Machine learning outperforms clinical experts in classification of hip fractures.

Hip fractures are a major cause of morbidity and mortality in the elderly, and incur high health and social care costs. Given projected population ageing, the number of incident hip fractures is predicted to increase globally. As fracture classification strongly determines the chosen surgical treatment, differences in fracture classification influence patient outcomes and treatment costs. We aimed to create a machine learning method for identifying and classifying hip fractures, and to compare its performance to experienced human observers. We used 3659 hip radiographs, classified by at least two expert clinicians. The machine learning method was able to classify hip fractures with 19% greater accuracy than humans, achieving overall accuracy of 92%.

The multiple effects of aspirin in prostate cancer patients.

Aspirin is a commonly used medication with anti-inflammatory and analgesic properties, and it is widely used to reduce the risk of ischaemic heart disease-related events and/or cerebrovascular accidents. However, there is also evidence from epidemiological and interventional studies to suggest that regular aspirin use can reduce the risk of prostate cancer development and progression, and can reduce the risk of disease recurrence following anti-prostate cancer therapy. Aspirin use in African-American men is associated with a reduced incidence of advanced PCa and reduced disease recurrence, and there is evidence from other studies of an association between regular aspirin use and decreased PCa-related mortality. The cyclooxygenase-2 enzyme inhibited by Aspirin and other NSAIDs, and which catalyses prostaglandin synthesis and mediates inflammation, is overexpressed in prostate cancer, therefore inhibition of cyclooxygenase-2 may have direct, and indirect, therapeutic effects. This review explores the evidence suggesting that aspirin use can modify prostate cancer biology and disease characteristics, and explores the potential mechanisms underpinning the observed associations between aspirin use and modification of prostate cancer risk. It also summarises the potential for adjuvant aspirin use to combine with other therapeutic approaches such as radical surgery and radiotherapy.

Impact of 5 fluorouracil chemotherapy on gut inflammation, functional parameters, and gut microbiota.

Emerging evidence suggests that gut microbiota may influence the response to chemotherapy. We sought to characterize the effects of 5 fluorouracil (5FU) chemotherapy on colon inflammation and functional measures in colorectal cancer (CRC) and to further determine whether gut microbiota can influence this response. 50 C57BL/6 were randomized into four groups; Control + Vehicle (n = 10), Control + 5FU (n = 10), AOM/DSS + Vehicle (n = 15), and AOM/DSS + 5FU (n = 15). CRC was induced chemically by a single 10 mg/kg injection of azoxymethane (AOM) followed by two cycles (2% and 1%) of dextran sodium sulfate (DSS). Mice were then treated with 3 cycles of vehicle or 5FU (cycle 1: 40 mg/kg, cycle 2 + 3: 20 mg/kg). Functional tests (grip strength and run-to-fatigue) were performed prior to 5FU treatment (baseline) and at the completion of the second cycle of 5FU. Following the third 5FU cycle, mice were euthanized and the colon was evaluated for expression of inflammatory genes using RT-qPCR and stool samples were profiled using 16S rRNA sequencing. A second experiment used fecal microbiota transplantation from 5FU treated mice to control mice (n = 10-15/group) to determine whether 5FU associated changes in the microbiota could influence functional measures and colon inflammation. 5FU reduced grip strength (p < 0.05) and caused a trending decrease in run-to-fatigue performance in cancer mice (p = 0.06). Select intestinal inflammatory genes were significantly elevated with 5FU treatment and this was further exacerbated with cancer (p < 0.05). Microbiota analysis revealed increased dissimilarity and alterations in bacterial taxonomy in 5FU and AOM/DSS-treated mice (p < 0.05). Fecal transplant from 5FU treated mice reduced functional performance (p < 0.05) and altered select colon inflammatory markers (p < 0.05). This study provides evidence of an effect of 5FU on inflammatory responses and functional measures in a mouse model of CRC and suggests that gut microbes may play a role in some, but not all, 5FU related perturbations.

Leptin resistance elicits depressive-like behaviors in rats.

There is a growing appreciation that the complications of obesity extend to the central nervous system (CNS) and include increased risk for development of neuropsychiatric co-morbidities such as depressive illness. The neurological consequences of obesity may develop as a continuum and involve a progression of pathological features which is initiated by leptin resistance. Leptin resistance is a hallmark feature of obesity, but it is unknown whether leptin resistance or blockage of leptin action is casually linked to the neurological changes which underlie depressive-like phenotypes. Accordingly, the aim of the current study was to examine whether chronic administration of a pegylated leptin receptor antagonist (Peg-LRA) elicits depressive-like behaviors in adult male rats. Peg-LRA administration resulted in endocrine and metabolic features that are characteristic of an obesity phenotype. Peg-LRA rats also exhibited increased immobility in the forced swim test, depressive-like behaviors that were accompanied by indices of peripheral inflammation. These results demonstrate that leptin resistance elicits an obesity phenotype that is characterized by peripheral immune changes and depressive-like behaviors in rats, supporting the concept that co-morbid obesity and depressive illness develop as a continuum resulting from changes in the peripheral endocrine and metabolic milieu.

Role of MCP-1 on inflammatory processes and metabolic dysfunction following high-fat feedings in the FVB/N strain.

BACKGROUND: Monocyte chemoattractant protein 1 (MCP-1) is known to be an important chemokine for macrophage recruitment. Thus, targeting MCP-1 may prevent the perturbations associated with macrophage-induced inflammation in adipose tissue. However, inconsistencies in the available animal literature have questioned the role of this chemokine in this process. The purpose of this study was to examine the role of MCP-1 on obesity-related pathologies. METHODS: Wild-type and MCP-1-deficient mice on an friend virus B NIH (FVB/N) background were assigned to either low-fat diet or high-fat diet (HFD) treatment for a period of 16 weeks. Body weight and body composition were measured weekly and monthly, respectively. Fasting blood glucose and insulin, and glucose tolerance were measured at 16 weeks. Macrophages, T-cell markers, inflammatory mediators and markers of fibrosis were examined in the adipose tissue at the time of killing the mice. RESULTS: As expected, HFD increased adiposity (body weight, fat mass, fat percent and adipocyte size), metabolic dysfunction (impaired glucose metabolism and insulin resistance) macrophage number (CD11b(+)F480(+) cells, and gene expression of EMR1 and CD11c), T-cell markers (gene expression of CD4 and CD8), inflammatory mediators (pNFκB and pJNK, and mRNA expression of MCP-1, CCL5, C-X-C motif chemokine-14, tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6)) and fibrosis (expression of IL-10, IL-13, TGF-ß and matrix metalloproteinase-2 (MMP2); P<0.05). However, contrary to our hypothesis, MCP-1 deficiency exacerbated many of these responses resulting in a further increase in adiposity (body weight, fat mass, fat percent and adipocyte size), metabolic dysregulation, macrophage markers (EMR1), inflammatory cell infiltration and fibrosis (formation of type I and III collagens, mRNA expression of IL-10 and MMP2; P<0.05). CONCLUSIONS: These data suggest that MCP-1 may be a necessary component of the inflammatory response required for adipose tissue protection, remodeling and healthy expansion in the FVB/N strain in response to HFD feedings.

Effects of the MCP-1 synthesis inhibitor bindarit on tumorigenesis and inflammatory markers in the C3(1)/SV40Tag mouse model of breast cancer.

Breast cancer, the most deadly cancer in women, is characterized by elevated levels of inflammation within and surrounding the tumor, which can lead to accelerated growth, invasion and metastasis. Macrophages are central to the inflammatory milieu and are recruited to the tumor microenvironment by several factors including monocyte chemoattractant protein-1 (MCP-1). Using the anti-inflammatory molecule bindarit to target MCP-1, we investigated the role of this chemokine on macrophage related inflammation and mammary tumorigenesis in a transgenic mouse model of breast cancer. C3(1)/SV40Tag mice and wild type FVB/N were randomized to either control or 0.5% bindarit diet from 4 to 21weeks of age. Tumor number and volume were recorded over time and at sacrifice. Macrophage markers as well as inflammatory meditators were examined in the tumor tissue and mammary glands. Circulating MCP-1 and IL-6 were measured by ELISA. Bindarit treatment reduced tumor number (P<0.05), but did not affect tumor size, tumor weight or tumor latency in C3(1)/SV40Tag mice. Within the tumor, mRNA expression of bindarit's primary targets, MCP-1 and IL-12/p35, were significantly decreased by bindarit treatment (P<0.05), and this was consistent with trends for reduced expression of TNF-α, IL-6, F4/80, CD206, and IL-10. In mammary tissue, expression of MCP-1, TNF-α, IL-6, F4/80, IL-10 and IL-12/p35 was significantly elevated in C3(1)/SV40Tag mice compared to wild type FVB/N mice, but IL-6 was the only marker decreased by bindarit treatment (P<0.05). Plasma MCP-1 was highly correlated with tumor volume (P<0.05); however, it was not affected by bindarit at 21weeks of age. Similarly, circulating IL-6 was increased in C3(1)/SV40Tag mice but there was no effect of bindarit treatment. These results show that tumor multiplicity in the C3(1)/SV40Tag mouse model of breast cancer is reduced by bindarit, however these effects are independent of changes in plasma levels of MCP-1 and IL-6, but may be related to the attenuated expression of MCP-1 along with several inflammatory mediators and macrophage markers within the tumor.

Linking inflammation to tumorigenesis in a mouse model of high-fat-diet-enhanced colon cancer.

Many observational epidemiologic studies suggest an association between high-fat-diet (HFD) and colon cancer risk. However, the lack of controlled experimental studies that examine this relationship and the mechanisms involved weaken the basis for inferring a causal relationship. Inflammation plays a role in colon cancer progression and HFDs have been reported to increase inflammation; however, the inflammatory effects of HFD in colon cancer have yet to be firmly established. We examined the effects of a novel HFD that closely mimics the standard American diet (12% and 40% of total caloric intake from saturated fat and total fat, respectively) on macrophage markers and inflammatory mediators in a mouse model of intestinal tumorigenesis and relate this to polyp characteristics as well as measures of adiposity. Male Apc(Min/+) mice (7-8/group) were fed a Control Diet (Con) or novel high-fat-diet (HFD) from 4 to 12weeks of age. Body weight and body composition were measured weekly and monthly, respectively. Intestinal tissue was analyzed for polyp burden (number and size). Gene expression of macrophage markers and inflammatory mediators were examined in the adipose tissue and polyps. The HFD increased the expression of macrophage markers and inflammatory mediators in the adipose tissue (F4/80, CD11c, TLR-4 and MCP-1) and tumor microenvironment (IL-12, MCP-1, IL-6 and TNF-α). As expected, the HFD increased body weight, body fat percent, fat mass and blood glucose (P<0.05), and was associated with an increase in the number of large polyps (P<0.05) but not total polyps. In summary, consumption of a HFD, similar in macronutrient composition to the standard American diet, altered the expression of macrophage phenotypic markers and inflammatory mediators in adipose tissue and intestinal polyps and this was associated with increased tumorigenesis.

Effects of voluntary exercise on tumorigenesis in the C3(1)/SV40Tag transgenic mouse model of breast cancer.

Epidemiologic studies suggest an association between physical activity (PA) and breast cancer risk. We examined the relationship between voluntary wheel running and breast cancer in C3(1)/SV40Tag mice. Female FVB/N and C3(1)/SV40Tag mice were assigned to either PA [C3(1)-PA] (n=12) or sedentary (Sed) [C3(1)-Sed] (n=15) treatment and were placed in a cage with access to a running wheel (PA) or without (Sed) from 4 to 24 weeks of age (sacrifice). Physical activity data were analyzed for running distance, time and speed. Body composition was examined at 12 weeks of age. Tumors were counted twice weekly and at sacrifice to assess multiplicity. Tumor volume was calculated using external calipers [0.52 x (largest diameter) x (smallest diameter)2]. Heart and body weight were also recorded at sacrifice. Results showed that voluntary wheel running reduced tumor volume per tumor [C3(1)-Sed, 422.3±89.9 mm(3); C3(1)-PA, 260.2±61.7 mm(3)] (P<0.05), but was associated with increased tumor number (P<0.05). Body composition analysis showed no differences in body fat between the groups. Heart weight/body weight ratio was increased following physical activity (P<0.05) providing evidence of a training effect. In conclusion, voluntary wheel running activity was effective at slowing tumor growth in the C3(1)/SV40Tag mouse model of breast cancer, but did not inhibit tumor initiation. These data provide support for further development of the C3(1)/SV40Tag mouse model for use in understanding the role of physical activity on breast cancer progression and the mechanisms for its effects.

Negative interaction between indomethacin and exercise in mice.

We examined the possible negative interaction of the combined use of the NSAID indomethacin (IND) and exercise in mice. Mice were assigned to one of 4 groups: Exercise 2.5 mg/kg IND (Ex-2.5), Sedentary 2.5 mg/kg IND (Sed-2.5), Exercise 5.0 mg/kg IND (Ex-5.0) and Sedentary 5.0 mg/kg IND (Sed-5.0). Mice were given IND (gavage) 1 h prior to exercise (treadmill run at 30 m/min, 8% grade for 90 min) or rest for 14 consecutive days. Run times, body weight and mortality were recorded daily. Sed-5.0 was highly toxic and caused 70% mortality compared to Sed-2.5, which was well tolerated (0% mortality) (P<0.05). While the addition of exercise had no greater effect on mortality in Ex-5.0, it increased it in the 2.5 group (52% vs. 0%; P<0.05). Run time was reduced from baseline beginning on day 2 (Ex-5.0), or day 3 (Ex-2.5) (P<0.05). Body weight (recorded in the 2.5 mg/kg groups only) was decreased from baseline in Ex-2.5 and Sed-2.5 (P<0.05), but this effect occurred earlier and was of greater magnitude in Ex-2.5. Exercise combined with IND use can lead to serious side effects in mice. Future research is needed to test the hypothesis that this effect is due to increased GI permeability and whether humans are also at risk.

Effects of 5-fluorouracil chemotherapy on fatigue: role of MCP-1.

Chemotherapy has been known to cause severe side effects, including fatigue. While the mechanisms for chemotherapy induced fatigue (CIF) are likely to be multi-factorial in origin, it is thought that inflammation and anemia may play a role. The purpose of this study was to examine the effect of chemotherapy on fatigue in mice, and further, to begin to determine if inflammation and anemia may contribute to this response. For experiment 1, C57BL/6 mice were assigned to: vehicle (PBS), low (20 mg/kg), medium (40 mg/kg), or high (60 mg/kg) doses of 5-fluorouracil (5-FU). Voluntary physical activity (PA) was measured throughout the treatment period (day 1-5) as well as during the recovery period (day 6-14). In experiment 2, we examined the effects of 5-FU (60 mg/kg) on the inflammatory mediator MCP-1 and on markers of anemia (RBC, Hct and Hb). Finally, using MCP-1(-/-) mice we examined the role of MCP-1 on CIF (experiment 3). 5-FU reduced voluntary PA in a dose response manner (p<0.05). Plasma MCP-1 was increased following 5-FU treatment on both days 5 (p=0.10) and 14 (p<0.05). In addition, RBCs, Hct and Hb were reduced with 5-FU on days 5 and 14 (p<0.05). Both C57BL/6 and MCP-1(-/-) mice saw similar decrements in PA through the duration of the treatment period (days 1-5), however the MCP-1(-/-) mice recovered much earlier than wildtype mice. This study provides evidence of the dose response effect of a standard chemotherapy agent on fatigue and demonstrates a potential role of MCP-1 and presumably inflammation, and anemia.

Strike mechanics of an ambush predator: the spearing mantis shrimp.

Ambush predation is characterized by an animal scanning the environment from a concealed position and then rapidly executing a surprise attack. Mantis shrimp (Stomatopoda) consist of both ambush predators ('spearers') and foragers ('smashers'). Spearers hide in sandy burrows and capture evasive prey, whereas smashers search for prey away from their burrows and typically hammer hard-shelled, sedentary prey. Here, we examined the kinematics, morphology and field behavior of spearing mantis shrimp and compared them with previously studied smashers. Using two species with dramatically different adult sizes, we found that strikes produced by the diminutive species, Alachosquilla vicina, were faster (mean peak speed 5.72±0.91 m s(-1); mean duration 3.26±0.41 ms) than the strikes produced by the large species, Lysiosquillina maculata (mean peak speed 2.30±0.85 m s(-1); mean duration 24.98±9.68 ms). Micro-computed tomography and dissections showed that both species have the spring and latch structures that are used in other species for producing a spring-loaded strike; however, kinematic analyses indicated that only A. vicina consistently engages the elastic mechanism. In the field, L. maculata ambushed evasive prey primarily at night while hidden in burrows, striking with both long and short durations compared with laboratory videos. We expected ambush predators to strike with very high speeds, yet instead we found that these spearing mantis shrimp struck more slowly and with longer durations than smashers. Nonetheless, the strikes of spearers occurred at similar speeds and durations to those of other aquatic predators of evasive prey. Although counterintuitive, these findings suggest that ambush predators do not actually need to produce extremely high speeds, and that the very fastest predators are using speed to achieve other mechanical feats, such as producing large impact forces.

EGFR-dependent pancreatic carcinoma cell metastasis through Rap1 activation.

Tyrosine kinase receptors have an essential role in various aspects of tumor progression. In particular, epidermal growth factor receptor (EGFR) and its ligands have been implicated in the growth and dissemination of a wide array of human carcinomas. Here, we describe an EGFR-mediated signaling pathway that regulates human pancreatic carcinoma cell invasion and metastasis, yet does not influence the growth of primary tumors. In fact, ligation/activation of EGFR induces Src-dependent phosphorylation of two critical tyrosine residues of p130CAS, leading to the assembly of a Crk-associated substrate (CAS)/Nck1 complex that promotes Ras-associated protein-1 (Rap1) signaling. Importantly, GTP loading of Rap1 is specifically required for pancreatic carcinoma cell migration on vitronectin but not on collagen. Furthermore, Rap1 activation is required for EGFR-mediated metastasis in vivo without impacting primary tumor growth. These findings identify a molecular pathway that promotes the invasive/metastatic properties of human pancreatic carcinomas driven by EGFR.

Racial disparities in hematopoietic cell transplantation in the United States.

Hematopoietic cell transplantation (HCT) is a highly specialized, expensive and resource-intense medical procedure that can be associated with racial disparities. We review the prevailing literature on racial disparities in HCT in the United States and describe areas for future research and interventions. We discuss the complexity of interpreting race as a biological and social determinant of disease in biomedical research, especially as it relates to HCT. In the United States, race is often a surrogate for socioeconomic, education and health insurance status. We also discuss some of the nuances to consider while reviewing the literature on racial disparities. Disparities by race exist in three areas related to HCT: donor availability, access to HCT and outcomes of HCT. African-Americans/Blacks have a lower likelihood of finding an unrelated donor. Race and ethnicity definitions are country-specific and reconciling race data can represent significant challenges to unrelated donor registries worldwide. African-Americans/Blacks do not have the same access to autologous and allogeneic HCT as Whites. Racial disparities in outcomes of HCT are more prevalent among allogeneic HCT than autologous HCT recipients. More research is required to understand the biological, social, cultural, medical and financial aspects of race that may influence access to HCT and survival after transplantation. Better understanding of racial disparities will minimize inequities, inform health policy, guide development of interventions targeted to eliminate disparities and ensure equitable access to HCT for all populations.

Benefits of exercise training on breast cancer progression and inflammation in C3(1)SV40Tag mice.

Many observational epidemiologic studies suggest an association between exercise and breast cancer risk. However, the lack of controlled experimental studies that examine this relationship and the mechanisms involved weaken the basis for inferring a causal relationship. Inflammation plays a role in breast cancer progression and exercise has been reported to reduce inflammation; however, the anti-inflammatory effects of exercise in breast cancer have yet to be established. We examined the relationship between exercise training and systemic inflammation in relation to breast cancer progression in C3(1)SV40Tag mice. Female C3(1)SV40Tag mice were assigned to either exercise (Ex) or sedentary (Sed) treatment (n=12-14/group). Beginning at 4 wks of age mice (Ex) were run on a treadmill for 60 min/d (20 m/min and 5% grade), 6 d/wk for a period of 20 wks. Mice were examined weekly for palpable tumors, and tumor number and volume were recorded. At 24 wks of age mice were sacrificed and a more direct measure of tumor number and volume, and spleen weight was recorded. Plasma was analyzed for MCP-1 and IL-6 concentration using ELISA. Ex reduced palpable tumor number at sacrifice (24 wks) by approximately 70% (P<0.05). Tumor volume was also reduced in Ex at 21-23 wks (P<0.05). This reduction in tumor progression by Ex was associated with a reduction in plasma concentration of MCP-1 and IL-6, and spleen weight (P<0.05). These data provide strong support for a beneficial effect of exercise training on tumor progression in the C3(1)SV40Tag mouse model of breast cancer that may be partly mediated by its anti-inflammatory potential.

Oncogenic Ras/Src cooperativity in pancreatic neoplasia.

Pancreas cancer is one of the most lethal malignancies and is characterized by activating mutations of Kras, present in 95% of patients. More than 60% of pancreatic cancers also display increased c-Src activity, which is associated with poor prognosis. Although loss of tumor suppressor function (for example, p16, p53, Smad4) combined with oncogenic Kras signaling has been shown to accelerate pancreatic duct carcinogenesis, it is unclear whether elevated Src activity contributes to Kras-dependent tumorigenesis or is simply a biomarker of disease progression. Here, we demonstrate that in the context of oncogenic Kras, activation of c-Src through deletion of C-terminal Src kinase (CSK) results in the development of invasive pancreatic ductal adenocarcinoma (PDA) by 5-8 weeks. In contrast, deletion of CSK alone fails to induce neoplasia, while oncogenic Kras expression yields PDA at low frequency after a latency of 12 months. Analysis of cell lines derived from Ras/Src-induced PDA's indicates that oncogenic Ras/Src cooperativity may lead to genomic instability, yet Ras/Src-driven tumor cells remain dependent on Src signaling and as such, Src inhibition suppresses growth of Ras/Src-driven tumors. These findings demonstrate that oncogenic Ras/Src cooperate to accelerate PDA onset and support further studies of Src-directed therapies in pancreatic cancer.

Six-month atrophy in MTL structures is associated with subsequent memory decline in elderly controls.

Neurodegeneration precedes the onset of dementias such as Alzheimer's by several years. Recent advances in volumetric imaging allow quantification of subtle neuroanatomical change over time periods as short as six months. This study investigates whether neuroanatomical change in medial temporal lobe subregions is associated with later memory decline in elderly controls. Using high-resolution, T1-weighted magnetic resonance images acquired at baseline and six-month follow-up, change in cortical thickness and subcortical volumes was measured in 142 healthy elderly subjects (aged 59-90 years) from the ADNI cohort. Regression analysis was used to identify whether change in fourteen subregions, selected a priori, was associated with declining performance on memory tests from baseline to two-year follow-up. Percent thickness change in the right fusiform and inferior temporal cortices and expansion of the right inferior lateral ventricle were found to be significant predictors of subsequent decline on memory-specific neuropsychological measures. These results demonstrate that six-month regional neurodegeneration can be quantified in the healthy elderly and might help identify those at risk for subsequent cognitive decline.

Exercise stress increases susceptibility to influenza infection.

Exercise stress is associated with an increased risk for upper respiratory tract infection (URTI) while moderate exercise has been associated with a decreased risk. We have shown that exercise stress can increase susceptibility (morbidity, symptom severity and mortality) to HSV-1 respiratory infection, but there is little evidence on the effects of stressful exercise on susceptibility to the principal etiological agents of human respiratory infections, including influenza viruses. This study examined the effects of stressful exercise on susceptibility to influenza virus (A/Puerto Rico/8/34 (H1N1)). Mice were assigned to one of two groups: exercise (Ex) or control (Con). Exercise consisted of a treadmill run to volitional fatigue ( approximately 120 min) performed on three consecutive days. Fifteen minutes after the last bout of exercise or rest, mice (n=20-21/group) were intranasally inoculated with a standardized dose of influenza virus (0.25 HAU). Mice were monitored daily for morbidity (time to sickness), symptom severity and mortality (time to death) for 21 days. Exercise stress was associated with an increase in susceptibility to infection (morbidity, mortality and symptom severity on days 6 and 7; P<0.05). These data from a controlled influenza virus challenge model add significantly to the growing body of evidence that severe exercise can increase susceptibility to URTI.

Quercetin reduces susceptibility to influenza infection following stressful exercise.

Exercise stress is associated with increased risk for upper respiratory tract infection. We have shown that exercise stress can increase susceptibility to infection. Quercetin, a flavonoid present in a wide variety of fruits and vegetables, has been reported to inhibit infectivity and replication of a broad spectrum of viruses and may offset the increase in susceptibility to infection associated with stressful exercise. This study examined the effects of quercetin feedings on susceptibility to the influenza virus A/Puerto Rico/8/34 (H1N1) following stressful exercise. Mice were randomly assigned to one of four treatment groups: exercise-placebo, exercise-quercetin, control-placebo, or control-quercetin. Exercise consisted of a run to fatigue (approximately 140 min) on a treadmill for 3 consecutive days. Quercetin (12.5 mg/kg) was administered via gavage for 7 days before viral challenge. At 30 min after the last bout of exercise or rest, mice (n=23-30) were intranasally inoculated with a standardized dose of influenza virus (0.04 hemagglutinating units). Mice were monitored daily for morbidity (time to sickness), symptom severity, and mortality (time to death) for 21 days. Exercise stress was associated with an increased susceptibility to infection [morbidity, mortality, and symptom severity on days 5-7 (P<0.05)]; quercetin offset the increase in susceptibility to infection [morbidity, mortality, and symptom severity on days 5-7 (P<0.05)] that was associated with stressful exercise. These data suggest that short-term quercetin feedings may prove to be an effective strategy to lessen the impact of stressful exercise on susceptibility to respiratory infection.

Benefits of oat beta-glucan on respiratory infection following exercise stress: role of lung macrophages.

Exercise stress is associated with an increased risk for upper respiratory tract infection (URTI). We have shown that consumption of the soluble oat fiber beta-glucan (ObetaG) can offset the increased risk for infection and decreased macrophage antiviral resistance following stressful exercise; however, the direct role of macrophages is unknown. This study examined the effect of macrophage depletion on the benefits of orally administered ObetaG on susceptibility to infection (morbidity, symptom severity, and mortality) following exercise stress. CL(2)MDP (Ex- H(2)O-CL(2)MDP, Ex-ObetaG-CL(2)MDP, Con-H(2)O-CL(2)MDP, Con-ObetaG-CL(2)MDP)-encapsulated liposomes were administered intranasally to deplete macrophages, and PBS (Ex-H(2)O-PBS, Ex-ObetaG-PBS, Con-H(2)O-PBS, Con-ObetaG-PBS)-encapsulated liposomes were given to macrophage-intact groups. Ex mice ran to volitional fatigue on a treadmill for 3 consecutive days, and ObetaG mice were fed a solution of 50% ObetaG in their drinking water for 10 consecutive days before infection. Fifteen minutes following the final bout of Ex or rest, mice were intranasally inoculated with 50 microl of a standardized dose of herpes simplex virus-1. Ex increased morbidity (P < 0.001) and symptom severity (P < 0.05) but not mortality (P = 0.09). The increase in morbidity and symptom severity was blocked by ObetaG consumption for 10 consecutive days before exercise and infection [morbidity (P < 0.001) and symptom severity (P < 0.05)]. Depletion of macrophages negated the beneficial effects of ObetaG on reducing susceptibility to infection following exercise stress, as evidenced by an increase in morbidity (P < 0.01) and symptom severity (P < 0.05). Results indicate that lung macrophages are at least partially responsible for mediating the beneficial effects of ObetaG on susceptibility to respiratory infection following exercise stress.

Susceptibility to HSV-1 infection and exercise stress in female mice: role of estrogen.

Exhaustive exercise has been associated with an increased risk for upper respiratory tract infections in mice and humans. We have previously shown (Brown AS, Davis JM, Murphy AE, Carmichael MD, Ghaffer A, Mayer EP. Med Sci Sports Exerc 36: 1290-1295, 2004) that female mice are better protected from the lethal effects of herpes simplex virus type 1 (HSV-1) infection, both at rest and following exercise stress, but little is known about possible mechanisms. This study tested the effects of estrogen on HSV-1 infection and macrophage antiviral resistance following repeated exhaustive exercise. Female mice were assigned to either exercise (Ex) or control (C): intact female (I-C or I-Ex), ovariectomized female (O-C or O-Ex), or ovariectomized estrogen-supplemented female (E-C or E-Ex). Exercise consisted of treadmill running to volitional fatigue ( approximately 125 min) for 3 consecutive days. Intact female mice had a later time to death than O and E (P < 0.05) and fewer deaths than both O and E (P < 0.05). Exercise stress was associated with increased time to sickness (P < 0.05) and symptom severity at days 6 and 12-21 postinfection (P < 0.05) and decreased macrophage antiviral resistance (P < 0.001) in all groups. E had increased symptom severity at days 6 and 13-21 postinfection (P < 0.05). Results indicate that intact female mice are better protected from the lethal effects of HSV-1 infection and that exercise stress had a similar negative impact in all groups. This protective effect was lost in ovariectomized mice, but it was not reinstated by 17beta-estradiol replacement. This indicates that other ovarian factors, alone or in combination with estrogen, are responsible for the protective effects in females.