a neuropsychological test battery including measures of executive functioning, working memory, and verbal recall. Vascular function was indexed by carotid artery IMT and brachial artery flow mediated dilation (FMD). Hierarchical multiple regression analyses were used to investigate the association between CVRFs, vascular disease, and neurocognitive performance.
Greater FSRP scores were associated with poorer executive functioning (b = −0.86; p = .041) and working memory (b = −0.90; p = .024). Lower high-density lipoprotein levels also were associated with poorer executive functioning (b = 1.03; p = .035). Higher IMT (b = −0.83; p = .028) and lower FMD (b = 1.29; p = .032) were associated with poorer executive functioning after controlling for CVRFs. Lower FMD was also associated with poorer working memory (b = 1.58; p = .015).
Greater CVRFs were associated with poorer neuropsychological performance. Vascular dysfunction also was associated with neuropsychological decrements independent of traditional CVRFs.
cerebrovascular risk; vascular disease; neuropsychological performance; depression; endothelial function
Patients with end-stage lung disease experience significant decrements in quality of life (QOL). Although coping strategies are related to QOL in patients with end-stage lung disease, the extent to which specific native lung disease moderates this relationship is unknown.
We investigated the relationship between coping, native lung disease, and QOL among 187 patients awaiting lung transplantation, including 139 patients with chronic obstructive pulmonary disease (COPD) and 48 patients with cystic fibrosis (CF). Participants completed a psychosocial battery assessing psychological QOL, physical QOL, and coping strategies.
For both COPD and CF patients, higher levels of Active Coping (P < .0001) and lower levels of Disengagement (P < .0001) were associated with better psychological QOL. For physical QOL, we observed a native disease by coping interaction (P = .01) such that Active Coping was associated with better physical QOL in patients with COPD but not in patients with CF.
The relationship between coping and QOL may vary as a function of native lung disease. In order to develop effective interventions to help patients cope successfully with end stage lung disease, patients’ native disease may need to be considered.
cystic fibrosis; chronic obstructive pulmonary disease; coping; lung transplant; quality of life
The relationship between diet and cognitive function has been a topic of increasing interest, as numerous studies have shown that variations in dietary practices and nutrient intake are may protect against age-related cognitive decline, as well as the development of dementia and Alzheimer’s Disease (AD). Various dietary practices and specific nutrient components of these diets have been examined in relation to cognitive performance including 1) dietary fatty acids (including fish oil) and the Mediterranean diet, 2) antioxidants (including vitamins E and C) and fruits and vegetables, 3) vitamins B6, B12 (cobolamine), and folate, and, more recently, 4) caloric restriction. Although observational studies have generally reported significant associations between dietary practices and reduced incidence of cognitive dysfunction, randomized trials of dietary interventions have yielded mixed findings, with many trials yielding small gains or equivocal findings. In addition, findings appear to vary based on sample characteristics, methods of dietary assessment, and length of study follow-up. The influence of dietary practices on cognitive function in middle aged and older adults remains uncertain, and further research is needed to clarify the nature of this relationship and identify mechanisms by which diet may affect neurocognition.
The Children and War Foundation was established after the authors’ experiences following the civil war in former Yugoslavia in the mid-1990s. Many organizations tried to mitigate the effects of the war on children but few interventions were based on evidence and fewer were properly evaluated. The Foundation was established in Norway with the aim of promoting better evidence-based interventions to help children after wars and natural disasters.
The Foundation has developed a number of empirically grounded manuals that aim to help children learn strategies that will lessen the stress reactions that they have developed. The manuals are designed to be delivered by personnel who are not necessarily very experienced in child mental health. They are aimed at groups of children using a public health approach to reach large numbers in a short space of time. The strategies are not intended as individual therapy.
The Teaching Recovery Techniques manual has been used following a number of earthquakes and other natural disasters and data from a number of these will be discussed. A Writing for Recovery manual is aimed at helping adolescents and is based on the seminal work of James Pennebaker. It is currently being evaluated in three separate studies. A group-based manual to help children bereaved by war or disaster has recently been developed.
Children; war; disasters; evidence-based interventions
This analysis was conducted to determine whether the hepatitis C virus (HCV) viral kinetics (VK) model can predict viral load (VL) decreases for nonnucleoside polymerase inhibitors (NNPolIs) and protease inhibitors (PIs) after 3-day monotherapy studies of patients infected with genotype 1 chronic HCV. This analysis includes data for 8 NNPolIs and 14 PIs, including VL decreases from 3-day monotherapy, total plasma trough concentrations on day 3 (Cmin), replicon data (50% effective concentration [EC50] and protein-shifted EC50 [EC50,PS]), and for PIs, liver-to-plasma ratios (LPRs) measured in vivo in preclinical species. VK model simulations suggested that achieving additional log10 VL decreases greater than one required 10-fold increases in the Cmin. NNPolI and PI data further supported this result. The VK model was successfully used to predict VL decreases in 3-day monotherapy for NNPolIs based on the EC50,PS and the day 3 Cmin. For PIs, however, predicting VL decreases using the same model and the EC50,PS and day 3 Cmin was not successful; a model including LPR values and the EC50 instead of the EC50,PS provided a better prediction of VL decrease. These results are useful for designing phase 1 monotherapy studies for NNPolIs and PIs by clarifying factors driving VL decreases, such as the day 3 Cmin and the EC50,PS for NNPolIs or the EC50 and LPR for PIs. This work provides a framework for understanding the pharmacokinetic/pharmacodynamic relationship for other HCV drug classes. The availability of mechanistic data on processes driving the target concentration, such as liver uptake transporters, should help to improve the predictive power of the approach.
Alix and cellular paralogs HD-PTP and Brox contain N-terminal Bro1 domains that bind ESCRT-III CHMP4. In contrast to HD-PTP and Brox, expression of the Bro1 domain of Alix alleviates HIV-1 release defects due to interrupted access to ESCRT. In an attempt to elucidate this functional discrepancy, we solved the crystal structures of the Bro1 domains of HD-PTP and Brox. They revealed typical “boomerang” folds they share with the Bro1 Alix domain. However, they each contain unique structural features that may be relevant to their specific function(s). In particular, phenylalanine residue in position 105 (Phe105) of Alix belongs to a long loop that is unique to its Bro1 domain. Concurrently mutation of Phe105 and surrounding residues at the tip of the loop compromises the function of Alix in HIV-1 budding without affecting its interactions with Gag or CHMP4. These studies identify a new functional determinant in the Bro1 domain of Alix.
Danoprevir is a hepatitis C virus (HCV) NS3/4A protease inhibitor that promotes multi-log10 reductions in HCV RNA when administered as a 14-day monotherapy to patients with genotype 1 chronic HCV. Of these patients, 14/37 experienced a continuous decline in HCV RNA, 13/37 a plateau, and 10/37 a rebound. The rebound and continuous-decline groups experienced similar median declines in HCV RNA through day 7, but their results diverged notably at day 14. Plateau group patients experienced a lesser, but sustained, median HCV RNA decline. Baseline danoprevir susceptibility was similar across response groups but was reduced significantly at day 14 in the rebound group. Viral rebound in genotype 1b was uncommon (found in 2/23 patients). Population-based sequence analysis of NS3 and NS4A identified treatment-emergent substitutions at four amino acid positions in the protease domain of NS3 (positions 71, 155, 168, and 170), but only two (155 and 168) were in close proximity to the danoprevir binding site and carried substitutions that impacted danoprevir potency. R155K was the predominant route to reduced danoprevir susceptibility and was observed in virus isolated from all 10 rebound, 2/13 plateau, and 1/14 continuous-decline patients. Virus in one rebound patient additionally carried partial R155Q and D168E substitutions. Treatment-emergent substitutions in plateau patients were less frequently observed and more variable. Single-rebound patients carried virus with R155Q, D168V, or D168T. Clonal sequence analysis and drug susceptibility testing indicated that only a single patient displayed multiple resistance pathways. These data indicate the ascendant importance of R155K for viral escape during danoprevir treatment and may have implications for the clinical use of this agent.
To examine the relationship between vascular health, including flow-mediated dilation (FMD), intima medial thickness (IMT), and neurocognitive performance in a sample of 124 sedentary, middle-aged adults with high blood pressure (SBP 130–159 mmHg or DBP 85–99 mmHg) who were overweight or obese (body mass index 25.0 – 39.99 kgs/m2). Patients completed a neuropsychological test battery including measures of Executive Function and Psychomotor Speed, along with measures of IMT and FMD. Hierarchical multiple regression analyses were used to investigate the association between vascular measures and neurocognitive performance after controlling for demographic factors and cerebrovascular risk factors. Higher levels of FMD predicted better Executive Function (b = 0.90, P = .045). Greater IMT tended to be associated with slower Psychomotor Speed (b = −0.82, P = .084), with the effect attenuated after controlling for FMD. Impaired FMD is associated with worse neurocognitive functioning among overweight adults with high blood pressure.
Infection with the trematode parasite Schistosoma mansoni results in distinct heterogeneity of disease severity both in humans and in mice. In the experimental mouse model, severe disease is characterized by pronounced hepatic egg-induced granulomatous inflammation mediated by CD4 Th17 cells, whereas mild disease is associated with reduced hepatic inflammation in a Th2-skewed cytokine environment. Even though the host’s genetic background significantly impacts the clinical outcome of schistosomiasis, specific gene(s) that contribute to disease severity remain elusive. We investigated the schistosome infection in wild-derived mice, which possess a more diverse gene pool than classically inbred mouse strains and thus makes them more likely to reveal novel mechanisms of immune regulation. We now show that inbred wild-derived MOLF mice develop severe hepatic inflammation with high levels of IL-17. Congenic mice with a MOLF locus in chromosome 6, designated Why1, revealed high pathology and enabled the identification of Irak2 as the pathogenic gene. Although IRAK-2 is classically associated with TLR signaling, adoptive transfer of CD4 T cells revealed that IRAK-2 mediates pathology in a CD4 T cell specific manner by promoting Th17 cell development through enhancement of IL-1β-induced activation of transcription factors RORγt and BATF. The use of wild-derived mice unravels IRAK-2 as a novel regulator of IL-1-induced pathogenic Th17 cells in schistosomiasis, which likely has wide-ranging implications for other chronic inflammatory and autoimmune diseases.
Schistosomes are trematode helminths that cause widespread disease in vertebrates and are responsible for over 200 million human infections worldwide. The species Schistosoma mansoni causes a hepatic granulomatous inflammatory and fibrosing reaction against tissue trapped parasite eggs that varies greatly in humans and among mouse strains, implying that the host’s genetic background plays a critical role in determining disease severity. Although exacerbated hepatic inflammation is known to be associated with an increase in CD4 Th17 cells, specific genes conducive to high pathology are unknown. In this study we used genetically diverse inbred wild-derived mice and found that their natural severe immunopathology and high IL-17 levels are regulated by the interleukin-1 (IL-1) receptor-associated kinase-like 2 (IRAK-2). We demonstrate that T cell intrinsic IRAK-2 affects disease severity by enhancing the development of Th17 cells, which results from an increased sensitivity to IL-1β induced activation of the lineage-specific transcription factors RORγt and BATF. Our findings thus identify IRAK-2 as a single regulator of pathogenic Th17 cell development in murine schistosomiasis and reveal a novel mechanism that is likely to operate in other chronic inflammatory and autoimmune diseases.
Danoprevir is a potent and selective direct-acting antiviral agent that targets the protease activity of hepatitis C virus (HCV) NS3/4A. This agent results in a significant rapid decline in HCV RNA levels when it is used in monotherapy. The present study evaluated whether plasma concentrations of the inflammatory markers gamma interferon-inducible protein 10 (IP-10) and neopterin or the interferon-stimulated gene product 2′-5′-oligoadenylate synthetase (OAS-1) were correlated with the plasma HCV RNA concentration before or during 14-day danoprevir monotherapy. In contrast to pegylated interferon and ribavirin treatment, a higher baseline IP-10 concentration was positively correlated with a greater first-phase HCV RNA decline upon danoprevir administration. Changes in the IP-10 plasma concentration during danoprevir administration were also associated with categorical changes in HCV RNA concentration at days 7 and 14. The neopterin concentration appeared to be moderately decreased during danoprevir administration, although these changes were not statistically significant. However, changes in neopterin concentration showed a statistically significant correlation with changes in IP-10 concentration. Considerable variation in the OAS-1 concentration was observed before and during treatment, including in patients treated with placebo and/or patients with minimal virologic response. Overall, these results suggest that effective treatment with a direct-acting antiviral agent may reduce hepatic inflammation and that first-phase HCV RNA decline during treatment with an NS3/4A protease inhibitor is more robust in patients with high baseline IP-10 concentrations.
It is intuitive that immune cells in the gut may require microbiota-derived cues for their differentiation. The proximity between host and microbe in the intestine would seemingly necessitate co-adaptation. However, it has been challenging to determine the members and features of the gut microbiota that influence immune system development and function. The recent identification of immunomodulatory members of the commensal microbiota is providing insight into the dependence of select, intestinal immune cell subsets on specific microbial species. In this review, we focus on the gut microbiota's influence on the development and function of mucosal T cells subsets, specifically intraepithelial lymphocytes and lamina propria CD4 T cells.
gut microbiota; T cells; mucosal immunity
To examine the association between cerebral hyperintensities and cerebrovascular risk factors (CVRF) among middle-aged and older adults with major depressive disorder (MDD).
Thirty patients (aged 55–77 years) with MDD and no history of stroke participated in a magnetic resonance imaging assessment to assess for the presence of cerebral hyperintensities and underwent a physical examination to assess stroke risk as indexed by the Framingham Stroke Risk Profile (FSRP). In addition, intima medial thickness (IMT) was measured in the left and right carotid arteries.
Higher FSRP levels were associated with total greater cerebral hyperintensities (r = 0.64), as well as greater subependymal hyperintensities (r = 0.47), confluent periventricular changes (r = 0.46), and tended to be associated with subcortical gray matter hyperintensities (r = 0.34). A quadratic relationship was observed between IMT and total cerebral hyperintensities (b = 4.84), and higher IMT levels were associated with greater subependymal hyperintensities (r = 0.40).
Higher levels of CVRF are associated with graded increases in cerebral hyperintensities among middle-aged and older adults with MDD.
Cerebrovascular risk factors; vascular disease; cerebral hyperintensities; major depression
Although the effects of exercise on neurocognition have been the subject of several previous reviews and meta-analyses, they have been hampered by methodological shortcomings and are now outdated as a result of the recent publication of several large-scale randomized controlled trials (RCTs).
We conducted a systematic literature review of RCTs examining the association between aerobic exercise training on neurocognitive performance conducted between January, 1966 and July, 2009. Suitable studies were selected for inclusion according to the following criteria: randomized treatment allocation, mean age ≥ 18 years of age, duration of treatment > 1 month, incorporated aerobic exercise components, exercise training was supervised, the presence of a non-aerobic-exercise control group, and sufficient information to derive effect size (ES) data.
Twenty-nine studies met inclusion criteria and were included in our analyses, representing data from 2,049 participants and 234 effect sizes. Individuals randomly assigned to receive aerobic exercise training demonstrated modest improvements in attention and processing speed (g = .158 [95% CI: .055 to .260], P = .003), executive function (g = .123 [95% CI: .021 to .225], P = .018), and memory (g = .128 [95% CI: .015 - .241], P = .026).
Aerobic exercise training is associated with modest improvements in attention and processing speed, executive function, and memory, although the effects of exercise on working memory are less consistent. Rigorous RCTs are needed with larger samples, appropriate controls, and longer follow-up periods.
Cognitive performance; aerobic exercise; neuropsychological performance; executive function; randomized controlled trial; meta-analysis
The the influence of temperature on taste cues and the ability to discriminate and learn about different temperatures of foods are important factors regulating ingestion. The goal of this research was to demonstrate that thermal orosensory input can serve as a salient stimulus to guide ingestive behavior in the rat, and also that it interacts with gustatory input during choice and conditioned aversion experiments. A novel apparatus with Peltier refrigerators was used to control the temperature of solutions in 10-minute, 2-bottle tests. It was determined that naive rats preferred cold water (10°C) to warm water (40°). When cold water was paired with a toxic LiCl injection, rats avoided cold water and drank warm water, thus demonstrating that cold water could serve as the conditioned stimulus in a conditioned temperature aversion. Rats conditioned against cold water could discriminate 10° C water from 16° C water, but not from 13° C water, thus showing an ability to discriminate orosensory thermal cues to within 3–6° C. Rats also generalized conditioned aversions from cold water to cold saccharin and cold sucrose solutions. However, if rats were conditioned against a compound taste and thermal stimulus (10° C, 0.125% saccharin), the rats could distinguish and avoid each component individually, i.e., by avoiding cold water or warm saccharin. Finally, daily 2-bottle extinction tests were used to assess the strength of aversions conditioned against a taste cue (0.25 M sucrose), a thermal cue (10°C water), or the combination. Aversions to taste or temperature alone persisted for 7–14 days of extinction testing, but the combined taste-temperature aversion was stronger and did not extinguish after 20 days of extinction testing. These results demonstrate that temperature can serve as a salient cue in conditioned aversions that affect ingestion independent of taste cues or by potentiating taste cues.
conditioned taste aversion; conditioned temperature aversion; lithium; sucrose; saccharin
C57BL/6 mice infected with Schistosoma mansoni naturally develop mild CD4+ T cell-mediated immunopathology characterized by small hepatic granulomas around parasite eggs. However, immunization with soluble egg antigens in CFA (SEA/CFA) markedly exacerbates the lesions by inducing a potent proinflammatory environment with high levels of IFN-γand IL-17, which are signature cytokines of distinct Th1 vs. Th17 cell lineages. To determine the relative role of these subsets in disease exacerbation, we examined mice deficient in T-bet (T-bet-/-), which is required for Th1 cell differentiation and IFN-γ production. We now report that SEA/CFA immunization caused a significant enhancement of egg-induced hepatic immunopathology in T-bet-/- mice compared to BL/6 WT controls, and analysis of their granulomas disclosed a higher proportion of activated DC and CD4+ T cells, as well as a marked influx of neutrophils. The absence of IFN-γ in the T-bet-/- mice correlated with a marked increase in IL-23p19, IL-17 and TNF-α in granulomas and MLN. In contrast, T-bet-/- mice had lower levels of IL-4, IL-5 and IL-10 and a reduction in FIZZ1 and Foxp3 expression, suggesting diminished regulatory activity, respectively, by alternatively activated macrophages and regulatory T cells. These findings demonstrate that T-bet-dependent signaling negatively regulates Th17 cell-mediated immunopathology in severe schistosomiasis.
Helminth infection; Inflammation; Cytokines
High blood pressure increases the risks of stroke, dementia, and neurocognitive dysfunction. Although aerobic exercise and dietary modifications have been shown to reduce blood pressure, no randomized trials have examined the effects of aerobic exercise combined with dietary modification on neurocognitive functioning in individuals with high blood pressure (ie, prehypertension and stage 1 hypertension). As part of a larger investigation, 124 participants with elevated blood pressure (systolic blood pressure 130 to 159 mm Hg or diastolic blood pressure 85 to 99 mm Hg) who were sedentary and overweight or obese (body mass index: 25 to 40 kg/m2) were randomized to the Dietary Approaches to Stop Hypertension (DASH) diet alone, DASH combined with a behavioral weight management program including exercise and caloric restriction, or a usual diet control group. Participants completed a battery of neurocognitive tests of executive function-memory-learning and psychomotor speed at baseline and again after the 4-month intervention. Participants on the DASH diet combined with a behavioral weight management program exhibited greater improvements in executive function-memory-learning (Cohen’s D=0.562; P=0.008) and psychomotor speed (Cohen’s D=0.480; P=0.023), and DASH diet alone participants exhibited better psychomotor speed (Cohen’s D=0.440; P=0.036) compared with the usual diet control. Neurocognitive improvements appeared to be mediated by increased aerobic fitness and weight loss. Also, participants with greater intima-medial thickness and higher systolic blood pressure showed greater improvements in executive function-memory-learning in the group on the DASH diet combined with a behavioral weight management program. In conclusion, combining aerobic exercise with the DASH diet and caloric restriction improves neurocognitive function among sedentary and overweight/obese individuals with prehypertension and hypertension.
hypertension; exercise; nutrition; clinical trial; neurocognition
Postoperative delirium is associated with increased morbidity and mortality. Pre-existing cognitive impairment and depression have been frequently cited as important risk factors for this complication. This prospective cohort study was designed to determine if individuals who perform poorly on preoperative cognitive tests and/or exhibited depressive symptoms would be at high risk for the development of postoperative delirium.
One hundred nondemented patients, 50 years and older, scheduled for major, elective noncardiac surgery completed a preoperative test battery that included measures of global cognition, executive function and symptoms of depression. Known preoperative risk factors for delirium were collected and examined with the results of the preoperative test battery to determine the independent predictors of delirium.
The overall incidence of delirium was 16% and was associated with increased hospital length of stay (p<0.05) and an increased incidence of postoperative complications (p<0.01). Delirious subjects did not differ from their non-delirious cohorts with regard to their preoperative global cognitive function, preexisting medical comorbidities, age, anesthetic management or history of alcohol use. Preoperative executive scores (p<0.001) and depression (p<0.001), as measured by the Trail Making B test and Geriatric Depression Scale Short Form, respectively, were found to be independent predictors of postoperative delirium.
Low preoperative executive scores and depressive symptoms independently predict postoperative delirium in older individuals. A rapid, simple test combination including tests of executive function and depression could improve physicians’ ability to recognize patients who might benefit from a perioperative intervention strategy to prevent postoperative delirium.
Infection with the trematode parasite Schistosoma mansoni results in a distinct heterogeneity of disease severity, both in humans and in an experimental mouse model. Severe disease is characterized by pronounced hepatic egg-induced granulomatous inflammation in a proinflammatory cytokine environment, whereas mild disease corresponds with reduced hepatic inflammation in a Th2 skewed cytokine environment. This marked heterogeneity indicates that genetic differences play a significant role in disease development, yet little is known about the genetic basis of dissimilar immunopathology. To investigate the role of genetic susceptibility in murine schistosomiasis, quantitative trait loci analysis was performed on F2 progeny derived from SJL/J and C57BL/6 mice, which develop severe and mild pathology, respectively. In this study, we show that severe liver pathology in F2 mice 7 wk after infection significantly correlated with an increase in the production of the proinflammatory cytokines IL-17, IFN-γ, and TNF-α by schistosome egg Ag-stimulated mesenteric lymph node cells. Quantitative trait loci analysis identified several genetic intervals controlling immunopathology as well as IL-17 and IFN-γ production. Egg granuloma size exhibited significant linkage to two loci, D4Mit203 and D17Mit82, both of which were inherited in a BL/6 dominant manner. Furthermore, a significant reduction of hepatic granulomatous inflammation and IL-17 production in interval-specific congenic mice demonstrated that the two identified genetic loci have a decisive effect on the development of immunopathology in murine schistosomiasis.
Postoperative delirium has been associated with greater complications, medical cost, and increased mortality during hospitalization. Recent evidence suggests that preoperative executive dysfunction and depression may predict postoperative delirium; however, the combined effect of these risk factors remains unknown. We therefore examined the association between preoperative executive function, depressive symptoms, and established clinical predictors of postoperative delirium among 998 consecutive patients undergoing major non-cardiac surgery.
Nine hundred ninety eight patients were screened for postoperative delirium (n = 998) using the Confusion Assessment Method as well as through retrospective chart review. Patients underwent cognitive, psychosocial, and medical assessments preoperatively. Executive function was assessed using the Concept Shifting Task, Letter-Digit Coding, and a modified Stroop Color Word Interference Test. Depression was assessed by the Beck Depression Inventory.
Preoperative executive dysfunction (P = .007) and greater levels of depressive symptoms (P = .049) were associated with a greater incidence of postoperative delirium, independent of other risk factors. Secondary analyses of cognitive performance demonstrated that the Stroop Color Word Interference Test, the executive task with the greatest complexity in this battery, was more strongly associated with postoperative delirium than simpler tests of executive function. Furthermore, patients exhibiting both executive dysfunction and clinically significant levels of depression were at greatest risk for developing delirium postoperatively.
Preoperative executive dysfunction and depressive symptoms were predictive of postoperative delirium among non-cardiac surgical patients. Executive tasks with greater complexity are more strongly associated with postoperative delirium relative to tests of basic sequencing.
Infection with schistosomes results in a CD4 T cell-mediated inflammatory reaction against parasite eggs that varies greatly in magnitude both in humans as well as in mice. In the murine disease, the severe form of immunopathology correlates with high levels of IL-17. We now report that live schistosome eggs stimulate dendritic cells from high pathology-prone CBA mice to produce IL-12p40, IL-6, and TGF-β, whereas those from low pathology-prone BL/6 mice only make TGF-β. Moreover, egg-stimulated dendritic cells plus naive CD4 T cells from CBA mice resulted in increased levels of IL-6, IL-23, IL-1β, as well as IL-17 and the chemokines CXCL1, CXCL2, and CCL2, whereas similarly treated BL/6 cell cocultures instead expressed higher IL-4, IL-5, IL-10, and the transcription factor Foxp3. Neutralization of IL-23 and IL-1, but not of IL-6 or IL-21, profoundly inhibited egg-induced IL-17 production in the CBA cocultures. Conversely, stimulation with schistosome eggs in the presence of exogenous IL-23 and IL-1β induced BL/6 cells to make IL-17. These findings identify IL-23 and IL-1 as critical host factors that drive IL-17 production, and suggest that parasite recognition followed by a genetically determined innate proinflammatory response induces the development of Th17 cells and thus controls the outcome of immunopathology in schistosomiasis.
Although cross-sectional studies have demonstrated an association between higher levels of aerobic fitness and improved neurocognitive function, there have been relatively few interventional studies investigating this relationship, and results have been inconsistent. We assessed the effects of aerobic exercise on neurocognitive function in a randomized controlled trial of patients with major depressive disorder (MDD).
Two-hundred and two sedentary men (n = 49) and women (n = 153), aged 40 yr and over and who met diagnostic criteria for MDD, were randomly assigned to the following: a) supervised exercise, b) home-based exercise, c) sertraline, or d) placebo pill. Before and after 4 months of treatment, participants completed measures of: Executive Function (Trail Making Test B-A difference score, Stroop Color/Word, Ruff 2 & 7 Test, Digit Symbol), Verbal Memory (Logical Memory, Verbal Paired Associates), and Verbal Fluency/Working Memory (Animal Naming, Controlled Oral Word Association Test, Digit Span). Multivariate analyses of covariance were performed to test the effects of treatment on posttreatment neuropsychological test scores, with baseline neuropsychological test scores, age, education, and change in depression scores entered as covariates.
The performance of exercise participants was no better than participants receiving placebo across all neuropsychological tests. Exercise participants performed better than participants receiving sertraline on tests of executive function but not on tests of verbal memory or verbal fluency/working memory.
We found little evidence to support the benefits of an aerobic exercise intervention on neurocognitive performance in patients with MDD.
FITNESS; DEPRESSION; COGNITIVE FUNCTION; EXECUTIVE FUNCTION
Monocytes are primary targets for human cytomegalovirus (HCMV) infection and are proposed to be responsible for haematogenous dissemination of the virus. Monocytes acquire different functional traits during polarization to the classical pro-inflammatory M1 macrophage or the alternative anti-inflammatory M2 macrophage. We hypothesized that HCMV induced a pro-inflammatory M1 macrophage following infection in order to promote viral dissemination because, biologically, a pro-inflammatory state provides the necessary tools to drive infected monocytes from the blood into the tissue. To test this hypothesis of monocyte conversion from a normal quiescent phenotype to an inflammatory phenotype, we utilized Affymetrix Human Microarray to acquire a transcriptional profile of infected monocytes at a time point our data emphasized as being a key temporal regulatory point following infection. We found that HCMV significantly upregulated 583 (5.2%) of the total genes and downregulated 621 (5.5%) of the total genes ≥1.5-fold at 4 hours post infection. Further ontology analysis revealed that genes implicated in classical M1 macrophage activation were stimulated by HCMV infection. Specifically, we found that 65% of genes strictly associated with M1 polarization were upregulated, while only 4% of genes solely associated with M2 polarization were upregulated. Analysis of the monocyte chemokinome at the transcriptional level showed that 44% of M1 and 33% of M2 macrophage chemokines were upregulated, respectively. Proteomic analysis using human chemokine antibody arrays confirmed the secretion of these chemotactic proteins from HCMV-infected monocytes. Overall, the results identify that the HCMV-infected monocyte transcriptome displayed a unique M1/M2 polarization signature that was skewed towards the classical M1 activation phenotype.
Late life depression, including patients with vascular depression, has been associated with higher levels of intima-media thickness (IMT). Although individuals with vascular depression tend to report a later onset of depression, the relationship of IMT and age of first depressive episode is uncertain in younger adults. We therefore investigated the relationship between IMT and age of first depressive episode in a sample of 202 adults (age range 40−81 years) with major depression (MDD).
Depression status was assessed using the Structured Clinical Interview Schedule and the Hamilton Depression Rating Scale. Patients underwent a physical examination in which a medical history was obtained. IMT was measured from the left and right common carotid arteries. Simple regression analyses were used to investigate the association between IMT and self-reported age of first depressive episode.
IMT was associated with a later onset of first major depressive episode (b = .225, P = .0005) and this association remained significant after controlling for age, Framingham Stroke Risk Profile, smoking pack years, physical activity, high- and low-density lipoprotein, body mass index, triglyceride levels, and history of chronic medical conditions (b = .142, P = .028). Each .10 mm increase in IMT was associated with a 2.6-year later reported occurrence of first major depressive episode (MDE). Similarly, higher levels of IMT were associated with fewer previous MDEs (b = −.149, P = .020) and this effect remained significant in our multivariate model (b = −.140, P = .030). In contrast, IMT was not associated with current depressive severity (b = −.024, P = .720).
Greater levels of IMT are associated with a later onset of depression and fewer previous depressive episodes among middle-aged and older adults, independent of cardiovascular co-morbidities. These findings provide preliminary evidence that increased vascular burden may be associated with a later onset of depression.
Intima-media thickness; Vascular disease; Depression; Vascular depression
Infection with the trematode helminth Schistosoma mansoni results in a parasite egg-induced, CD4 T-cell-mediated, hepatointestinal granulomatous and fibrosing inflammation that varies greatly in severity, with a higher frequency of milder forms typically occurring in regions where the disease is endemic. One possible explanation for this is that in these regions the degree of inflammation is lessened by widespread concurrent infection with gastrointestinal nematodes. We tested this hypothesis by establishing a murine coinfection model in which mice were infected with the intestinal nematode parasite Heligmosomoides polygyrus prior to infection with S. mansoni. In CBA mice that naturally display a severe form of schistosomiasis, preinfection with H. polygyrus resulted in a marked reduction in schistosome egg-induced hepatic immunopathology, which was associated with significant decreases in the levels of interleukin-17 (IL-17), gamma interferon, tumor necrosis factor alpha, IL-23, IL-6, and IL-1β and with increases in the levels of IL-4, IL-5, IL-10, and transforming growth factor β in mesenteric lymph node cells, purified CD4 T cells, and isolated liver granuloma cells. There also were increases in liver Ym1 and forkhead box P3 transcription factor expression. In another model of high-pathology schistosomiasis induced in C57BL/6 mice by immunization with schistosome egg antigens in complete Freund's adjuvant, coinfection with the nematodes also resulted in a marked inhibition of hepatic immunopathology accompanied by similar shifts in cytokine production. These findings demonstrate that intestinal nematodes prevent Th1- and Th17-cell-mediated inflammation by promoting a strong Th2-polarized environment associated with increases in the levels of alternatively activated macrophages and T regulatory cells, which result in significant amelioration of schistosome-induced immunopathology.