Exploring human biology with N-of-1 clinical trials.

Studies on humans that exploit contemporary data-intensive, high-throughput 'omic' assay technologies, such as genomics, transcriptomics, proteomics and metabolomics, have unequivocally revealed that humans differ greatly at the molecular level. These differences, which are compounded by each individual's distinct behavioral and environmental exposures, impact individual responses to health interventions such as diet and drugs. Questions about the best way to tailor health interventions to individuals based on their nuanced genomic, physiologic, behavioral, etc. profiles have motivated the current emphasis on 'precision' medicine. This review's purpose is to describe how the design and execution of N-of-1 (or personalized) multivariate clinical trials can advance the field. Such trials focus on individual responses to health interventions from a whole-person perspective, leverage emerging health monitoring technologies, and can be used to address the most relevant questions in the precision medicine era. This includes how to validate biomarkers that may indicate appropriate activity of an intervention as well as how to identify likely beneficial interventions for an individual. We also argue that multivariate N-of-1 and aggregated N-of-1 trials are ideal vehicles for advancing biomedical and translational science in the precision medicine era since the insights gained from them can not only shed light on how to treat or prevent diseases generally, but also provide insight into how to provide real-time care to the very individuals who are seeking attention for their health concerns in the first place.

Acute exercise increases hippocampal TNF-α, Caspase-3 and Caspase-7 expression in healthy young and older mice.

AIM: Regular exercise may protect against cognitive decline by preventing central inflammation. The effect of an acute exercise bout on central cytokine and apoptotic protein expression is not known. The brain may be protected from transient oxidative stress such as that induced by acute-exercise. The purpose of this exploratory study was to determine the effect of a single bout of intense exercise on hippocampal expression of inflammatory mediators (TNF-α) and apoptotic proteins (caspase-3, caspase-7), and to evaluate any potential age-related differences. METHODS: Using a C57BL/6 mouse model (N.=98), we evaluated the effect of an acute exercise bout (90 minutes of treadmill running: 10 min warm-up, 30 min at 22 m.min⁻¹, 30 min at 25 m.min⁻¹, and 30 min at 28 m.min⁻¹, 2° slope) on hippocampal inflammation in young (3-4 months), middle-aged (13-14 months) and older (16-17 months) C57BL/6 mice. RESULTS: Our results show post-exercise increases in hippocampal TNF-α and caspase-3/7 in each age group (main effect of acute exercise, P<0.05). Older mice displayed higher TNF-α (main effect of age, P<0.05) expression compared with younger animals at baseline. Young mice demonstrated greater increases in caspase-7 following acute exercise, compared to older mice (interaction effect for caspase-7, P<0.05). CONCLUSION: Given the relationship between aging, inflammation and neurodegenerative disease, and the protective effects of exercise, we cautiously propose that acute-exercise induced inflammation may be a normal physiologic response that elicits a favorable (anti-inflammatory) hippocampal environment.

Low-frequency versus high-frequency stimulation of the pedunculopontine nucleus area in Parkinson's disease: a randomised controlled trial.

OBJECTIVE: To compare the influence of low-frequency (10-25 Hz) versus higher (60-80 Hz) frequency stimulation of the pedunculopontine nucleus area (PPNa) on akinaesia, freezing of gait and daytime sleepiness. METHOD: We included nine patients with Parkinson's disease (PD) and severe gait disorders. In this double-blind randomised cross-over study, patients were assessed after 24 h of PPNa stimulation. Assessments included the motor part of the Unified Parkinson's Disease Rating Scale, the Epworth Sleepiness Scale and a behavioural gait assessment. RESULTS: Compared with 60-80 Hz, 10-25 Hz PPNa stimulation led to decreased akinaesia, gait difficulties and daytime sleepiness in 7/9 patients. In one patient, these symptoms were aggravated under 10-25 Hz stimulation compared with 60-80 Hz. CONCLUSION: These results are in keeping with the benefits of chronic PPNa stimulation for gait and postural difficulties in patients with PD, and with regard to the influence of patients' clinical characteristics, differential neuronal loss in the PPNa and electrode location. We conclude that in patients with PPNa stimulation, low frequency provides a better outcome than high-frequency stimulation.

Inhibitory control and error monitoring by human subthalamic neurons.

The subthalamic nucleus (STN) has been shown to be implicated in the control of voluntary action, especially during tasks involving conflicting choice alternatives or rapid response suppression. However, the precise role of the STN during nonmotor functions remains controversial. First, we tested whether functionally distinct neuronal populations support different executive control functions (such as inhibitory control or error monitoring) even within a single subterritory of the STN. We used microelectrode recordings during deep brain stimulation surgery to study extracellular activity of the putative associative-limbic part of the STN while patients with severe obsessive-compulsive disorder performed a stop-signal task. Second, 2-4 days after the surgery, local field potential recordings of STN were used to test the hypothesis that STN oscillations may also reflect executive control signals. Extracellular recordings revealed three functionally distinct neuronal populations: the first one fired selectively before and during motor responses, the second one selectively increased their firing rate during successful inhibitory control, and the last one fired selectively during error monitoring. Furthermore, we found that beta band activity (15-35 Hz) rapidly increased during correct and incorrect behavioral stopping. Taken together, our results provide critical electrophysiological support for the hypothesized role of the STN in the integration of motor and cognitive-executive control functions.

Hip abscess due to Aerococcus urinae in a man with paraplegia: case report.

STUDY DESIGN: Single case report. OBJECTIVE: Present a case of hip abscess culture positive for Aerococcus urinae in a man with paraplegia. BACKGROUND: Aerococcus species are uncommonly reported and may be misinterpreted as alpha streptococci or staphylococci. This organism can cause significant morbidity due to urinary tract infection with septicemia or endocarditis. METHODS: Single case report. RESULTS: The patient required surgical incision and debridement. Open joint inspection was performed, which was complicated by superior dislocation. The patient later required a Girdlestone procedure. CONCLUSIONS: A. urinae was cultured from a hip abscess in a man with paraplegia. Bacteremia, with the bladder as the reservoir, likely led to this abscess. Aerococcus is pathogenic and should be considered when culture results reveal unusual staph or strep species.

International Spinal Cord Injury Urinary Tract Infection Basic Data Set.

OBJECTIVES: To develop an International Spinal Cord Injury (SCI) Urinary Tract Infection (UTI) Basic Data Set presenting a standardized format for the collection and reporting of a minimal amount of information on UTIs in daily practice or research. SETTING: International working group. METHODS: The draft of the Data Set developed by a working group was reviewed by the Executive Committee of the International SCI Standards and Data Sets, and later by the International Spinal Cord Society (ISCoS) Scientific Committee and the American Spinal Injury Association (ASIA) Board. Relevant and interested scientific and professional (international) organizations and societies (∼40) were also invited to review the data set, and it was posted on the ISCoS and ASIA websites for 3 months to allow comments and suggestions. The ISCoS Scientific Committee, Executive Committee and ASIA Board received the data set for final review and approval. RESULTS: The International SCI UTI Basic Data Set includes the following variables: date of data collection, length of time of sign(s)/symptom(s), results of urine dipstick test for nitrite and leukocyte esterase, urine culture results and resistance pattern. The complete instructions for data collection and the data form itself are freely available on the website of ISCoS (http://www.iscos.org.uk).

Ureteroscopy with laser lithotripsy for urolithiasis in the spinal cord injury population.

STUDY DESIGN: Retrospective study. OBJECTIVES: The purpose of this investigation was to review the outcomes and safety of retrograde ureteroscopic laser lithotripsy (URS) for the treatment of urolithiasis in the spinal cord injury (SCI) population. SETTING: Virginia, USA. METHODS: All patients with SCI who underwent URS with holmium:YAG laser lithotripsy for urolithiasis over a 15-year period were identified. Stone size, location and number at presentation were recorded. Information regarding patient characteristics, intra-operative complications, surgical efficacy, stone clearance, peri-operative complications, and follow-up stone events was collected and analyzed. RESULTS: A total of 67 URS procedures were performed on 29 SCI patients during the study period with an average follow-up of 3.4 years. Patients had an average of 2.3 ipsilateral ureteroscopies. The majority (85.1%) used indwelling catheters for long-term bladder management, and complete stone clearance after the first procedure was 34.3%. Of the 44 cases with residual stones >4 mm, 20 (45.5%) were secondary to technical or procedural limitations. The intra-operative complication rate was comparable to non-SCI studies at 1.5%, but peri-operative complications were significantly higher at 29.9% with the majority due to urosepsis. Factors associated with peri-operative complications include chronic obstructive pulmonary disease, motor incomplete injuries and lack of a pre-operative ureteral stent. CONCLUSION: URS in the SCI population is an effective treatment for ureteral or renal stones but may be associated with greater risks and reduced efficacy.

Apoptotic and inflammatory cytokine protein expression in intestinal lymphocytes after acute treadmill exercise in young and old mice.

AIM: Gastrointestinal disturbances are common in athletes following intense exercise. Variations in apoptotic protein expression and cell death may contribute to acute exercise-induced intestinal inflammation. The effect of age on apoptotic protein response in the intestinal compartment in response to exercise is not known. Using a mouse model, we examined the effects of a single bout of treadmill running in young and old mice on intestinal lymphocyte (IL) expression of the apoptosis-inducing cytokine TNF-α, the pro-apoptotic proteins caspase-3 and 7, the anti-apoptotic protein Bcl-2, and IL apoptotic status (% AnnexinV+). METHODS: Young (3-4 months, N.=44) and old (13-14 months, N.=45) female C57Bl/6 mice were randomized to treadmill exercise (10 min warm-up, 20 min at 22 m min-1, 30 min at 25 m min-1, 30 min at 28 m min-1, 2º slope) with sacrifice immediately (IMM) or 2hr after (2Hr), or to a non-exercised control (SED). IL were removed and prepared for analysis of % apoptosis (flow cytometry) and determination of apoptotic protein and cytokine expression (Western blotting). Plasma corticosterone and 8-iso-PGF2α were measured by EIA. RESULTS: Exercise was associated with a higher IL expression of caspase-3 in IMM and 2Hr groups vs. SED (P<0.001), a higher expression of TNF-α in the IMM group vs. SED (P<0.001), and a lower Bcl-2 expression in the IMM and 2Hr groups vs. SED (P<0.01). There was a trend (P=0.07) for increased caspase-7 expression after exercise. IL caspase-3 and 7 and TNF-α expression did not differ by age whereas Bcl-2 expression was lower (P<0.001) and % Annexin V+ IL was higher (P<0.05) in old vs. young mice. Plasma corticosterone and 8-iso-PGF2α were higher (P<0.001 and P<0.05) in IMM vs. SED mice but did not differ by age. CONCLUSION: The expression of the pro-apoptotic proteins, caspase-3 and caspase-7, and the apoptosis-inducing cytokine, TNF-α, in IL did not differ by age in this animal model in response to a single intense exercise challenge. However, Old mice had lower expression of the 'protective' anti-apoptotic protein Bcl-2 and a higher percentage of early apoptotic IL. Whether repeated exercise results in less IL resiliency in elderly individuals remains to be determined.

Can you see what they are saying? Breast cancer images and text in Canadian women's and fashion magazines.

Media are an important source of breast cancer information for women. Visual images influence recall and comprehension of information. Research on breast cancer in the media has infrequently focused on images. Using directed content analysis, we compared content, tone, and themes in images (n = 91) and articles (n = 31) in Canadian women's and fashion (n = 6) magazines (2005-2010). About half of the articles (51.6%) had both positive and negative tone; in contrast, 87.7% of women in the images had positive facial expressions. Women in the images were Caucasian (80.9%), young (81.3%), attractive (99.2%), had a healthy body type (93.8%), and appeared to have intact breasts (100%). Images of screening/treatment (5.5%) and visual impact of disease/treatment on the body (4.4%) were rare. The most common theme in the articles was medical issues (35.5%); in the images, it was beauty or fashion (15.4%). The potential impact of these divergent messages for breast cancer education is discussed.

Application of the health literacy framework to diet-related cancer prevention conversations of older immigrant women to Canada.

Health literacy, conceptualized as a framework involving basic (functional), interactive and critical skill sets, is a key determinant of health. Application of the health literacy framework (HLF) to immigrant populations has been limited. Our objective was to apply the HLF to discourses about diet-related colon cancer prevention among English-as-a-Second-Language (ESL) immigrant women. We also explored whether these discussions could inform the development of culturally appropriate information and potentially increase health literacy. Interviews were conducted with 64 older Spanish-speaking ESL immigrant women. Directed content analysis guided by the HLF was used to identify themes. Diet-related conversations were initiated by 43 (67%) participants. Four themes were identified: general information requests-low functional health literacy (FHL) (n = 23/43), specific nutrition inquiries-high FHL (n = 17/43), actions for healthy eating-low interactive health literacy (IHL) (n = 8/43) and community communication issues-high IHL (n = 3/43). No conversations representing critical health literacy were identified. Five women discussed both FHL and IHL themes. Women's diet-related conversations followed a continuum of increasing information needs supporting the HLF.

A non-human primate model of bipedal locomotion under restrained condition allowing gait studies and single unit brain recordings.

For decades, several animal models of locomotion have allowed a better understanding of the basic physiological mechanisms of gait. However, unlike most of the mammals, the Order Primates is characterized by fundamental changes in locomotor behaviour. In particular, some primates use a specific pattern of locomotion and are able to naturally walk bipedally due possibly to a specific supra-spinal control of locomotion. These features must be taken into account when one considers to study the intrinsic properties of human gait. Thus, an experimental model of bipedal locomotion allowing precise and reproducible analysis of gait in non-human primate is still lacking. This study describes a non-human primate model of bipedal locomotion under restrained condition. We undertook a kinematic and biomechanic study in three Macaca fascicularis trained to walk bipedally on a treadmill. One of the primate was evaluated in complete head fixation. Gait visual analysis and electromyographic recordings provided pertinent description of the gait pattern. Step frequencies, step lengths, cycle and stance phase durations were correlated with Froude number (dimensionless velocity), whereas swing phase durations remained non-correlated. Gait patterns observed in our model were similar to those obtained in freely bipedal Macaca fuscata and to a lesser extend to Humans. Gait pattern was not modified by head fixation thereby allowing us to perform precise and repetitive micro electrode recordings of deep cerebral structures. Thus, the present model could provide a pertinent pre-clinical tool to study gait parameters and their neuronal control but also could be helpful to validate new therapeutics interventions.

Freewheel training alters mouse hippocampal cytokines.

The effects of 16 weeks of voluntary wheel running in healthy female mice on hippocampal expression of pro-(TNF-α, IL-1ß, IL-12) and anti-(IL-10, IL-1ra) inflammatory and pleiotropic (IL-6) cytokines and apoptotic status of specific cell subsets (CD45+, CD11b+) were studied. Mice were assigned to wheel running (WR; n=20) or a control condition (No WR; n=22) and sacrificed after the 16 weeks. Data collected included measures of training status (running volume, body weight, run-to-exhaustion time, and skeletal muscle cytochrome c oxidase activity), flow cytometric analysis of cell phenotypes and apoptosis (CD45+, CD11b+, Annexin+, Annexin+/PI+, PI+), and cytokine concentrations in cell lysates. WR mice had measurable training effects and significantly lower TNF-α (p<0.05) and higher IL-6 (p<0.05), IL-1ra (p<0.05) and IL-12 (p<0.05) expression in the hippocampus compared to controls. IL-1ß, IL-10, and the percent of apoptotic and dead cells did not change due to training. Taken together, and in relation to the complex interactions between cytokines, the results suggest a possible mechanism whereby exercise training may buffer from dementia and cognitive decline through changes in the central cytokine milieu in the hippocampus.

Cancer information comprehension by English-as-a-second-language immigrant women.

Limited acculturation and socioeconomic factors have been associated with lower participation in cancer screening. Limited comprehension of cancer prevention information may contribute to this association. The authors used a stepwise linear regression to model acculturation and socioeconomic factors as predictors of comprehension (colon cancer and general health information) and screening intention in a sample of 78 Spanish-speaking immigrant women in Canada. The authors used the McNemar test to look for changes in women's screening intention. They used the Bidimensional Acculturation Scale, a language-based scale, to assess acculturation. Among English-as-a-second-language immigrant women, acculturation, television and Internet use, age, and Spanish-language education predicted comprehension of cancer prevention information, F(3, 69) = 6.76, p < .001, R(2) = .23. These variables also predicted comprehension of general health information, via the short form of the Test of Functional Health Literacy in Adults, F(4, 68) = 12.13, p < .001, R(2) = .42; and the Rapid Estimate of Adult Literacy in Medicine, F(2, 70) = 7.54, p = .001, R(2) = .17. However, the variables did not predict screening intention. More women expressed intention to be screened after reading the cancer prevention information than expected by chance alone, p = .002. Acculturation is an important influence on the comprehension of health information by older English-as-a-second-language immigrant women. However, other culture-related factors not measured by the Bidimensional Acculturation Scale likely influence their exposure to and understanding of health and cancer prevention information.

Does exercise protect from cognitive decline by altering brain cytokine and apoptotic protein levels? A systematic review of the literature.

Regular exercise is thought to provide protection against age-related cognitive decline and possibly reduce risk of dementias. The mechanisms for the exercise protective effects are not known although changes in inflammatory cytokine levels may be involved. We conducted a systematic review of the literature to assess (1) the effects of exercise on cytokines in the brain, (2) the methodological rigour of studies which have examined these exercise effects and (3) the potential role of regular exercise in reducing the pro-inflammatory cytokine milieu that may contribute to dementia. We also reviewed the effects of exercise on concurrent pro and anti-apoptotic protein expression in the brain as related to cytokine changes. Five databases were searched until January 2010 with an initial 630 articles identified; 61 articles were retrieved of which 10 met study inclusion criteria. Investigations of both acute and chronic (training) exercise were assessed for methodological quality using a modified PEDro scale. Two studies were carried out with human participants and eight with mouse or rat models; studies differed markedly in design and methodological rigour; the types, intensities and durations of exercise, the cytokine and apoptotic proteins measured, and the regions of the brain (or proxy compartments) sampled. Despite variations in design, specific cytokine outcomes, and exercise type, the 10 studies provide limited evidence that acute strenuous exercise increases and exercise training decreases pro-inflammatory cytokines centrally. Two animal studies relate training associated decreases in pro-inflammatory cytokines with improved cognitive function using behavioural assessments such as the Morris maze. Recommendations for the design of future research on exercise, central cytokines, and cognition are offered.

Freewheel training decreases pro- and increases anti-inflammatory cytokine expression in mouse intestinal lymphocytes.

Intestinal inflammation and inflammatory bowel diseases (IBD) may occur due to imbalances in pro- and anti-inflammatory cytokines. Long-term exercise reduces the risk for IBD. The purpose of this study was to determine the effect of long-term wheel running in healthy mice on intestinal lymphocyte (IL) expression of pro- and anti-inflammatory cytokine proteins. In addition, pro- and anti-apoptotic proteins and the percentage of early apoptotic, late apoptotic, and dead IL were measured with wheel running and following acute aerobic exercise. Female C57BL/6 mice were given 16 weeks of wheel running (WR) or a control condition (No WR) and at the end of training were assigned to a single acute treadmill exercise session with sacrifice immediately, 2h after, or 24h after completion of exercise, or were not run (sedentary) with respect to the acute treadmill exercise. Intestinal lymphocytes were assessed for pro-(TNF-α, IL-17) and anti-(IL-10) inflammatory, and pleiotropic (IL-6) cytokines, and pro-(caspase 3 and 7, AIF) and anti-(Bcl-2) apoptotic protein expression. The percent of early (Annexin(+)) and late (Annexin(+)PI(+)) apoptotic, and dead (PI(+)) IL was determined. WR mice had lower TNF-α and caspase 7, and higher IL-10 and IL-6 expression in IL than No WR mice. A single exposure to intense aerobic treadmill exercise increased pro-(TNF-α) and anti-(IL-10) inflammatory cytokine and pro-apoptotic protein (caspase 3) expression in IL. The percent of early and late apoptotic, and dead IL were higher after acute exercise. Although long-term voluntary wheel running did not protect against acute exercise-induced changes in IL cytokine expression or apoptosis, there was an overall 'anti-inflammatory' effect observed as a result of wheel running in healthy mice.

Does physical activity affect quality of life, disease symptoms and immune measures in patients with inflammatory bowel disease? A systematic review.

Inflammatory bowel diseases (IBD) are a group of chronic, episodic inflammatory conditions of the large and small intestines. Individuals with IBD have been reported to use physical activity (PA) as a complementary therapy although the effectiveness of PA for reducing disease burden in patients with IBD is not known. The review objective is to evaluate published studies on physical activity and IBD focusing on quality of life, disease burden markers and immunological outcomes. A literature search was carried out using MEDLINE, WEB OF SCIENCE, CINHAL, and SCOPUS (to December 2008). Studies were included if they 1) were provided in English; 2) dealt with IBD in humans; 3) focused on the outcome measures of health related quality of life, clinical disease indicators or immune function; and 4) included PA as a primary intervention for IBD cases. In total, 7 studies were included in this systematic review: 5 were on PA and quality of life measures and inflammatory disease markers, and 2 on PA and immune measures. Four studies showed that PA significantly increased quality of life for IBD patients as assessed by various questionnaires. PA was also associated with decreased disease activity. There was no evidence that PA affected immune outcomes in patients with IBD. The role of PA as an adjunctive therapy for patients with IBD has not been well characterized in the literature. However, there is some evidence that PA may improve quality of life and reduce disease activity in patients with IBD.

Occurrence of candiduria in a population of chronically catheterized patients with spinal cord injury.

STUDY DESIGN: Prospective data collection. OBJECTIVES: To evaluate occurrence and characteristics of candiduria in a population of individuals with spinal cord injury (SCI) or multiple sclerosis (MS) and chronic catheter usage. Candiduria, or presence of Candida species in the urine, is a common clinical problem. It is most frequently seen in patients with indwelling urinary catheters. Many patients have these catheters in place chronically. Previous studies have shown that despite therapy, most patients with candiduria will develop the infection again and that complications such as invasive candidiasis are rare. However, there are no studies that specifically examine the role of candiduria in patients with SCI and long-term catheter use. SETTING: Inpatients and outpatients in a US Veterans Affairs spinal cord injury center. METHODS: Urinalysis, culture, patient demographic and clinical characteristics through chart review. RESULTS: Of 100 total patients, 52 had paraplegia, 45 tetraplegia and 3 MS. Overall, 17 (17%) patients had candiduria, which was observed in urine culture. Antibiotic use was associated with an increased risk of developing candiduria. Indwelling catheter (urethral or suprapubic) usage was also significantly associated with candiduria; only one person on intermittent catheterization developed candiduria, which was not associated with adverse clinical outcomes. CONCLUSIONS: Antibiotic usage and indwelling catheterization were associated with candiduria. No participant in our study population developed invasive candidiasis, and persistence of candiduria was not frequent.

Effects of pedunculopontine nucleus area stimulation on gait disorders in Parkinson's disease.

Gait disturbances are frequent and disabling in advanced Parkinson's disease. These symptoms respond poorly to usual medical and surgical treatments but were reported to be improved by stimulation of the pedunculopontine nucleus. We studied the effects of stimulating the pedunculopontine nucleus area in six patients with severe freezing of gait, unresponsive to levodopa and subthalamic nucleus stimulation. Electrodes were implanted bilaterally in the pedunculopontine nucleus area. Electrode placement was checked by postoperative magnetic resonance imaging. The primary outcome measures were a composite gait score, freezing of gait questionnaire score and duration of freezing episodes occurring during a walking protocol at baseline and one-year follow-up. A double-blind cross-over study was carried out from months 4 to 6 after surgery with or without pedunculopontine nucleus area stimulation. At one-year follow-up, the duration of freezing episodes under off-drug condition improved, as well as falls related to freezing. The other primary outcome measures did not significantly change, nor did the results during the double-blind evaluation. Individual results showed major improvement of all gait measures in one patient, moderate improvement of some tests in four patients and global worsening in one patient. Stimulation frequency ranged between 15 and 25 Hz. Oscillopsia and limb myoclonus could hinder voltage increase. No serious adverse events occurred. Although freezing of gait can be improved by low-frequency electrical stimulation of the pedunculopontine nucleus area in some patients with Parkinson's disease our overall results are disappointing compared to the high levels of expectation raised by previous open label studies. Further controlled studies are needed to determine whether optimization of patient selection, targeting and setting of stimulation parameters might improve the outcome to a point that could transform this experimental approach to a treatment with a reasonable risk-benefit ratio.

Voluntary exercise training in mice increases the expression of antioxidant enzymes and decreases the expression of TNF-alpha in intestinal lymphocytes.

Acute exercise in mice induces intestinal lymphocyte (IL) apoptosis. Freewheel running reduces apoptosis and forced exercise training increases splenocyte antioxidant levels. The purpose of this study was to examine the effect of freewheel running and acute exercise on mouse IL numbers and concentrations of apoptosis and antioxidant proteins and pro-inflammatory cytokines in IL. Female C57BL/6 mice had access to in-cage running wheels (RW) or cages without wheels (NRW) for 16 weeks and were randomized at the end of training to no exercise control (TC) or to treadmill exercise with sacrifice after 90 min of running (TREAD; 30 min, 22 m min(-1); 30 min, 25 m min(-1); 30 min, 28 m min(-1); 2 degrees slope). IL were analyzed for pro-(caspase 3 and 7) and anti-(Bcl-2) apoptotic proteins, endogenous antioxidants (glutathione peroxidase: GPx; catalase: CAT) and the pro-inflammatory cytokine, TNF-alpha. RW mice had higher cytochrome oxidase (p<0.001) and citrate synthase (p<0.01) activities in plantaris and soleus muscles and higher GPx and CAT expression in IL (p<0.05) (indicative of training) compared with NRW mice. TNF-alpha expression was lower (p<0.05) and IL numbers higher (p<0.05) in RW vs. NRW mice. No training effect was observed for apoptotic protein expression, although TREAD resulted in higher caspase and lower Bcl-2. These results suggest that freewheel running in mice for 16 weeks enhances antioxidant and reduces TNF-alpha expression in IL but does not reduce pro-apoptotic protein expression after acute exercise. Results are discussed in terms of implications for inflammatory bowel diseases where apoptotic proteins and TNF-alpha levels are elevated.