Voluntary wheel running produces resistance to inescapable stress-induced potentiation of morphine conditioned place preference

In rodents, exposure to acute inescapable, but not escapable, stress potentiates morphine conditioned place preference (CPP), an effect that is dependent upon hyperactivation of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN). Six weeks of voluntary wheel running constrains activation of DRN 5-HT neurons during exposure to inescapable stress. Six weeks of voluntary wheel running before inescapable stress blocked stress-induced potentiation of morphine CPP.     

Does prophylactic subcutaneous heparin increase the risk of wound infection after colorectal surgery?

Chemical prophylaxis using unfractionated heparin (UH) and low-molecular weight heparin is used in surgical patients to prevent venous thromboembolism. There is some evidence that prophylactic doses of heparin may increase the rate of surgical site infection (SSI) after elective orthopedic procedures. Little is known regarding the effect of heparin on SSI after colorectal procedures. We performed this study to study the effect of prophylactic unfractionated heparin on the rate of SSI after colorectal procedures. We did a retrospective analysis of 155 consecutive cases of patients of a single colorectal surgeon who underwent colorectal resection. Subcutaneous unfractionated heparin was given to 52 patients (29%). The rate of SSI in the group that received UH was 33 per cent versus 28 per cent in the group that did not receive UH (P = 0.31). There was also no significant effect of prophylactic heparin on SSI noted among any patient subgroup. The use of prophylactic unfractionated heparin after colorectal procedures does not seem to increase the rate of surgical site infection.     

Loss of androgen receptor expression is not associated with pathological stage, grade, gender or outcome in bladder cancer: a large multi-institutional study

Study Type – Prognosis (multi‐centre cohort)
Level of Evidence 1b What’s known on the subject? and What does the study add? More men than women develop bladder cancer (BC) but reasons why are unclear. Recent findings have implicated androgens, androgen receptors (AR) and AR expression in BC. Previous studies showed that a significant loss of AR expression was associated with aggressive BC. However, these results have been gathered on limited series of patients. We analyzed the expression of AR in BC and its correlation with gender, grade, stage and clinical outcome on a large multi‐institutional (Toronto/Dallas) cohort. In contrast to previous reports, our data do not suggest that loss of AR expression is gender‐related nor associated with invasive BC. In fact, in this large cohort, we showed that AR positivity is actually uncommon in BC, that there are no differences in expression among high and low grade tumours and no statistically significant differences between muscle‐invasive AR‐positive and AR‐negative cases in time to death, or time to recurrence.

OBJECTIVE

? To investigate androgen receptor (AR) expression in a large series of patients with bladder cancer (BC) because data on a limited number of patients showed that loss of AR expression was associated with invasive BC.

PATIENTS AND METHODS

? A total of 472 patients with urothelial bladder carcinoma (UBC) from two institutional centres (Toronto and Dallas) were analysed. Tissue microarrays comprising both non‐muscle‐invasive UBC (n= 167) and muscle‐invasive UBC (n= 305) were accrued and immunohistochemical staining for AR was performed. ? We used bright‐field microscopy imaging coupled with advanced colour detection software to detect, classify and count stained cellular objects and manual scoring. ? Results obtained in Dallas were blindly reviewed and validated in Toronto and samples randomly chosen were further analysed in Rochester, NY, USA.

RESULTS

? The AR were positively expressed in 61/472 (12.9%) bladder tumours. No statistically significant difference in AR expression between men and women was observed. ? Only 9.0% of non‐muscle‐invasive BC expressed the AR compared with 15.1% of muscle‐invasive tumours (P= 0.059). The highest percentage of AR positivity (28.9% of cases) was found in T2 tumours. ? There was no statistically significant difference in death from BC, time to death, or time to recurrence between AR‐positive and AR‐negative cases.

CONCLUSION

? In contrast to previous reports, based on our large BC series, we did not observe a decrease in AR protein expression in bladder tumours with increased pathological stage. Our data do not suggest that loss of AR expression is gender‐related nor is it associated with invasive BC.     

The impact of acute-stressor exposure on splenic innate immunity: a gene expression analysis

Exposure to intense, acute-stressors modulates immune function. We have previously reported, for example, that exposure to a single session of inescapable tailshock suppresses acquired and potentiates innate immune responses mediated by the spleen. The mechanisms for these changes remain unknown, however, they likely involve stress-induced modulation of cytokines. Cytokines operate in coordinated networks that include other immunoregulatory factors. Broad-scoped analyses are required to gain an understanding of the net-impact of stress on these immunoregulatory factors and the immune system. The goal of this study, therefore, is to examine the impact of acute-stressor exposure on network-wide changes in splenic immunoregulatory factor expression. One hundred and sixty-one genes linked to innate immune responses were quantified in the spleen following exposure to tailshock using an RT-PCR based gene array. Expression changes in 17 of the measured genes were confirmed using individual RT-PCR reactions. Further assessment of the expression changes using Exploratory Gene Association Networks (EGAN) identified important ontologies, processes and pathways that are indicative of a broader impact of stress on the immune system. Interestingly, EGAN identified several linkages between immunoregulatory factors that may be important in explaining previous results concerning the functional consequences of stress on splenic immunity. Additional processes, some of which are novel to this study, were also uncovered that may be important in directing future studies examining the impact of stress on the immune system. In this way, these analyses provide a better understanding of how acute stressor exposure modulates splenic immunity and may function as predictive tool for future related studies.     

NOD2 variants and antibody response to microbial antigens in Crohn's disease patients and their unaffected relatives

BACKGROUND & AIMS: The Cdcs1 locus of the C3Bir mouse confers severe colitis associated with a decrease in innate immune function and an increase in adaptive T-cell responses to commensal bacterial products. The aim of our study was to determine if defects in innate immunity are similarly associated with increased adaptive immune responses to microbial antigens in Crohn's disease patients. METHODS: Sera from 732 patients, 220 unaffected relatives, and 200 healthy controls were tested for antibodies to oligomannan, the Pseudomonas fluorescens-related protein, Escherichia coli outer membrane porin C, CBir1 flagellin, and DNA from the same subjects was tested for 3 Crohn's disease-associated variants of the NOD2 gene, and 5 toll-like receptor (TLR) 2, 2 TLR4, and 2 TLR9 variants. The magnitude of responses to microbial antigens was examined according to variant status. RESULTS: NOD2 variant carriage increased in frequency with increasing number of positive antibodies and increasing cumulative quantitative response as measured by quartile sum (P for trend, .0008 and .0003, respectively). Mean antibody and quartile sums were higher for patients carrying any NOD2 variant versus those carrying none (2.24 vs 1.92 and 10.60 vs 9.72; P = .0008 and P = 0.0003, respectively). The mean quartile sum was higher for unaffected relatives carrying any NOD2 variant versus those carrying none (10.67 vs 9.75, respectively; P = .02). No association was found between any TLR variant and the magnitude of response. CONCLUSIONS: Patients with Crohn's disease and unaffected relatives carrying variants of the NOD2 gene have increased adaptive immune responses to microbial antigens.     

Learned helplessness is independent of levels of brain-derived neurotrophic factor in the hippocampus

Reduced levels of brain-derived neurotrophic factor (BDNF) in the hippocampus have been implicated in human affective disorders and behavioral stress responses. The current studies examined the role of BDNF in the behavioral consequences of inescapable stress, or learned helplessness. Inescapable stress decreased BDNF mRNA and protein in the hippocampus of sedentary rats. Rats allowed voluntary access to running wheels for either 3 or 6 weeks prior to exposure to stress were protected against stress-induced reductions of hippocampal BDNF protein. The observed prevention of stress-induced deceases in BDNF, however, occurred in a time course inconsistent with the prevention of learned helplessness by wheel running, which is evident following 6 weeks, but not 3 weeks, of wheel running. BDNF suppression in physically active rats was produced by administering a single injection of the selective serotonin reuptake inhibitor fluoxetine (10 mg/kg) just prior to stress. Despite reduced levels of hippocampal BDNF mRNA following stress, physically active rats given the combination of fluoxetine and stress remained resistant against learned helplessness. Sedentary rats given both fluoxetine and stress still demonstrated typical learned helplessness behaviors. Fluoxetine by itself reduced BDNF mRNA in sedentary rats only, but did not affect freezing or escape learning 24 h later. Finally, bilateral injections of BDNF (1 mug) into the dentate gyrus prior to stress prevented stress-induced reductions of hippocampal BDNF but did not prevent learned helplessness in sedentary rats. These data indicate that learned helplessness behaviors are independent of the presence or absence of hippocampal BDNF because blocking inescapable stress-induced BDNF suppression does not always prevent learned helplessness, and learned helplessness does not always occur in the presence of reduced BDNF. Results also suggest that the prevention of stress-induced hippocampal BDNF suppression is not necessary for the protective effect of wheel running against learned helplessness.