Numerous studies have examined the relationship between physical activity and cognitive function, demonstrating that greater physical activity is associated with lower incidence of cognitive impairment in later life. Due to an increasingly large number of older adults at risk for cognitive impairment, the relationship between physical activity and cognition has garnered increasing public health relevance and multiple randomized trials have demonstrated that exercise interventions among sedentary adults improve cognitive performance in multiple domains of function. This article will examine the relationship between physical activity and cognitive function by reviewing several different areas of literature, including the prevalence of cognitive impairment, assessment methods, observational studies examining physical activity and cognition, and intervention studies. The present review is intended to provide a historical tutorial of existing literature linking physical activity, exercise, and cognitive function among both healthy and clinical populations.
Physical activity; Neurocognition; Aerobic exercise
Chronic obstructive pulmonary disease (COPD) is associated with increased morbidity and mortality and reduced quality of life. Novel interventions are needed to improve outcomes in COPD patients. The present study assessed the effects of a telephone-based coping skills intervention on psychological and somatic quality of life and on the combined medical endpoint of COPD-related hospitalizations and all-cause mortality.
We conducted a dual-site, randomized clinical trial with assessments at baseline and after 16 weeks of treatment. The study population comprised 326 outpatients with COPD aged 38 to 81 years, randomized to Coping Skills training (CST) or to COPD Education (COPD-ED). Patients completed a battery of quality of life (QoL) instruments, pulmonary function tests, and functional measures and were followed for up to 4.4 years to assess medical outcomes.
The CST group exhibited greater improvements in psychological QoL compared to controls (P = .001), including less depression (Cohen’s d=0.22 [95%CI 0.08, 0.36]) and anxiety (d=0.17 [95%CI 0.02, 0.33]), and better overall mental health (d=0.17 [95%CI 0.03, 0.32]), emotional role functioning (d= 0.29 [95%CI 0.10, 0.48]), vitality (d= 0.27 [95%CI 0.11, 0.42]), and social functioning (d= 0.21 [95%CI 0.03, 0.38]). A significant baseline psychological QoL by Treatment group interaction revealed that CST with lower QoL at baseline achieved even greater improvements in psychological QoL compared to COPE-ED. CST participants also exhibited greater improvements in Somatic QoL (P = .042), including greater improvements in pulmonary QoL (d= 0.13 [95%CI 0.01, 0.24]), less fatigue (d= 0.34 [95%CI 0.18, 0.50]), and less shortness of breath (d= 0.11 [95%CI −0.01, 0.23]) and greater improvement in distance walked on the 6 Minute Walk Test (d= 0.09 [95%CI 0.01, 0.16]). However, there was no significant difference in risk of time to COPD-related hospitalization or all-cause mortality between CST (34 events) and COPD-ED (32 events) (P= 0.430).
A telehealth coping skills training intervention produced clinically meaningful improvements in quality of life and functional capacity, but no overall improvement in risk of COPD-related hospitalization and all-cause mortality.
clinicaltrials.gov Identifier NCT00736268
COPD; stress; depression; coping skills; disease-management
Danoprevir (DNV) is a hepatitis C virus (HCV) protease inhibitor that achieves high sustained virologic response (SVR) rates in combination with peginterferon alfa-2a–ribavirin in treatment-naive HCV genotype 1 (G1)-infected patients. This study explored the efficacy and safety of ritonavir-boosted DNV (DNVr) plus peginterferon alfa-2a–ribavirin in G1-infected prior peginterferon-ribavirin null responders. Null responders (<2-log10 reduction in HCV RNA level at week 12) were given an open-label combination of 100 mg of ritonavir and 100 mg of DNV (100/100 mg DNVr) every 12 h (q12h) plus peginterferon alfa-2a–ribavirin for 12 weeks. All patients achieving an early virologic response (EVR; ≥2-log10 decrease in HCV RNA by week 12) continued treatment with peginterferon alfa-2a–ribavirin; those without an EVR discontinued all study drugs. Twenty-four prior null responders were enrolled; 16 patients (67%) were infected with HCV G1b, and 8 (33%) were infected with G1a. Ninety-six percent of patients had an IL28B non-CC genotype. A sustained virologic response at 24 weeks posttreatment (SVR24) was achieved in 67% of patients, with a higher rate in G1b-infected (88%) than G1a-infected (25%) patients. Resistance-related breakthrough occurred in 4/8 G1a and 1/16 G1b patients through the DNV resistance-associated variant (RAV) NS3 R155K. NS3 R155K was also detected in 2/2 G1a patients who relapsed. Treatment was well tolerated. Two patients withdrew prematurely from study medications due to adverse events. Two serious adverse events were reported; both occurred after completion of DNVr therapy and were considered unrelated to treatment. No grade 3 or 4 alanine aminotransferase (ALT) elevations were observed. DNVr plus peginterferon alfa-2a–ribavirin demonstrated high SVR24 rates in HCV G1b-infected prior null responders and was well tolerated. (This study has been registered at ClinicalTrials.gov under registration no. NCT01185860.)
The crystal structure of the first zebrafish caspase-recruitment domain at 1.47 Å resolution illustrates a six-helix bundle fold similar to that of the human NLRP1 CARD.
The caspase-recruitment domain (CARD) mediates homotypic protein–protein interactions that assemble large oligomeric signaling complexes such as the inflammasomes during innate immune responses. Structural studies of the mammalian CARDs demonstrate that their six-helix bundle folds belong to the death-domain superfamily, whereas such studies have not been reported for other organisms. Here, the zebrafish interferon-induced guanylate-binding protein 1 (zIGBP1) was identified that contains an N-terminal GTPase domain and a helical domain typical of the mammalian guanylate-binding proteins, followed by a FIIND domain and a C-terminal CARD similar to the mammalian inflammasome proteins NLRP1 and CARD8. The structure of the zIGBP1 CARD as a fusion with maltose-binding protein was determined at 1.47 Å resolution. This revealed a six-helix bundle fold similar to the NLRP1 CARD structure with the bent α1 helix typical of all known CARD structures. The zIGBP1 CARD surface contains a positively charged patch near its α1 and α4 helices and a negatively charged patch near its α2, α3 and α5 helices, which may mediate its interaction with partner domains. Further studies using binding assays and other analyses will be required in order to address the physiological function(s) of this zebrafish protein.
CARDs; six-helix bundle; zebrafish; guanylate-binding proteins
The structure of the CARD8 caspase-recruitment domain suggests that its regulatory functions may be mediated by electrostatic attractions between the CARD8 CARD and its partner domains.
CARD8 plays crucial roles in regulating apoptotic and inflammatory signaling pathways through the association of its caspase-recruitment domain (CARD) with those of procaspase-9 and procaspase-1. The CARD8 CARD has also been predicted to form an intramolecular complex with its FIIND domain. Here, the first crystal structure of the CARD8 CARD is reported; it adopts a six-helix bundle fold with a unique conformation of the α6 helix that is described here for the first time. The surface of the CARD8 CARD displays a prominent acidic patch at its α2, α3 and α5 helices that may interact with the procaspase-9 CARD, whereas an adjacent charged surface at its α3 and α4 helices may associate with the CARD8 FIIND domain without interfering with the CARD–CARD interaction. This suggests that the function of CARD8 may be regulated by both intramolecular and intermolecular interactions involving electrostatic attractions.
CARD8; CARDs; death-domain fold; electrostatic attraction
To examine the association of anxiety and depression with pulmonary-specific symptoms of Chronic Obstructive Pulmonary Disease (COPD), and to determine the extent to which disease severity and functional capacity modify this association.
Patients (N = 162) enrolled in the INSPIRE-II study, an ongoing randomized, clinical trial of COPD patients and their caregivers who received either telephone-based coping skills training or education and symptom monitoring. Patients completed a psychosocial test battery including: Brief Fatigue Inventory, St. George’s Respiratory Questionnaire, UCSD Shortness of Breath Questionnaire, State-Trait Anxiety Inventory, and Beck Depression Inventory. Measures of disease severity and functional capacity (i.e., FEV1 and six-minute walk test) were also obtained.
After covariate adjustment, higher anxiety and depression levels were associated with greater fatigue levels (ps < .001, ΔR2 = 0.16 and 0.29, respectively), shortness of breath (ps < .001, ΔR2 = 0.12 and 0.10), and frequency of COPD symptoms (ps < .001, ΔR2 = 0.11 and 0.13). In addition, functional capacity was a moderator of anxiety and pulmonary-specific COPD symptoms. The association between anxiety and shortness of breath (p = 0.009) and frequency of COPD symptoms (p = 0.02) was greater among patients with lower functional capacity.
Anxiety and depression were associated with higher levels of fatigue, shortness of breath, and frequency of COPD symptoms. It is important for clinicians to be aware of the presence of anxiety and depression in COPD patients, which appears to correlate with pulmonary-specific COPD symptoms, especially in patients with lower functional capacity. Prospective design studies are needed to elucidate the causal relationships between anxiety and depression and pulmonary-specific symptoms in COPD patients.
anxiety; depression; COPD
Mathematical modeling; Viral kinetics; Direct-acting antiviral agents; Protease inhibitors; Hepatitis C virus
Oseltamivir is a potent inhibitor of influenza virus neuraminidase enzymes essential for viral replication. This study aimed to investigate the impact of covariates on pharmacokinetic (PK) variability of oseltamivir and its active metabolite form, oseltamivir carboxylate (OC). Dosing history, plasma drug concentrations, and demographic information were pooled from 13 clinical trials providing data for 390 healthy and infected subjects ranging in age from 1 to 78 years and given oseltamivir doses of 20 to 1,000 mg. Candidate population PK models simultaneously characterizing the time course of oseltamivir and OC in plasma were evaluated by using the NONMEM software program, and subject covariates were assessed using stepwise forward selection (α = 0.01) and backward elimination (α = 0.001). A two-compartment model with first-order absorption of oseltamivir and first-order conversion of oseltamivir to OC and a one-compartment model with first-order elimination of OC were utilized. Body weight when evaluated using a power function was a significant predictor of the apparent oseltamivir clearance and both apparent OC clearance (CLm/F) and central volume of distribution (Vcm/F). Creatinine clearance was a significant predictor of CLm/F, while Vcm/F also decreased linearly with age. A visual predictive check indicated that the final model described oseltamivir and OC concentrations in plasma adequately across dose regimens and subject covariate ranges. Concordance of population mean and individual post hoc predictions of maximum concentration of drug at steady state (Cmax) and area under the plasma drug concentration-time curve from 0 to 24 h at steady state (AUC0–24) was high (r2 = 0.81 and 0.71, respectively). In conclusion, a comprehensive population PK model was constructed to bridge the adult to pediatric oseltamivir PK data, allowing for reasonable estimation of the PK of OC using subject demographic data alone.
Objective: Certain thought control strategies for managing the intrusive symptoms of posttraumatic stress disorder (PTSD) are thought to play a key role in its onset and maintenance. Whereas measures exist for the empirical assessment of such thought control strategies in adults, relatively few studies have explored how children and adolescents manage posttraumatic intrusive phenomena.
Methods: In a prospective longitudinal study of 10–16-year-olds with PTSD, who were survivors of road traffic collisions and assaults, a variety of thought control strategies were assessed in the acute phase. These included strategies thought to be protective (reappraisal, social support) as well as maladaptive (distraction, punishment, worry). Ruminative responses to the trauma were assessed at the follow-up assessment.
Results: Posttraumatic stress symptoms (PTSS) at each assessment were associated with the use of punishment and reappraisal, whereas social support and rumination were associated with PTSS symptoms at follow-up. Distraction was unrelated to PTSS at any time point. Rumination accounted for variance in PTSS symptoms at follow-up, even when accounting for baseline PTSS, and was found to mediate the relationships between reappraisal and punishment at baseline and PTSS at the follow-up assessment.
Conclusions: The present study found no evidence to support advocating any particular thought control strategy for managing the intrusive symptoms of PTSD in youth in the acute posttrauma phase, and raised concerns over the use of reappraisal coping strategies. The study underscores the importance of ruminative responses in the onset and maintenance of PTSD in trauma-exposed youth.
Humeral avulsion of the inferior glenohumeral ligament (HAGL) has recently gained more recognition as a cause of shoulder instability. Posterior HAGL lesions, being much more infrequent than anterior disruptions, have only recently been documented as a notable cause of posterior instability. We detail the treatment of a previously unreported case of a posterior HAGL variant lesion consisting of a bony avulsion with involvement of the teres minor tendon. Arthroscopic fixation was facilitated by use of a “sheathless” arthroscopic approach with a 70° arthroscope and suture anchor.
Risk factors for cardiovascular disease (CVD) not only increase the risk for clinical CVD events, but also are associated with a cascade of neurophysiologic and neuroanatomic changes that increase the risk of cognitive impairment and dementia. Although epidemiological studies have shown that exercise and diet are associated with lower CVD risk and reduced incidence of dementia, no randomized controlled trial (RCT) has examined the independent effects of exercise and diet on neurocognitive function among individuals at risk for dementia. The ENLIGHTEN trial is a RCT of patients with CVD risk factors who also are characterized by subjective cognitive complaints and objective evidence of neurocognitive impairment without dementia (CIND)
A 2 by 2 design will examine the independent and combined effects of diet and exercise on neurocognition. 160 participants diagnosed with CIND will be randomly assigned to 6 months of aerobic exercise, the DASH diet, or a combination of both exercise and diet; a (control) group will receive health education but otherwise will maintain their usual dietary and activity habits. Participants will complete comprehensive assessments of neurocognitive functioning along with biomarkers of CVD risk including measures of blood pressure, glucose, endothelial function, and arterial stiffness.
The ENLIGHTEN trial will (a) evaluate the effectiveness of aerobic exercise and the DASH diet in improving neurocognitive functioning in CIND patients with CVD risk factors; (b) examine possible mechanisms by which exercise and diet improve neurocognition; and (c) consider potential moderators of treatment, including subclinical CVD.
Neurocognition; Cognitive impairment; Dementia; Aerobic exercise; Nutrition; DASH diet; CIND; Randomized Clinical Trial
The NLRP1 inflammasome responds to microbial challenges such as Bacillus anthracis infection and is implicated in autoimmune disease such as vitiligo. Human NLRP1 contains both an N-terminal pyrin domain (PYD) and a C-terminal caspase recruitment domain (CARD), with the latter being essential for its association with the downstream effector procaspase-1. Here we report a 2.0 Å crystal structure of the human NLRP1 CARD as a fusion with the maltose-binding protein. The structure reveals the six-helix bundle fold of the NLRP1 CARD, typical of the death domain superfamily. The charge surface of the NLRP1 CARD structure and a procaspase-1 CARD model suggests potential mechanisms for their association through electrostatic attraction.
NLRP1; CARD; death domain fold; electrostatic attraction
Although the DASH (Dietary Approaches to Stop Hypertension) diet is an accepted non-pharmacologic treatment for hypertension, little is known about what patient characteristics affect dietary adherence and what level of adherence is needed to reduce blood pressure (BP).
To determine what factors predict dietary adherence and the extent to which dietary adherence is necessary to produce clinically meaningful BP reductions.
Ancillary study of the ENCORE trial-- a 16-week randomized clinical trial of diet and exercise.
Participants included 144 sedentary, overweight or obese adults (BMI’s 25-39.9 kg/m2) with high BP (systolic BP 130-159 and/or diastolic BP 85-99 mm Hg).
Patients were randomized to one of 3 groups: DASH diet alone (DASH-A), DASH diet plus weight management (DASH+WM), and Usual diet controls (UC).
Main outcome measures
Our primary outcomes were a composite index of adherence to the DASH diet and clinic BP.
Statistical analyses performed
General linear models were used to compare treatment groups on post-treatment adherence to the DASH diet. Linear regression was used to examine potential predictors of post-treatment DASH adherence. Analysis of covariance (ANCOVA) was used to examine the relation of adherence to the DASH diet and BP.
Participants in the DASH+WM (16.1 SBP [95% CI = 13.0, 19.2], 9.9 DBP [95% CI = 8.1, 11.6] mm Hg) and DASH+A (11.2 SBP [95% CI = 8.1, 14.3], 7.5 DBP [95% CI = 5.8, 9.3] mm Hg) groups showed significant reductions in BP in comparison with UC participants (3.4 SBP [95% CI = 0.4, 6.4], DBP 3.8 [95% CI = 2.2, 5.5] mm Hg). Greater post-treatment consumption of DASH foods was noted in both the DASH-A (M=6.20 [95% CI = 5.83, 6.57]) and DASH+WM groups (M=6.23 [95% CI = 5.88, 6.59]) compared to UC (M=3.66 [95% CI = 3.30, 4.01]) (p<.0001), and greater adherence to the DASH diet was associated with larger reductions in clinic SBP and DBP (p ≤.01). Only ethnicity predicted dietary adherence, with African Americans less adherent to the DASH diet compared to whites (4.68 [95% CI = 4.34, 5.03] v 5.83 [95% CI = 5.50, 6.11], p< .001).
Greater adherence to the DASH diet was associated with larger BP reductions independent of weight loss. African Americans were less likely to be adherent to the DASH dietary eating plan compared to whites, suggesting that culturally sensitive dietary strategies may be needed to improve adherence to the DASH diet.
Hypertension; DASH diet; Blood pressure; Adherence; Psychological testing; Non-pharmacological treatment
Schistosomiasis is a major tropical disease caused by trematode helminths in which the host mounts a pathogenic immune response against tissue-trapped parasite eggs. The immunopathology consists of egg antigen-specific CD4 T cell-mediated granulomatous inflammation that varies greatly in magnitude in humans and among mouse strains in an experimental model. New evidence, covered in this review, intimately ties the development of severe pathology to CD4 T helper 17 cells, a finding that adds a new dimension to the traditional CD4 Th1 vs. Th2 cell paradigm. Most examined mouse strains, in fact, develop severe immunopathology with substantial Th17 as well as Th1 and Th2 cell responses; a Th2 polarized response is an exception that is only observed in low-pathology strains such as the C57BL/6.The ability to mount pathogenic Th17 cell responses is genetically determined and depends on the ability of antigen presenting cells to produce IL-23 and IL-1â following recognition of egg antigens; analyses of several F2 progenies of (high × low)-pathology strain crosses demonstrated that quantitative trait loci governing IL-17 levels and disease severity vary substantially from cross to cross. Low pathology is dominant, which may explain the low incidence of severe disease in humans; however, coinfection with nematodes can also dampen pathogenic Th17 responses by promoting regulatory mechanisms such as those afforded by alternatively activated macrophages and T regulatory cells. A better understanding of the pathways conducive to severe forms of schistosomiasis and their regulation should lead to interventions similar to those presently used to manage other immune-mediated diseases.
Regulatory T cells (Tregs) that express the transcription factor Foxp3 are critical for regulating intestinal inflammation. Candidate microbe approaches have identified bacterial species and strain-specific molecules that can affect intestinal immune responses, including species that modulate Treg responses. Because neither all humans nor mice harbor the same bacterial strains, we posited that more prevalent factors exist that regulate the number and function of colonic Tregs. We determined that short chain fatty acids (SCFA), gut microbiota-derived bacterial fermentation products, regulate the size and function of the colonic Treg pool and protect against colitis in a Ffar2(GPR43)-dependent manner in mice. Our study reveals that a class of abundant microbial metabolites underlies adaptive immune microbiota co-adaptation and promotes colonic homeostasis and health.
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