Insertion of light-gated channels into inner retina neurons restores neural light responses, light evoked potentials, visual optomotor responses and visually-guided maze behavior in mice blinded by retinal degeneration. This method of vision restoration bypasses damaged outer retina, providing stimulation directly to retinal ganglion cells in inner retina. The approach is similar to that of electronic visual protheses, but may offer some advantages, such as avoidance of complex surgery and direct targeting of many thousands of neurons. However, the promise of this technique for restoring human vision remains uncertain because rodent animal models, in which it has been largely developed, are not ideal for evaluating visual perception. On the other hand, psychophysical vision studies in macaque can be used to evaluate different approaches to vision restoration in humans. Furthermore, it has not been possible to test vision restoration in macaques, the optimal model for human-like vision, because there has been no macaque model of outer retina degeneration. In this study, we describe development of a macaque model of photoreceptor degeneration that can in future studies be used to test restoration of perception by visual prostheses. Our results show that perceptual deficits caused by focal light damage are restricted to locations at which photoreceptors are damaged, that optical coherence tomography (OCT) can be used to track such lesions, and that adaptive optics retinal imaging, which we recently used for in vivo recording of ganglion cell function, can be used in future studies to examine these lesions.
retina; light damage; ganglion cells; macaque; adaptive optics
In screening a library of natural and synthetic products for eukaryotic translation modulators, we identified two natural products, isohymenialdisine and hymenialdisine, that exhibit stimulatory effects on translation. The characterization of these compounds lead to the insight that mRNA used to program the translation extracts during high throughput assay set-up was leading to phosphorylation of eIF2α, a potent negative regulatory event that is mediated by one of four kinases. We identified double-stranded RNA-dependent protein kinase (PKR) as the eIF2α kinase that was being activated by exogenously added mRNA template. Characterization of the mode of action of isohymenialdisine revealed that it directly acts on PKR by inhibiting autophosphorylation, perturbs the PKR-eIF2α phosphorylation axis, and can be modeled into the PKR ATP binding site. Our results identify a source of false positives for high throughput screening (HTS) campaigns using translation extracts, raising a cautionary note for this type of screen.
High Throughput Screens; Translation; PKR; eIF2α; Isohymenialdisine; Hymenialdisine
Several factors contribute to the risk of percutaneous coronary intervention (PCI) related major entry site complications (MES). We sought to examine the trends in MES among unselected patients during the stent era. Data from the Dynamic Registry including five distinct recruitment waves from 1997 to 2006 (N=10,932) were used to assess baseline characteristics and MES among consecutive patients undergoing PCI. MES was defined as bleeding requiring transfusion, pseudoaneurysm, arterial thrombosis or dissection, vascular complication requiring surgery, or retroperitoneal bleed. Uncomplicated hematomas were not included. Several trends were observed in baseline characteristics including an increase from wave 1 to wave 5 in BMI >30 kg/m2 (30.2% to 40.4%), renal disease (3.5% to 9.1%), diabetes (28.0% to 34.1%), and hypertension (59.4% to 78%) (ptrend <0.001 for all). Use of a thienopyridine increased significantly from wave 1 (49.7%) to wave 5 (84%) whereas glycoprotein (GP) IIbIIIa inhibitor use peaked in wave 3 (53.1%) and then decreased (p<0.001). Access site was predominately femoral but radial access increased over time (0.3% wave 1, 6.6% wave 5) (p=<.0001). The rates of MES (2.8% to 2.2%, ptrend =0.01) and MES requiring transfusion (2.0% to 0.74%, ptrend <0.001) were low and decreased with time. The trend in lower risk for MES in later time periods remained after adjustment. In conclusion, MES has decreased over time however opportunity for bleeding avoidance strategies still exists.
percutaneous coronary intervention; complications; bleeding; arterial access
Socioeconomic status is associated with health disparities, but underlying psychosocial mechanisms have not been fully identified. Dispositional optimism may be a psychosocial process linking socioeconomic status with health. We hypothesized that lower optimism would be associated with greater social disadvantage and poorer social mobility. We also investigated whether life satisfaction and positive affect showed similar patterns. Participants from the Midlife in the United States study self-reported their optimism, satisfaction, positive affect, and socioeconomic status (gender, race/ethnicity, education, occupational class and prestige, income). Social disparities in optimism were evident. Optimistic individuals tended to be white and highly educated, had an educated parent, belonged to higher occupational classes with more prestige, and had higher incomes. Findings were generally similar for satisfaction, but not positive affect. Greater optimism and satisfaction were also associated with educational achievement across generations. Optimism and life satisfaction are consistently linked with socioeconomic advantage and may be one conduit by which social disparities influence health.
Controlling single-particle wave functions in single semiconductor quantum dots is in demand to implement solid-state quantum information processing and spintronics. Normally, particle wave functions can be tuned transversely by an perpendicular magnetic field. We report a longitudinal wave function control in single quantum dots with a magnetic field. For a pure InAs quantum dot with a shape of pyramid or truncated pyramid, the hole wave function always occupies the base because of the less confinement at base, which induces a permanent dipole oriented from base to apex. With applying magnetic field along the base-apex direction, the hole wave function shrinks in the base plane. Because of the linear changing of the confinement for hole wave function from base to apex, the center of effective mass moves up during shrinking process. Due to the uniform confine potential for electrons, the center of effective mass of electrons does not move much, which results in a permanent dipole moment change and an inverted electron-hole alignment along the magnetic field direction. Manipulating the wave function longitudinally not only provides an alternative way to control the charge distribution with magnetic field but also a new method to tune electron-hole interaction in single quantum dots.
Following acute denervation of the ear, I experienced altered cutaneous sensory perception analogous to that reported by patients after limb amputation. This suggests that any sudden, complete loss of somaesthetic sensation can result in cortical reorganisation reflecting lost peripheral input. Although the short time course of the phenomenon suggests an initial functional reorganisation, it does not preclude longer time course structural alterations at multiple levels of the nervous system.
Reversible chemical modifications
of protein cysteine residues by S-nitrosylation and S-oxidation are increasingly recognized as important regulatory
mechanisms for many protein classes associated with cellular signaling
and stress response. Both modifications may theoretically occur under
cellular nitrosative or nitroxidative stress. Therefore, a proteomic
isotope-coded approach to parallel, quantitative analysis of cysteome S-nitrosylation and S-oxidation was developed.
Modifications of cysteine residues of (i) human glutathione-S-transferase
P1-1 (GSTP1) and (ii) the schistosomiasis drug target thioredoxin
glutathione reductase (TGR) were studied. Both S-nitrosylation (SNO) and S-oxidation to disulfide
(SS) were observed for reactive cysteines, dependent on concentration
of added S-nitrosocysteine (CysNO) and independent
of oxygen. SNO and SS modifications of GSTP1 were quantified and compared
for therapeutically relevant NO and HNO donors from different chemical
classes, revealing oxidative modification for all donors. Observations
on GSTP1 were extended to cell cultures, analyzed after lysis and
in-gel digestion. Treatment of living neuronal cells with CysNO, to
induce nitrosative stress, caused levels of S-nitrosylation
and S-oxidation of GSTP1 comparable to those of cell-free
studies. Cysteine modifications of PARK7/DJ-1, peroxiredoxin-2, and
other proteins were identified, quantified, and compared to overall
levels of protein S-nitrosylation. The new methodology
has allowed identification and quantitation of specific cysteome modifications,
demonstrating that nitroxidation to protein disulfides occurs concurrently
with S-nitrosylation to protein-SNO in recombinant
proteins and living cells under nitrosative stress.
Innate immune and inflammatory responses mediated by Toll like receptors (TLRs) have been implicated in myocardial ischemia/reperfusion (I/R) injury. This study examined the role of TLR3 in myocardial injury induced by two models, namely, myocardial infarction (MI) and I/R.
First, we examined the role of TLR3 in MI. TLR3 deficient (TLR3−/−) and wild type (WT) mice were subjected to MI induced by permanent ligation of the left anterior descending coronary artery (LAD) for 21 days. Cardiac function was measured by echocardiography. Next, we examined whether TLR3 contributes to myocardial I/R injury. TLR3−/− and WT mice were subjected to myocardial ischemia (45 min) followed by reperfusion for up to 3 days. Cardiac function and myocardial infarct size were examined. We also examined the effect of TLR3 deficiency on I/R-induced myocardial apoptosis and inflammatory cytokine production.
TLR3−/− mice showed significant attenuation of cardiac dysfunction after MI or I/R. Myocardial infarct size and myocardial apoptosis induced by I/R injury were significantly attenuated in TLR3−/− mice. TLR3 deficiency increases Bcl2 levels and attenuates I/R-increased Fas, FasL, FADD, Bax and Bak levels in the myocardium. TLR3 deficiency also attenuates I/R-induced myocardial NF-κB binding activity, TNF-α and IL-1β production as well as I/R-induced infiltration of neutrophils and macrophages into the myocardium.
TLR3 plays an important role in myocardial injury induced by MI or I/R. The mechanisms involve activation of apoptotic signaling and NF-κB binding activity. Modulation of TLR3 may be an effective approach for ameliorating heart injury in heart attack patients.
TLRs; myocardial I/R; apoptosis; NF-κB; inflammatory cytokines
We investigated the association between anticipatory stress, also known as racism-related vigilance, and hypertension prevalence in Black, Hispanic, and White adults.
We used data from the Chicago Community Adult Health Study, a population-representative sample of adults (n=3105) surveyed in 2001 to 2003, to regress hypertension prevalence on the interaction between race/ethnicity and vigilance in logit models.
Blacks reported the highest vigilance levels. For Blacks, each unit increase in vigilance (range=0–12) was associated with a 4% increase in the odds of hypertension (odds ratio [OR]=1.04; 95% confidence interval [CI]=1.00, 1.09). Hispanics showed a similar but nonsignificant association (OR=1.05; 95% CI=0.99, 1.12), and Whites showed no association (OR=0.95; 95% CI=0.87, 1.03).
Vigilance may represent an important and unique source of chronic stress that contributes to the well-documented higher prevalence of hypertension among Blacks than Whites; it is a possible contributor to hypertension among Hispanics but not Whites.
Researchers have long speculated that exposure to discrimination may increase cardiovascular disease (CVD) risk but compared to other psychosocial risk factors, large-scale epidemiologic and community based studies examining associations between reports of discrimination and CVD risk have only emerged fairly recently. This review summarizes findings from studies of self-reported experiences of discrimination and CVD risk published between 2011–2013. We document the innovative advances in recent work, the notable heterogeneity in these studies, and the considerable need for additional work with objective clinical endpoints other than blood pressure. Implications for the study of racial disparities in CVD and clinical practice are also discussed.
Racial; Ethnic; Discrimination; Cardiovascular disease
Aerobic exercise has been proposed as a stand-alone or adjunct smoking cessation treatment, but findings have been mixed. Laboratory studies have shown that individual exercise sessions lead to decreases in withdrawal symptoms and cigarette cravings, but findings are limited by lack of follow-up and artificial settings. On the other hand, smoking cessation treatment RCTs have generally failed to show positive effects of exercise on smoking cessation, but have been plagued by poor and/or unverified compliance with exercise programs. This paper describes the rationale and design for Quit for Health (QFH)—an RCT designed to determine the efficacy of aerobic exercise as an adjunct smoking cessation treatment among women. To overcome limitations of previous research, compliance with the exercise (and wellness contact control) program is incentivized and directly observed, and ecological momentary assessment is used to examine change over time in withdrawal symptoms and cigarette cravings in participants’ natural environments.
Study design; aerobic exercise; smoking cessation; nicotine withdrawal symptoms; cigarette cravings; weight concerns
Two-photon excitation microscopy (TPM) can image retinal molecular processes in vivo. Intrinsically fluorescent retinyl esters in sub-cellular structures called retinosomes are an integral part of the visual chromophore regeneration pathway. Fluorescent condensation products of all–trans–retinal accumulate in the eye with age and are also associated with age-related macular degeneration (AMD). Here we report repetitive, dynamic imaging of these compounds in live mice, through the pupil of the eye. Leveraging advanced adaptive optics we developed a data acquisition algorithm that permitted the identification of retinosomes and condensation products in the retinal pigment epithelium (RPE) by their characteristic localization, spectral properties, and absence in genetically modified or drug-treated mice. This imaging approach has the potential to detect early molecular changes in retinoid metabolism that trigger light and AMD-induced retinal defects and to assess the effectiveness of treatments for these conditions.
Noninvasive two-photon imaging of a living mammalian eye can reveal details of molecular processes in the retina and RPE. Retinyl esters and all-trans-retinal condensation products are two types of retinoid fluorophores present in these tissues. We measured the content of these two types of retinoids in monkey and human eyes to validate the potential of two-photon imaging for monitoring retinoid changes in human eyes.
Two-photon microscopy (TPM) was used to visualize excised retina from monkey eyes. Retinoid composition and content in human and monkey eyes were quantified by HPLC and mass spectrometry (MS).
Clear images of inner and outer segments of rods and cones were obtained in primate eyes at different eccentricities. Fluorescence spectra from outer segments revealed a maximum emission at 480 nm indicative of retinols and their esters. In cynomolgus monkey and human retinal extracts, retinyl esters existed predominantly in the 11-cis configuration along with notable levels of 11-cis-retinol, a characteristic of cone-enriched retinas. Average amounts of di-retinoid-pyridinium-ethanolamine (A2E) in primate and human eyes were 160 and 225 pmol/eye, respectively.
These data show that human retina contains sufficient amounts of retinoids for two-photon excitation imaging. Greater amounts of 11-cis-retinyl esters relative to rodent retinas contribute to the fluorescence signal from both monkey and human eyes. These observations indicate that TPM imaging found effective in mice could detect early age- and disease-related changes in human retina.
Two-photon excitation tracks early changes in primate retina.
rod photoreceptors; cone photoreceptors; retinoid cycle; two-photon microscopy; primate retina
Scavenger receptor A (SR-A), also known as the macrophage scavenger receptor and cluster of differentiation 204 (CD204), plays roles in lipid metabolism, atherogenesis, and a number of metabolic processes. However, recent evidence points to important roles for SR-A in inflammation, innate immunity, host defense, sepsis, and ischemic injury. Herein, we review the role of SR-A in inflammation, innate immunity, host defense, sepsis, cardiac and cerebral ischemic injury, Alzheimer’s disease, virus recognition and uptake, bone metabolism, and pulmonary injury. Interestingly, SR-A is reported to be host protective in some disease states, but there is also compelling evidence that SR-A plays a role in the pathophysiology of other diseases. These observations of both harmful and beneficial effects of SR-A are discussed here in the framework of inflammation, innate immunity, and endoplasmic reticulum stress.
Scavenger receptor-A; CD204; inflammation; sepsis; infection; innate immunity; atherosclerosis; brain and heart ischemia; reperfusion injury
Asian Americans experience significant underuse of mental health treatment. Religious clergy and spiritual advisors play a critical role in delivering mental health care in the United States. Limited knowledge exists about their use among Asian Americans.
We describe mental health service use from a religious/spiritual advisor among Asian Americans.
We analyzed data from 2095 respondents in the 2002–2003 National Latino and Asian American Study.
Lifetime and 12-month prevalence of mental health service use from a religious/spiritual advisor (5.5% and 1% overall, respectively) was generally higher among U.S.-born Asians and those with a 12-month mental disorder (23.6% and 7.5%, respectively). Religious/spiritual advisors were seen by 35% of treatment-seeking Asian Americans with a lifetime mental disorder. They were seen as commonly as psychiatrists but less commonly than a mental health specialist or general medical provider. Approximately 70% of those seeking treatment had a mental disorder, significant proportions of whom sought treatment in the absence of a psychiatrist, a mental health specialist or even a healthcare provider. A significant majority with 12-month use perceived the care as helpful, felt accepted/understood and satisfied (71–86%). However, only 31% rated the care as excellent, 28% quit completing care, and referral rates for specialty mental health treatment were low, even among those with a mental disorder (9.5%).
Religious/spiritual advisors are a key source of treatment-seeking for Asian Americans with a mental disorder. Quality of care and low referral rates for specialty mental health treatment warrant further attention and need for increased collaboration with the mental health system.
Asian Americans; Religious and spiritual advisor; Mental health service use; Mental disorder; Ethnicity; Nativity
Increased global connectivity has catalyzed technological development in almost all industries, in part through the facilitation of novel collaborative structures. Notably, open innovation and crowd-sourcing—of expertise and/or funding—has tremendous potential to increase the efficiency with which biomedical ecosystems interact to deliver safe, efficacious and affordable therapies to patients. Consequently, such practices offer tremendous potential in advancing development of cellular therapies.
In this vein, the CASMI Translational Stem Cell Consortium (CTSCC) was formed to unite global thought-leaders, producing academically rigorous and commercially practicable solutions to a range of challenges in pluripotent stem cell translation. Critically, the CTSCC research agenda is defined through continuous consultation with its international funding and research partners.
Herein, initial findings for all research focus areas are presented to inform global product development strategies, and to stimulate continued industry interaction around biomanufacturing, strategic partnerships, standards, regulation and intellectual property and clinical adoption.
Asbestos exposure results in pulmonary fibrosis (asbestosis) and malignancies (bronchogenic lung cancer and mesothelioma) by mechanisms that are not fully understood. Alveolar epithelial cell (AEC) apoptosis is important in the development of pulmonary fibrosis after exposure to an array of toxins, including asbestos. An endoplasmic reticulum (ER) stress response and mitochondria-regulated (intrinsic) apoptosis occur in AECs of patients with idiopathic pulmonary fibrosis, a disease with similarities to asbestosis. Asbestos induces AEC intrinsic apoptosis, but the role of the ER is unclear. The objective of this study was to determine whether asbestos causes an AEC ER stress response that promotes apoptosis. Using human A549 and rat primary isolated alveolar type II cells, amosite asbestos fibers increased AEC mRNA and protein expression of ER stress proteins involved in the unfolded protein response, such as inositol-requiring kinase (IRE) 1 and X-box–binding protein-1, as well as ER Ca²2+ release ,as assessed by a FURA-2 assay. Eukarion-134, a superoxide dismutase/catalase mimetic, as well as overexpression of Bcl-XL in A549 cells each attenuate asbestos-induced AEC ER stress (IRE-1 and X-box–binding protein-1 protein expression; ER Ca²2+ release) and apoptosis. Thapsigargin, a known ER stress inducer, augments AEC apoptosis, and eukarion-134 or Bcl-XL overexpression are protective. Finally, 4-phenylbutyric acid, a chemical chaperone that attenuates ER stress, blocks asbestos- and thapsigargin-induced AEC IRE-1 protein expression, but does not reduce ER Ca²2+ release or apoptosis. These results show that asbestos triggers an AEC ER stress response and subsequent intrinsic apoptosis that is mediated in part by ER Ca²2+ release.
alveolar epithelium; asbestos; mitochondria; endoplasmic reticulum; apoptosis
Assessment of cortisol concentrations in hair is one of the latest innovations for measuring long-term cortisol exposure. We performed a systematic review of correlates of cortisol in human hair to inform the design, analysis and interpretation of future epidemiologic studies. Relevant publications were identified through electronic searches on PubMed, WorldCat, and Web of Science using keywords, “cortisol” “hair” “confounders” “chronic” “stress” and “correlates.” Thirty-nine studies were included in this review. Notwithstanding scarce data and some inconsistencies, investigators have found hair cortisol concentrations to be associated with stress-related psychiatric symptoms and disorders (e.g., PTSD), medical conditions indicating chronic activation of the hypothalamic-pituitary-adrenal axis (e.g., Cushing´s syndrome) and other life situations associated with elevated risk of chronic stress (e.g., shiftwork). Results from some studies suggest that physical activity, adiposity, and substance abuse may be correlates of hair cortisol concentrations. In contrast to measures of short-term cortisol release (saliva, blood, and urine), cigarette smoking and use of oral contraceptives appear to not be associated with hair cortisol concentrations. Studies of pregnant women indicate increased hair cortisol concentrations across successive trimesters. The study of hair cortisol presents a unique opportunity to assess chronic alterations in cortisol concentrations in epidemiologic studies.
hair; cortisol; chronic stress; correlates; assessment; analysis; determinants; psychiatric disorders
Many retinal imaging instruments use infrared wavelengths to reduce the risk of light damage. However, we have discovered that exposure to infrared illumination causes a long-lasting reduction in infrared autofluorescence (IRAF). We have characterized the dependence of this effect on radiant exposure and investigated its origin.
A scanning laser ophthalmoscope was used to obtain IRAF images from two macaques before and after exposure to 790-nm light (15-450 J/cm2). Exposures were performed with either raster-scanning or uniform illumination. Infrared autofluorescence images also were obtained in two humans exposed to 790-nm light in a separate study. Humans were assessed with direct ophthalmoscopy, Goldmann visual fields, multifocal ERG, and photopic microperimetry to determine whether these measures revealed any effects in the exposed locations.
A significant decrease in IRAF after exposure to infrared light was seen in both monkeys and humans. In monkeys, the magnitude of this reduction increased with retinal radiant exposure. Partial recovery was seen at 1 month, with full recovery within 21 months. Consistent with a photochemical origin, IRAF decreases caused by either raster-scanning or uniform illumination were not significantly different. We were unable to detect any effect of the light exposure with any measure other than IRAF imaging. We cannot exclude the possibility that changes could be detected with more sensitive tests or longer follow-up.
This long-lasting effect of infrared illumination in both humans and monkeys occurs at exposure levels four to five times below current safety limits. The photochemical basis for this phenomenon remains unknown.
Exposure to infrared illumination at irradiances well below current safety limits can cause a long-lasting decrease in infrared autofluorescence from the retina. It is unclear whether this effect is benign or indicative of a subcellular change that could be cumulatively harmful.
retina; light damage; radiation damage; scanning laser ophthalmoscopy; retinal pigment epithelium
Variance in pain following total knee and hip arthroplasty may be due to a number of procedural and peripheral factors but also, in some individuals, to aberrant central pain processing as is described in conditions like fibromyalgia. To test this hypothesis, we conducted a prospective, observational cohort study of patients undergoing lower extremity joint arthroplasty.
519 patients were preoperatively phenotyped using validated self-reported pain questionnaires, psychological measures, and health information. In addition to assessing factors previously found to be associated with poor outcomes in arthroplasty, participants also completed the American College of Rheumatology survey criteria for fibromyalgia. Previous studies have suggested that rather than being “present” or “absent,” features of fibromyalgia as measured by this instrument, occur over a wide continuum. Postoperative pain control was assessed by total postoperative opioid consumption.
Preoperatively, patients with higher fibromyalgia survey scores were younger, more likely to be female, taking more opioids, reported higher pain severity, and had a more negative psychological profile. In the multivariate analysis, the fibromyalgia survey score, younger age, preoperative opioid use, knee (vs. hip), pain severity at baseline, and the anesthetic technique were all predictive of increased postoperative opioid consumption.
Using the survey criteria for fibromyalgia distinct phenotypic differences were found, and the measure was independently predictive of opioid consumption. This self-report measure may provide an additional simple means of predicting postoperative pain outcomes and analgesic requirements. Future studies are needed to determine whether tailored therapies can improve postoperative pain control in this population.
It is said that carbon, the most abundant element in organic matter, supplies life’s quantity, whereas nitrogen supplies its quality. It is therefore unsurprising that many natural products that contain basic nitrogens (alkaloids) are coveted for their benefit to human health. However, nitrogen is known to mire many chemical syntheses because of its basicity and susceptibility to oxidation. This challenge may be heightened by the presence of more than one nitrogen atom in a targeted complex alkaloid, but can be met by the selective introduction and removal of functional groups that mitigate basicity, as highlighted herein with the first chemical syntheses of citrinalin B and cyclopiamine B. The chemical connections that have been realized as a result of these syntheses, in addition to the isolation of both 17-hydroxycitrinalin B and citrinalin C through 13C feeding studies, supports the existence of a common bicyclo[2.2.2]diazaoctane containing biogenetic precursor to these compounds as has been proposed previously.
The fovea dominates primate vision, and its anatomy and perceptual abilities are well studied, but its physiology has been little explored because of limitations of current physiological methods. In this study, we adapted a novel in vivo imaging method, originally developed in mouse retina, to explore foveal physiology in the macaque, which permits the repeated imaging of the functional response of many retinal ganglion cells (RGCs) simultaneously. A genetically encoded calcium indicator, G-CaMP5, was inserted into foveal RGCs, followed by calcium imaging of the displacement of foveal RGCs from their receptive fields, and their intensity-response functions. The spatial offset of foveal RGCs from their cone inputs makes this method especially appropriate for fovea by permitting imaging of RGC responses without excessive light adaptation of cones. This new method will permit the tracking of visual development, progression of retinal disease, or therapeutic interventions, such as insertion of visual prostheses.
calcium imaging; in vivo adaptive optics imaging; intrinsic signal imaging; primate fovea; retinal ganglion cells
This paper reviews research relevant to a proposed conceptual model of exercise adherence that integrates the dual mode model and hedonic theory. Exercise intensity is posited to influence affective response to exercise via interoceptive (e.g., ventilatory drive) and cognitive (e.g., perceived autonomy) pathways; affective response to exercise is posited to influence exercise adherence via anticipated affective response to future exercise. The potential for self-paced exercise to enhance exercise adherence is examined in the context of the proposed model and suggestions are given for future research. Further evidence in support of self-paced exercise could have implications for exercise prescription, especially among overweight, sedentary adults, who are most in need of interventions that enhance adherence to exercise programs.