To assess the efficacy of exercise and antidepressant medication in reducing depressive symptoms and improving cardiovascular biomarkers in depressed patients with coronary heart disease (CHD).
Although there is good evidence that clinical depression is associated with poor prognosis, optimal therapeutic strategies are currently not well-defined.
101 outpatients with CHD and elevated depressive symptoms underwent assessment of depression including a psychiatric interview and the Hamilton Rating Scale for Depression (HAM-D). Participants were randomized to 4 months of aerobic exercise (3 times/week), sertraline (50-200 mg/day), or placebo. Additional assessments of cardiovascular biomarkers included measures of heart rate variability (HRV), endothelial function, baroreflex sensitivity, inflammation, and platelet function.
After 16 weeks, all groups showed improvement on HAM-D scores. Participants in both aerobic exercise (M= −7.5 [95% CI = −9.8, −5.0]) and sertraline (M= −6.1 [95% CI = −8.4, −3.9] achieved larger reductions in depressive symptoms compared to placebo (M= −4.5 [95% CI = −7.6, −1.5]; p = .034); exercise and sertraline were equally effective in reducing depressive symptoms (p = .607). Exercise and medication tended to result in greater improvements in HRV compared to placebo (p = .052); exercise tended to result in greater improvements in HRV compared to sertraline (p =.093)
Both exercise and sertraline resulted in greater reductions in depressive symptoms compared to placebo in CHD patients. Evidence that active treatments may also improve cardiovascular biomarkers suggests that they may have a beneficial effect on clinical outcomes as well as quality of life.
Depression; Exercise; Sertraline; Heart rate variability; Inflammation; Biomarkers; antidepressant medication; SSRI
Two recent studies published in the Journal of the American College of Cardiology report the prognostic significance of anxiety in the development of coronary heart disease in initially healthy adults. These findings are placed in the context of other published reports and highlight the need for future research that includes representative samples of women and minorities using precise assessment tools and careful ascertainment of clinical endpoints.
Depression is a common disorder that is associated with compromised quality of life, increased health care costs, and greater risk for a variety of medical conditions, particularly coronary heart disease. This review examines methods for assessing depression and discusses current treatment approaches. Traditional treatments include psychotherapy and antidepressant medications, but such treatments are not effective for all patients and alternative approaches have recently received increased attention, especially the use of aerobic exercise. This review examines evidence that exercise is effective in improving depressive symptoms among patients with major depression and offers practical suggestions for helping patients initiate and maintain exercise in their daily lives.
Aerobic exercise; physical activity; cardiovascular disease; myocardial infarction; depression; major depressive disorder
Purpose of review
Mood regulation problems, such as severe chronic irritability or short episodes of mania like symptoms are common, impairing and a topic of intense recent interest to clinicians, researchers and the DSM-5 process. Here we review the most recent findings about these two presentations and discuss approaches to their treatment.
Longitudinal and genetic findings suggest that chronic irritability should be regarded as a mood problem that is distinct from bipolar disorder.
A proportion of children with short (less than 4 days) episodes of mania like symptoms seem to progress to classical (Type I or II) bipolar disorder over time in US clinic samples. In a UK sample, such episodes were independently associated with psychosocial impairment.
The evidence base for the treatment of either irritability or short-lived episodes to mania-like symptoms is still small. Clinicians should be cautious with extrapolating treatments from classical bipolar disorder to these mood regulation problems. CBT-based approaches targeting general mood regulation processes may be effective for cases with severe irritability or short episodes of mania like symptoms.
There is increasing research evidence for the importance of mood regulation problems in the form of either irritability or short episodes of mania like symptoms in youth. The evidence base for their drug treatment has yet to be developed. CBT-based interventions to modify processes of mood regulation may be a useful and safe intervention for patients with these presentations.
CBA mice infected with the helminthSchistosomamansonidevelop severe CD4 T cell-mediated hepaticgranulomatous inflammation against parasite eggs associated with a robust Th17 cell response.We investigated the requisites for Th17 cell development using novel CD4 T cells expressing a transgenic (Tg) TCR specific for the major Sm-p40 egg Ag, which produce IL-17 when stimulated with live schistosome eggs. Neutralization of IL-23 or blockade of the IL-1 receptor, but not IL-6 neutralization, abrogated egg-induced IL-17 secretion by Tg T cells, whereas exogenous IL-23 or IL-1β reconstituted their ability to produce IL-17 stimulated by syngeneic IL-12p40-deficient DCs. Kinetic analysis demonstrated that IL-17 production was initiated by IL-23 and amplified by IL-1β. Significantly, schistosome-infected IL-12p40-deficientor IL-1R antagonist treated CBA mice developed markedly reduced hepatic immunopathologywith a dampened egg Ag-specific IL-17 response. These results demonstrate the IL-23-IL-1-IL-17 axis to play a central role in the development of severe schistosome egg-induced immunopathology.
Rodent; T cells; Parasitic–Helminth; Cytokines; Transgenic/Knockout mice
Erectile dysfunction (ED) is especially common in men with major depressive disorder (MDD). This study examined the extent to which risk factors for cardiovascular disease (CVD) and vascular dysfunction were associated with ED severity in a series of MDD patients.
The sample included 46 middle-aged [M (SD) age = 53 (7)], sedentary men diagnosed with MDD. ED severity was assessed by the Arizona Sexual Experiences Scale (ASEX), item 3. Depression severity was measured by the Beck Depression Inventory (BDI). CVD risk factors were quantitated by the Framingham Cardiovascular Disease Risk Profile score. Vascular function was measured by flow-mediated dilation (FMD) of the brachial artery.
The average ASEX score for this sample was 3.2 (SD = 1.2). Regression analysis revealed that ASEX scores were predicted by greater CVD risk factors (p = .008, β = .41) and lower FMD (p = .03, β = −.33). When FMD was included in the regression model, the relationship between CVD risk factors and ASEX scores was partially attenuated (p = .08, β = .28).
ED was associated with CVD risk and impaired vascular function, although it appears that CVD risk factors may affect ED through impairment of vascular functioning.
Erectile dysfunction; cardiovascular disease; endothelium; depression
Recognition of DNA by the innate immune system is central to anti-viral and anti-bacterial defenses, as well as an important contributor to autoimmune diseases involving self DNA. AIM2 (absent in melanoma 2) and IFI16 (interferon-inducible protein 16) have been identified as DNA receptors that induce inflammasome formation and interferon production, respectively. Here we present the crystal structures of their HIN domains in complex with double-stranded (ds) DNA. Non-sequence specific DNA recognition is accomplished through electrostatic attraction between the positively charged HIN domain residues and the dsDNA sugar-phosphate backbone. An intramolecular complex of the AIM2 Pyrin and HIN domains in an autoinhibited state is liberated by DNA binding, which may facilitate the assembly of inflammasomes along the DNA staircase. These findings provide novel mechanistic insights into dsDNA as the activation trigger and oligomerization platform for the assembly of large innate signaling complexes such as the inflammasomes.
Mericitabine (RG7128) is a first-in class nucleoside polymerase inhibitor (NPI), which requires intracellular uptake and phosphorylation to two active triphosphates. Mathematical modeling has provided important insights for characterizing HCV-RNA decline and estimating in vivo effectiveness of antiviral agents; however it has not been used to characterize viral kinetics with NPIs. HCV RNA was frequently measured in 32 treatment-experienced patients infected with HCV genotype-1 during and after mericitabine monotherapy for 14 days with 750-mg or 1500-mg administered once (QD) or twice daily (BID). Initial decline of HCV RNA was typically slower than with interferon-alpha or protease inhibitors and 12 patients presented a novel pattern of HCV RNA kinetics characterized by a monophasic viral decline. Viral kinetics could be well fitted by assuming that the effectiveness in blocking viral production gradually increased over time to reach its final value, ε2, consistent with previous accumulation time estimates of intracellular triphosphates. ε2 was high with BID dosing (mean 750-mg and 1500-mg: 98.0% and 99.8%, P=0.018) and significantly higher than in patients treated QD (mean QD vs BID: 90% vs 99%, P<10−7). Virus rebounded rapidly upon drug discontinuation, which was attributed to the elimination of active drug and the subsequent decline of drug effectiveness with mean t1/2=13.9 h in the BID regimens.
The observed slower initial decline likely represents the time needed to accumulate intracellular triphosphates and is consistent with in vitro data. When administered BID, mericitabine reached a high, dose-dependent, final effectiveness in blocking viral production, that rapidly dropped upon treatment cessation. Understanding HCV RNA kinetics with mericitabine could provide valuable insights for combining it with other direct-acting antiviral agents.
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
Women with substance use issues and their children have unique needs that are best met through collaborative and coordinated service delivery offered by a variety of agencies. However, in Canada and elsewhere, services tend to be fragmented and fail to address children’s needs. This study aimed to describe the partnership patterns, activities, and qualities among Canadian agencies serving women with addictions and to determine predictors of partnerships. We found that a number of partnerships exist, and that the extent and characteristics of these partnerships vary. Agency responsiveness to clients was predictive of sending referrals whereas friendliness predicted joint programming and consultation. Four central agencies played key linkage roles. Efforts should be made to build on the social capital inherent in these agencies to strengthen existing networks, further develop linkages to improve service delivery, and promote evidence-informed practice in a field where there is an identified research-practice gap.
Substance abuse; Women; Agency partnerships; Service collaboration; Social network analysis
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