miR155 deficiency reduces breast tumor burden in the MMTV-PyMT mouse model.

miRNA155 (miR155) has emerged as an important regulator of breast cancer (BrCa) development. Studies have consistently noted an increase in miR155 levels in serum and/or tissues in patients with BrCa. However, what is less clear is whether this increase in miR155 is a reflection of oncogenic or tumor suppressive properties. To study the effects of miR155 in a transgenic model of BrCA, we developed an MMTV-PyMT mouse deficient in miR155 (miR155-/- PyMT). miR155-/- mice (n = 11) exhibited reduced tumor number and volume palpations at ∼14-18 wk of age compared with miR155 sufficient littermates (n = 12). At 19 wk, mammary glands were excised from tumors for RT-PCR, and tumors were counted, measured, and weighed. miR155-/- PyMT mice exhibited reduced tumor volume, number, and weight, which was confirmed by histopathological analysis. There was an increase in apoptosis with miR155 deficiency and a decrease in proliferation. As expected, miR155 deficiency resulted in upregulated gene expression of suppressor of cytokine signaling 1 (Socs1)-its direct target. There was a reduction in gene expression of macrophage markers (CD68, Adgre1, Itgax, Mrc1) with miR-155-/- and this was confirmed with immunofluorescence staining for F4/80. miR155-/- increased expression of M1 macrophage marker Nos2 and reduced expression of M2 macrophage markers IL-10, IL-4, Arg1, and MMP9. Overall, miR155 deficiency reduced BrCA and improved the tumor microenvironment through the reduction of genes associated with protumorigenic processes. However, given the inconsistencies in the literature, additional studies are needed before any attempts are made to harness miR155 as a potential oncogenic or tumor suppressive miRNA.NEW & NOTEWORTHY To examine the effects of miR155 in a transgenic model of breast cancer, we developed an MMTV-PyMT mouse-deficient in miR155. We demonstrate that global loss of miR155 resulted in blunted tumor growth through modulating the tumor microenvironment. Specifically, miR155-deficient mice had smaller and less invasive tumors, an increase in apoptosis and a decrease in proliferation, a reduction in tumor-associated macrophages, and the expression of genes associated with protumoral processes.

Macrophage tumor necrosis factor-alpha deletion does not protect against obesity-associated metabolic dysfunction.

The pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF-α), has been suggested to be a key factor in the induction of obesity-associated metabolic dysfunction. However, the role that macrophage-derived TNF-α has on regulating metabolic perturbations in obesity is not completely understood. Therefore, we utilized the TNF-αFlox/Flox(F/F) , LyzMcre± mouse model to determine the impact that macrophage TNF-α deletion has on the development of high-fat diet (HFD)-induced obesity. At 10 weeks of age, male littermates were randomly assigned to 1 of 4 groups: TNF-αF/F low-fat diet (TNF-αF/F LFD), TNF-αF/F,LyzMCre LFD, TNF-αF/F HFD, or TNF-αF/F,LyzMCre HFD (n = 16-28/group) and were fed their respective diets for 18 weeks. Body weight was assessed throughout the course of the experiment. Body composition, hepatic lipid accumulation, and metabolic outcomes were also examined. A microarray gene expression experiment was performed from RNA isolated from epididymal adipose tissue of the HFD-fed groups (n = 10/group) and results were verified via qRT-PCR for all groups. Macrophage-derived TNF-α deletion significantly reduced adipose tissue TNF-α gene expression and circulating TNF-α and downregulated genes linked to the toll-like receptor (TLR) and NFκB signaling pathways. However, macrophage TNF-α deletion had no effect on hindering the development of obesity, hepatic lipid accumulation, or improving glucose metabolism or insulin sensitivity. In conclusion, macrophage-derived TNF-α is not a causative factor for the induction of obesity-associated metabolic dysfunction.

Feasting, not fasting: winter diets of cave hibernating bats in the United States.

Temperate bat species use extended torpor to conserve energy when ambient temperatures are low and food resources are scarce. Previous research suggests that migratory bat species and species known to roost in thermally unstable locations, such as those that roost in trees, are more likely to remain active during winter. However, hibernating colonies of cave roosting bats in the southeastern United States may also be active and emerge from caves throughout the hibernation period. We report what bats are eating during these bouts of winter activity. We captured 2,044 bats of 10 species that emerged from six hibernacula over the course of 5 winters (October-April 2012/2013, 2013/2014, 2015/2016, 2016/2017, and 2017/2018). Using Next Generation sequencing of DNA from 284 fecal samples, we determined bats consumed at least 14 Orders of insect prey while active. Dietary composition did not vary among bat species; however, we did record variation in the dominant prey items represented in species' diets. We recorded Lepidoptera in the diet of 72.2% of individual Corynorhinus rafinesquii and 67.4% of individual Lasiurus borealis. Diptera were recorded in 32.4% of Myotis leibii, 37.4% of M. lucifugus, 35.5% of M. sodalis and 68.8% of Perimyotis subflavus. Our study is the first to use molecular genetic techniques to identify the winter diet of North American hibernating bats. The information from this study is integral to managing the landscape around bat hibernacula for insect prey, particularly in areas where hibernating bat populations are threatened by white-nose syndrome.

Repeated clodronate-liposome treatment results in neutrophilia and is not effective in limiting obesity-linked metabolic impairments.

Depletion of macrophages is thought to be a therapeutic option for obesity-induced inflammation and metabolic dysfunction. However, whether the therapeutic effect is a direct result of reduced macrophage-derived inflammation or secondary to decreases in fat mass is controversial, as macrophage depletion has been shown to disrupt energy homeostasis. This study was designed to determine if macrophage depletion via clodronate-liposome (CLD) treatment could serve as an effective intervention to reduce obesity-driven inflammatory and metabolic impairments independent of changes in energy intake. After 16 wk on a high-fat diet (HFD) or the AIN-76A control (low-fat) diet (LFD) ( n = 30/diet treatment), male C57BL/6J mice were assigned to a CLD- or PBS-liposome treatment ( n = 15/group) for 4 wk. Liposomes were administered biweekly via intraperitoneal injections (8 administrations in total). PBS-liposome-treated groups were pair-fed to their CLD-treated dietary counterparts. Metabolic function was assessed before and after liposome treatment. Adipose tissue, as well as the liver, was investigated for macrophage infiltration and the presence of inflammatory mediators. Additionally, a complete blood count was performed. CLD treatment reduced energy intake. When controlling for energy intake, CLD treatment was unable to regress metabolic dysfunction or nonalcoholic fatty liver disease and impaired adipose tissue insulin action. Moreover, repeated CLD treatment induced neutrophilia and anemia, increased adipose tissue mRNA expression of the proinflammatory cytokines IL-6 and IL-1ß, and augmented circulating IL-6 and monocyte chemoattractant protein-1 concentrations ( P < 0.05). This study suggests that repeated intraperitoneal administration of CLD to deplete macrophages attenuates obesity by limiting energy intake. Moreover, after controlling for the benefits of weight loss, the accompanying detrimental side effects limit regular CLD treatment as an effective therapeutic strategy.

The presence of antibiotic resistance genes in coastal soil and sediment samples from the eastern seaboard of the USA.

Infections from antibiotic resistant microorganisms are considered to be one of the greatest global public health challenges that result in huge annual economic losses. While genes that impart resistance to antibiotics (AbR) existed long before the discovery and use of antibiotics, anthropogenic uses of antibiotics in agriculture, domesticated animals, and humans are known to influence the prevalence of these genes in pathogenic microorganisms. It is critical to understand the role that natural and anthropogenic processes have on the occurrence and distribution of antibiotic resistance in microbial populations to minimize health risks associated with exposures. As part of this research, 15 antibiotic resistance genes were analyzed in coastal sediments and soils along the eastern seaboard of the USA using presence/absence quantitative and digital polymerase chain reaction assays. Samples (53 soil and 192 sediment samples including 54 replicates) were collected from a variety of coastal settings where human and wildlife exposure is likely. At least one of the antibiotic resistance genes was detected in 76.4% of the samples. Samples that contained at least five or more antibiotic resistance genes (5.7%) where typically hydrologically down gradient of watersheds influenced by combined sewer outfalls (CSO). The most frequently detected antibiotic resistance target genes were found in 33.2%, 34.4%, and 42.2% of samples (target genes blaSHV, tetO, and aadA2, respectively). These data provide unique insight into potential exposure of AbR genes over a large geographical region of the eastern seaboard of the USA.

Macrophage depletion using clodronate liposomes decreases tumorigenesis and alters gut microbiota in the AOM/DSS mouse model of colon cancer.

We examined the role of macrophages in inflammation associated with colorectal cancer (CRC). Given the emerging evidence on immune-microbiota interactions in CRC, we also sought to examine the interaction between macrophages and gut microbiota. To induce CRC, male C57BL/6 mice ( n = 32) received a single injection of azoxymethane (AOM), followed by three cycles of dextran sodium sulfate (DSS)-supplemented water in weeks 1, 4, and 7. Prior to the final DSS cycle ( week 7) and twice weekly until euthanasia, mice ( n = 16/group) received either 200 µl ip of clodronate-filled liposomes (CLD) or phosphate-buffered saline (PBS) encapsulated liposomes to deplete macrophages. Colon tissue was analyzed for polyp burden, macrophage markers, transcription factors, and inflammatory mediators. Stool samples were collected, and DNA was isolated and subsequently sequenced for 16S rRNA. Clodronate liposomes decreased tumor number by ∼36% and specifically large (≥1 mm) tumors by ∼36% ( P < 0.05). This was consistent with a decrease in gene expression of EMR1 in the colon tissue and polyp tissue as well as expression of select markers associated with M1 (IL-6) and M2 macrophages (IL-13, IL-10, TGFß, CCL17) in the colon tissue ( P < 0.05). Similarly, there was a decrease in STAT3 and p38 MAPK and ERK signaling in colon tissue. Clodronate liposomes increased the relative abundance of the Firmicutes phylum ( P < 0.05) and specifically Lactobacillaceae and Clostridiaceae families, which have been associated with reduced CRC risk. Overall, these data support the development of therapeutic strategies to target macrophages in CRC and provide support for further evaluation of immune-microbiota interactions in CRC. NEW & NOTEWORTHY We found that macrophage depletion during late-stage tumorigenesis is effective at reducing tumor growth. This was associated with a decrease in macrophage markers and chemokines in the colon tissue and a decrease in transcription factors that are linked to colorectal cancer. The macrophage-depleted group was found to have an increased abundance of Firmicutes, a phylum with documented anti-tumorigenic effects. Overall, these data support the development of therapeutic strategies to target macrophages in colorectal cancer.

Molecular characterization of non-aureus Staphylococcus spp. from heifer intramammary infections and body sites.

The purpose of this study was to investigate non-aureus Staphylococcus spp. intramammary infections (IMI) in periparturient heifers and determine the relationship of precalving body site isolation with precalving IMI and postcalving IMI using molecular speciation and strain-typing methods. Primiparous heifers were enrolled at approximately 14 d before expected calving date. Precalving mammary quarter secretions and body site swabbing samples (teat skin, inguinal skin, muzzle, and perineum) were collected. Postcalving, mammary quarter milk samples were collected for culture and somatic cell counting. Precalving body site samples were cultured, and up to 10 staphylococcal colonies were saved for characterization. Staphylococcal isolates were speciated using matrix-assisted laser/desorption ionization time-of-flight mass spectrometry or sequencing of rpoB or tuf. Pulsed-field gel electrophoresis was used to strain type a subset of isolates. Overall, Staphylococcus chromogenes, Staphylococcus agnetis, and Staphylococcus simulans were the most common species identified in precalving mammary secretions, whereas S. chromogenes, Staphylococcus xylosus, and S. agnetis were the most common species found in postcalving milk samples. The most common species identified from body site samples were S. chromogenes, S. xylosus, and Staphylococcus haemolyticus. Mammary quarters that had a precalving mammary secretion that was culture positive for S. agnetis, S. chromogenes, or Staphylococcus devriesei had increased odds of having an IMI with the same species postcalving. A S. chromogenes IMI postcalving was associated with higher somatic cell count when compared with postcalving culture-negative quarters. Among heifers identified with a non-aureus Staphylococcus spp. IMI either precalving or postcalving, heifers that had S. agnetis or S. chromogenes isolated from their teat skin had increased odds of having the same species found in their precalving mammary secretions, and heifers with S. chromogenes, S. simulans, and S. xylosus isolated from their teat skin precalving were at increased odds of having an IMI with the same species postcalving. Overall, 44% of all heifers with a S. chromogenes IMI around the time of parturition had the same strain isolated from a body site. Based on pulsed-field gel electrophoresis, a high level of strain diversity was found.

Cross-sectional study to identify staphylococcal species isolated from teat and inguinal skin of different-aged dairy heifers.

The purpose of this study was to describe the prevalence and distribution of staphylococcal species on the teat and inguinal skin of dairy heifers across the various stages of the heifer life cycle. The cross-sectional study included 106 Holstein heifers with an age range of 0 d to 27 mo that were selected from 11 different groups, based on housing type and age, on a single dairy operation. A composite swabbing sample including all 4 teats and a second composite sample including both inguinal regions of each heifer were collected using gas-sterilized electrostatic dusters (Swiffers; Procter and Gamble, Cincinnati, OH). Swabbing samples were mixed with 10 mL of sterile saline, agitated, and cultured on mannitol salt agar plates. At 24 h, plates were read and up to 10 staphylococcal colonies were saved for further analysis. Staphylococcal isolates were speciated using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry or PCR amplification and partial sequencing of rpoB or tuf. The prevalence of staphylococci was compared between the inguinal and teat regions using the chi-squared or Fisher's exact test, as applicable. Logistic regression models were used to investigate the relationship between a heifer's age (treated as a quantitative continuous variable) and the probability of isolating a given staphylococcal species from a given body site (inguinal region or teats). Overall, the most common species identified were Staphylococcus haemolyticus followed by Staphylococcus chromogenes, Staphylococcus xylosus, Staphylococcus devriesei, and Staphylococcus sciuri. Staphylococcus aureus was more prevalent on the teat than in the inguinal region, whereas Staphylococcus arlettae was more prevalent in the inguinal region than on the teat. All other staphylococcal species were as likely to be found on the teat skin as the inguinal region skin. Isolation from the inguinal and teat skin was associated with age for Staphylococcus agnetis, S. chromogenes, S. devriesei, Staphylococcus equorum, S. haemolyticus, Staphylococcus lentus, S. sciuri, Staphylococcus vitulinus, and S. xylosus. The probability of finding S. chromogenes and S. agnetis on the teat and inguinal region increased with age, whereas the probability of S. devriesei and S. haemolyticus decreased with age. This study provides further insight into the ecology of staphylococcal species involved in heifer mastitis.

High-fat diets rich in saturated fat protect against azoxymethane/dextran sulfate sodium-induced colon cancer.

High-fat-diet (HFD) consumption is associated with colon cancer risk. However, little is known about how the lipid composition of a HFD can influence prooncogenic processes. We examined the effects of three HFDs differing in the percentage of total calories from saturated fat (SF) (6, 12, and 24% of total caloric intake), but identical in total fat (40%), and a commercially available Western diet (26 and 41% saturated and total fat, respectively) on colon cancer development using the azoxymethane (AOM)/dextran sulfate sodium (DSS) murine model. A second dose-response experiment was performed using diets supplemented with the saturated-fatty-acid (SFA)-rich coconut oil. In experiment 1, we found an inverse association between SF content and tumor burden. Furthermore, increased SF content was associated with reduced inflammation, increased apoptosis, and decreased proliferation. The second dose-response experiment was performed to test whether this effect may be attributed to the SF content of the diets. Consistent with the initial experiment, we found that high SF content was protective, at least in male mice; there was a decrease in mortality in mice consuming the highest concentration of SFAs. To explore a potential mechanism for these findings, we examined colonic mucin 2 (Muc2) protein content and found that the HFDs with the highest SF content had the greatest concentration of Muc2. Our data suggest that high dietary SF is protective in the AOM/DSS model of colon cancer, which may be due, at least in part, to the ability of SF to maintain intestinal barrier integrity through increased colonic Muc2.

MicroRNA-155 deletion promotes tumorigenesis in the azoxymethane-dextran sulfate sodium model of colon cancer.

Clinical studies have linked microRNA-155 (miR-155) expression in the tumor microenvironment to poor prognosis. However, whether miR-155 upregulation is predictive of a pro- or antitumorigenic response is unclear, as the limited preclinical data available remain controversial. We examined miR-155 expression in tumor tissue from colon cancer patients. Furthermore, we investigated the role of this microRNA in proliferation and apoptosis, inflammatory processes, immune cell populations, and transforming growth factor-ß/SMAD signaling in a chemically induced (azoxymethane-dextran sulfate sodium) mouse model of colitis-associated colon cancer. We found a higher expression of miR-155 in the tumor region than in nontumor colon tissue of patients with colon cancer. Deletion of miR-155 in mice resulted in a greater number of polyps/adenomas, an increased symptom severity score, a higher grade of epithelial dysplasia, and a decrease in survival. Surprisingly, these findings were associated with an increase in apoptosis in the normal mucosa, but there was no change in proliferation. The protumorigenic effects of miR-155 deletion do not appear to be driven solely by dysregulation of inflammation, as both genotypes had relatively similar levels of inflammatory mediators. The enhanced tumorigenic response in miR-155(-/-) mice was associated with alterations in macrophages and neutrophils, as markers for these populations were decreased and increased, respectively. Furthermore, we demonstrated a greater activation of the transforming growth factor-ß/SMAD pathway in miR-155(-/-) mice, which was correlated with the increased tumorigenesis. Given the multiple targets of miR-155, careful evaluation of its role in tumorigenesis is necessary prior to any consideration of its potential as a biomarker and/or therapeutic target in colon cancer.

Weight loss following diet-induced obesity does not alter colon tumorigenesis in the AOM mouse model.

Obesity presents a significant public health concern given its association with increased cancer incidence, unfavorable prognosis, and metastasis. However, there is very little literature on the effects of weight loss, following obesity, on risk for colon cancer or liver cancer. Therefore, we sought to study whether intentional weight loss through diet manipulation was capable of mitigating colon and liver cancer in mice. We fed mice with a high-fat diet (HFD) comprised of 47% carbohydrates, 40% fat, and 13% protein for 20 wk to mimic human obesity. Subsequently, azoxymethane (AOM) was used to promote colon and liver carcinogenesis. A subset of obese mice was then switched to a low-fat diet (LFD) containing 67.5% carbohydrate, 12.2% fat, and 20% protein to promote intentional weight loss. Body weight loss and excess fat reduction did not protect mice from colon cancer progression and liver dysplastic lesion in the AOM-chemical-cancer model even though these mice had improved blood glucose and leptin levels. Intentional weight loss in AOM-treated mice actually produced histological changes that resemble dysplastic alterations in the liver and presented a higher percentage of F4/80+CD206+ macrophages and activated T cells (CD4+CD69+) in the spleen and lymph nodes, respectively. In addition, the liver of AOM-treated mice exposed to a HFD during the entire period of the experiment exhibited a marked increase in proliferation and pNF-κB activation. Altogether, these data suggest that intentional weight loss following chemical-induced carcinogenesis does not affect colon tumorigenesis but may in fact negatively impact liver repair mechanisms.

The effect of sodium nitroprusside on psychotic symptoms and spatial working memory in patients with schizophrenia: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Sodium nitroprusside (SNP) has been reported to rapidly reduce psychotic symptoms in patients with schizophrenia. This has the potential to revolutionize treatment for schizophrenia. In this study, we tested the hypothesis that SNP leads to a reduction in psychotic symptoms and an improvement in spatial working memory (SWM) performance in patients with schizophrenia. METHOD: This was a single-centre, randomized, double-blind, placebo-controlled trial performed from 27 August 2014 to 10 February 2016 (clinicaltrials.gov identifier: NCT02176044). Twenty patients with schizophrenia aged 18-60 years with a diagnosis of schizophrenia or schizoaffective disorder were recruited from psychiatric outpatient clinics in the South London and Maudsley NHS Trust, London, UK. Baseline symptoms were measured using the Positive and Negative Syndrome Scale (PANSS) and the 18-item Brief Psychiatric Rating Scale (BPRS-18), and SWM was assessed using the CANTAB computerized test. Participants received either an infusion of SNP (0.5 µg/kg per min for 4 h) or placebo and were re-assessed for symptoms and SWM performance immediately after the infusion, and 4 weeks later. RESULTS: SNP did not lead to any reduction in psychotic symptoms or improvement in SWM performance compared to placebo. CONCLUSIONS: Although this study was negative, it is possible that the beneficial effects of SNP may occur in patients with a shorter history of illness, or with more acute exacerbation of symptoms.

The influence of anthropometrics on physical employment standard performance.

BACKGROUND: The Canadian Armed Forces (CAF) recently implemented the Fitness for Operational Requirements of CAF Employment (FORCE), a new physical employment standard (PES). Data collection throughout development included anthropometric profiles of the CAF. AIMS: To determine if anthropometric measurements and demographic information would predict the performance outcomes of the FORCE and/or Common Military Task Fitness Evaluation (CMTFE). METHODS: We conducted a secondary analysis of data from FORCE research. We obtained bioelectrical impedance and segmental analysis. Statistical analysis included correlation and linear regression analyses. RESULTS: Among the 668 study subjects, as predicted, any task requiring lifting, pulling or moving of an object was significantly and positively correlated (r > 0.67) to lean body mass (LBM) measurements. LBM correlated with stretcher carry (r = 0.78) and with lifting actions such as sand bag drag (r = 0.77), vehicle extrication (r = 0.71), sand bag fortification (r = 0.68) and sand bag lift time (r = -0.67). The difference between the correlation of dead mass (DM) with task performance compared with LBM was not statistically significant. CONCLUSIONS: DM and LBM can be used in a PES to predict success on military tasks such as casualty evacuation and manual material handling. However, there is no minimum LBM required to perform these tasks successfully. These data direct future research on how we should diversify research participants by anthropometrics, in addition to the traditional demographic variables of gender and age, to highlight potential important adverse impact with PES design. In addition, the results can be used to develop better training regimens to facilitate passing a PES.

Ethics and health promotion practice: exploring attitudes and practices in Western Australian health organisations.

Issue addressed Evidence-informed practice underpinned by ethics is fundamental to developing the science of health promotion. Knowledge and application of ethical principles are competencies required for health promotion practice. However, these competencies are often inconsistently understood and applied. This research explored attitudes, practices, enablers and barriers related to ethics in practice in Western Australian health organisations. Methods Semistructured, in-depth interviews were conducted with 10 health promotion practitioners, purposefully selected to provide a cross-section of government and non-government organisations. Interviews were recorded, transcribed and then themed. Results The majority of participants reported consideration of ethics in their practice; however, only half reported seeking Human Research Ethics Committee (HREC) approval for projects in the past 12 months. Enablers identified as supporting ethics in practice and disseminating findings included: support preparing ethics applications; resources and training about ethical practice; ability to access HRECs for ethics approval; and a supportive organisational culture. Barriers included: limited time; insufficient resourcing and capacity; ethics approval not seen as part of core business; and concerns about academic writing. Conclusion The majority of participants were aware of the importance of ethics in practice and the dissemination of findings. However, participants reported barriers to engaging in formal ethics processes and to publishing findings. So what? Alignment of evidence-informed and ethics-based practice is critical. Resources and information about ethics may be required to support practice and encourage dissemination of findings, including in the peer-reviewed literature. Investigating the role of community-based ethics boards may be valuable to bridging the ethics-evidence gap.

Influence of Exercise on Inflammation in Cancer: Direct Effect or Innocent Bystander?

We propose the hypothesis that the benefits of exercise on inflammation in cancer are a result of a direct effect on inflammatory cytokines, including interleukin-6, tumor necrosis factor-α, and monocyte chemoattractant protein 1, that are critical for cancer growth as well as a bystander effect of the established relationship between exercise and cancer.

miR-155 deficiency protects mice from experimental colitis by reducing T helper type 1/type 17 responses.

Inflammatory bowel disease (IBD), a chronic intestinal inflammatory condition that affects millions of people worldwide, results in high morbidity and exorbitant health-care costs. The critical features of both innate and adaptive immunity are to control inflammation and dysfunction in this equilibrium is believed to be the reason for the development of IBD. miR-155, a microRNA, is up-regulated in various inflammatory disease states, including IBD, and is a positive regulator of T-cell responses. To date, no reports have defined a function for miR-155 with regard to cellular responses in IBD. Using an acute experimental colitis model, we found that miR-155(-/-) mice, as compared to wild-type control mice, have decreased clinical scores, a reversal of colitis-associated pathogenesis, and reduced systemic and mucosal inflammatory cytokines. The increased frequency of CD4+ lymphocytes in the spleen and lamina propria with dextran sodium sulphate induction was decreased in miR-155(-/-) mice. Similarly, miR-155 deficiency abrogated the increased numbers of interferon-γ expressing CD4+ T cells typically observed in wild-type mice in this model. The frequency of systemic and mucosal T helper type 17-, CCR9-expressing CD4+ T cells was also reduced in miR-155(-/-) mice compared with control mice. These findings strongly support a role for miR-155 in facilitating pro-inflammatory cellular responses in this model of IBD. Loss of miR-155 also results in decreases in T helper type 1/type 17, CD11b+) and CD11c+ cells, which correlated with reduced clinical scores and severity of disease. miR-155 may serve as a potential therapeutic target for the treatment of IBD.

Quercetin supplementation attenuates the progression of cancer cachexia in ApcMin/+ mice.

Although there are currently no approved treatments for cancer cachexia, there is an intensified interest in developing therapies because of the high mortality index associated with muscle wasting diseases. Successful treatment of the cachectic patient focuses on improving or maintaining body weight and musculoskeletal function. Nutraceutical compounds, including the natural phytochemical quercetin, are being examined as potential treatments because of their anti-inflammatory, antioxidant, and anticarcinogenic properties. The purpose of this study was to determine the effect of quercetin supplementation on the progression of cachexia in the adenomatous polyposis coli (Apc)(Min/+) mouse model of colorectal cancer. At 15 wk of age, C57BL/6 and male Apc(Min/+) mice were supplemented with 25 mg/kg of quercetin or vehicle solution mix of Tang juice and water (V) daily for 3 wk. Body weight, strength, neuromuscular performance, and fatigue were assessed before and after quercetin or V interventions. Indicators of metabolic dysfunction and inflammatory signaling were also assessed. During the treatment period, the relative decrease in body weight in the Apc(Min/+) mice gavaged with V (Apc(Min/+)V; -14% ± 2.3) was higher than in control mice gavaged with V (+0.6% ± 1.0), control mice gavaged with quercetin (-2% ± 1.0), and Apc(Min/+) mice gavaged with quercetin (Apc(Min/+)Q; -9% ± 1.3). At 18 wk of age, the loss of grip strength and muscle mass shown in Apc(Min/+)V mice was significantly attenuated (P < 0.05) in Apc(Min/+)Q mice. Furthermore, Apc(Min/+)V mice had an induction of plasma interleukin-6 and muscle signal transducer and activator of transcription 3 phosphorylation, which were significantly (P < 0.05) mitigated in Apc(Min/+)Q mice, despite having a similar tumor burden. Quercetin treatment did not improve treadmill run-time-to-fatigue, hyperglycemia, or hyperlipidemia in cachectic Apc(Min/+) mice. Overall, quercetin supplementation positively affected several aspects of cachexia progression in mice and warrants further exploration as a potential anticachectic therapeutic.

The glucagon-like peptide-1-based therapeutics exenatide and saxagliptin did not cause detrimental effects on the pancreas in mice, rats, dogs and monkeys.

AIMS: Recent reports in the literature have suggested that glucagon-like peptide-1 (GLP-1)-based therapies may lead to increased risk of pancreatic pathology leading to chronic pancreatic injury and pancreatic neoplasia. Extensive non-clinical and clinical safety testing was conducted to support the global development of exenatide twice daily, exenatide once weekly and saxagliptin. Our aim was to integrate these non-clinical data obtained with both mechanisms of GLP-1-based drugs to provide complementary data regarding the potential for drug-induced pancreatic safety signals. METHODS: More than 70 regulated non-clinical toxicology studies in rodents and non-rodents were conducted in accordance with International Conference on Harmonisation and US Food and Drug Administration guidance documents, current industry standards, animal welfare regulations and in compliance with Good Laboratory Practice regulations. Treatment duration was up to 2 years in rodents and up to 12 months in non-rodents using high doses representing large multiples of human exposures (up to 130× for exenatide and 2200× for saxagliptin). Comprehensive pancreas assessments involved more than 2400 pancreata from animals exposed to exenatide and over 1700 pancreata from animals exposed to saxagliptin. RESULTS: Neither exenatide nor saxagliptin treatment resulted in drug-related microscopic changes indicative of acute or chronic adverse effects (including neoplasia) in the endocrine or exocrine pancreas, at doses far exceeding the maximum human systemic exposures. CONCLUSIONS: These data substantially add to the weight of evidence supporting the lack of non-clinical drug-induced pancreatic safety signals in animals exposed to GLP-1-based therapies.

Are military fitness tests safe for members with a total hip arthroplasty?

INTRODUCTION: Canadian Armed Forces (CAF) members must complete an annual fitness evaluation. Members with a total hip arthroplasty (THA) may be at risk of injury during these strenuous tests. To inform CAF policy, we sought expert consensus on the safety of fitness testing for members with a THA. METHODS: We conducted a three-round Delphi study with a panel of hip arthroplasty experts to determine the safety of CAF operational fitness evaluations for members with a THA. The experts evaluated videos of the 10 individual tasks included in the evaluations. RESULTS: All individual tasks were judged to be safe by consensus. One task, which involves digging with a shovel, was considered safe provided that participants avoid deep hip flexion. The nine other tasks were judged to be safe without modifications or interventions. The experts also supported a policy recommendation that would allow members to perform military fitness evaluations if they (1) have a primary THA, (2) had no episodes of instability, (3) are at least 12 months postoperatively and (4) have been cleared by an orthopaedic surgeon and a physiatrist/physiotherapist. CONCLUSION: A panel of arthroplasty experts concluded, based on video analysis, that CAF fitness evaluations are generally safe for members with a THA.

Kenyan Free-Tailed Bats Demonstrate Seasonal Birth Pulse Asynchrony with Implications for Virus Maintenance.

Ecological information on wildlife reservoirs is fundamental for research targeting prevention of zoonotic infectious disease, yet basic information is lacking for many species in global hotspots of disease emergence. We provide the first estimates of synchronicity, magnitude, and timing of seasonal birthing in Mops condylurus, a putative ebolavirus host, and a co-roosting species, Mops pumilus (formerly Chaerephon pumilus). We show that population-level synchronicity of M. condylurus birthing is wide (~ 8.5 weeks) and even wider in M. pumilus (> 11 weeks). This is predicted to promote the likelihood of filovirus persistence under conditions of bi-annual birthing (two births per year). Ecological features underlying the magnitude of the birth pulse-relative female abundance (higher than expected for M. condylurus and lower for M. pumilus, based on literature) and reproductive rate (lower than expected)-will have countering effects on birthing magnitude. Species-specific models are needed to interpret how identified birth pulse attributes may interact with other features of molossid ebolavirus ecology to influence infection dynamics. As a common feature of wildlife species, and a key driver of infection dynamics, detailed information on seasonal birthing will be fundamental for future research on these species and will be informative for bat-borne zoonoses generally.