Activation in vagal afferents and central autonomic pathways: early responses to intestinal infection with Campylobacter jejuni

Abundant evidence now supports the idea that multiple pathways or mechanisms underlie communication from the immune system to the brain. The presence of a variety of mechanisms suggests that they may each contribute something different to immunosensory signaling. For instance, brain mediated immune signal transduction is dependent upon the presence of circulating mediators whereas peripheral sensory nerves are more likely to be important early on in an infection, prior to elevation of circulating cytokines, or in local infections within the terminal fields of these nerves. To test the hypothesis that local infection in the gut activates vagal sensory neurons, we assessed expression of the neuronal activation marker c-Fos in neurons in the vagal sensory ganglia and in the primary sensory relay nucleus for the vagus, the nucleus of the solitary tract (nTS) in mice treated orally either with saline or live Campylobacter jejuni (C. jejuni). Male CF1 mice were inoculated orally with either C. jejuni or saline, and c-Fos expression in the vagal sensory neurons and brain 4-12 h later was assessed via immunohistochemistry. Oral inoculation with C. jejuni led to a significant increase in c-Fos expression in neurons bilaterally in the vagal ganglia, in the absence of elevated levels of circulating pro-inflammatory cytokines. C. jejuni treatment activated neurons in the nTS, as well as in brain regions associated with primary viscerosensory pathways and the central autonomic network. These findings provide evidence that peripheral sensory neurons contribute an early signal to the brain regarding potential pathogens.     

Age-associated changes in the expression pattern of cyclooxygenase-2 and related apoptotic markers in the cancer susceptible region of rat prostate

Senescence-associated changes in the prostate are believed to play an important role in the genesis of prostate cancer. In order to provide further information on how aging increases the prostate susceptibility to cancer, we examined the pattern of cyclooxygenase (COX)-2 expression and the concomitant alterations in prostaglandin E(2) (PGE(2)) synthesis in the prostate glands of 4-, 10-, 50- and 100-week-old Fischer 344 rats. This was carried out in the prostatic areas where hormone-induced tumors arise, namely the periurethral ducts of the dorsolateral prostate (DLP). Age-associated changes were also evaluated for pro- and anti-apoptotic factors linked to COX-2 signaling and known to be involved in the normal development of the prostate gland as well as in carcinogenesis. COX-2 expression was increased in the DLP in an age-dependent manner where senescent rats had >3-4-fold higher COX-2 mRNA and protein levels than their juvenile counterparts (P<0.05). The age-related changes in COX-2 were accompanied by a similar up-regulation in the PGE(2) synthesis. Evaluation of mediators of apoptotic signaling showed a significant (P<0.05) decline in the expression levels of the pro-apoptotic BAX (>6-fold) and peroxisome proliferator-activated receptor gamma (>3-fold) and in caspase-3 activity (>2-fold) and an up-regulation of the anti-apoptotic Bcl(2) (>8-fold), PKCalpha (>2-fold) and pAkt (>4-fold) in the 100-week-old rats versus the 4-week-old animals. There was an approximately 15-fold age-dependent decrease in the pro-apoptotic ratio BAX:Bcl(2) and an increase in the anti-apoptotic variable PKCalpha(*)Bcl(2)/BAX in the senescent rats compared with the juvenile ones. These results suggest that increased COX-2 expression can be linked to the decline in the pro-apoptotic signaling in the prostate gland during aging. Subsequently, COX-2 inhibitors can be considered as a promising class of agents to attenuate the increased cell survival and, hence, protect against tumorigenesis in the aging prostate.     

Epidemiologic evaluation of the immunity against hepatitis B in Alexandria, Egypt

Background: Hepatitis B (HB) vaccine represents one of the major achievements in the 20th century. The most important epidemiologic factor affecting the chronic carrier rate is age of infection. The earlier in life an infection occurs, the higher the probability that this infection will result in chronic carriage. Methods: A seroepidemiologic study was conducted to examine the impact of HB vaccination on the carrier state among a vaccinated group of children (1000) compared to a non-vaccinated group (500) aged 6 years in Alexandria, Egypt. Results: The rate of HbsAg positivity among the vaccinated group was found to be 0.8% compared to 2.2% among the non-vaccinated group. The study showed that the efficacy of HB vaccine in preventing the carriage of HbsAg, 5 years after full course vaccination, was estimated to be around 67%. However, long-term monitoring should continue to confirm the efficacy of the vaccine in preventing chronic carrier state. On the other hand, studying the exposure to some risk factors associated with hepatitis B virus (HBV) infection revealed more or less a similar pattern of exposure among both vaccinated and unvaccinated children. Conclusion: It can be concluded that the significantly lower rate of HbsAg positivity among the vaccinated compared to the rate among the non-vaccinated is attributed to the preventive effect of the vaccine.     

PoleStriding exercise and vitamin E for management of peripheral vascular disease

PURPOSE: The purpose of this investigation was to evaluate the efficacy of PoleStriding exercise (a form of walking that uses muscles of the upper and lower body in a continuous movement similar to cross-country skiing) and vitamin E (alpha-tocopherol) to improve walking ability and perceived quality of life (QOL) of patients with claudication pain secondary to peripheral arterial disease (PAD). METHODS: Fifty-two subjects were randomized into four groups: PoleStriding with vitamin E (N = 13), PoleStriding with placebo (N= 14), vitamin E without exercise (N= 13), and placebo without exercise (N = 12). The dose of vitamin E was 400 IU daily. Only the PoleStriding with vitamin E and PoleStriding with placebo groups received PoleStriding instruction and training. Assignment to vitamin E or placebo was double blind. Subjects trained three times weekly for 30-45 min (rest time excluded). Individuals in vitamin E and placebo groups came to the laboratory biweekly for ankle blood-pressure measurements. RESULTS: Results of this randomized clinical trial provide strong evidence that PoleStriding significantly (P< 0.001) improved exercise tolerance on the constant work-rate and incremental treadmill tests. Ratings of perceived claudication pain were significantly less after the PoleStriding training program (P= 0.02). In contrast, vitamin E did not have a statistically significant effect on the subjects' ratings of perceived leg pain (P= 0.35) or treadmill walking duration ( P= 0.36). Perceived distance and walking speed (Walking Impairment Questionnaire) and perceived physical function (Rand Short Form-36) improved in the PoleStriding trained group only (P< 0.001, 0.022 and 0.003, respectively). CONCLUSION: PoleStriding effectively improved the exercise tolerance and perceived QOL of patients with PAD. Little additional benefit to exercise capacity was realized from vitamin E supplementation.     

Expression of cyclooxygenase-2 and peroxisome proliferator-activated receptor-gamma and levels of prostaglandin E2 and 15-deoxy-delta12,14-prostaglandin J2 in human breast cancer and metastasis

Cyclooxygenase-2 (COX-2) expression and peroxisome proliferator-activated receptor-gamma (PPARgamma) inactivation are linked to increased risk of human breast cancer. The purpose of our study was to examine the relationship between COX-2 (with the resulting prostaglandins E(2), PGE(2)) and PPARgamma (and its natural endogenous ligand 15-Deoxy-Delta(12,14)-prostaglandin J(2), 15d-PGJ(2)) at various stages during the development of human breast cancer and its progression to metastasis. Human breast tissue specimens were collected from normal breasts or from individuals with fibrocystic disease and served as controls (n = 22). Tissues were also collected from uninvolved (n = 25), tumor (n = 25) and lymph node metastasis (n = 15) regions from breast cancer patients. COX-2 and PPARgamma mRNA expression were increased and downregulated, respectively, in tissues from cancer patients compared to controls. Metastatic tissues tended to have higher alterations compared to non-metastatic tissues (p < 0.05). These altered expressions in COX-2 and PPARgamma were paralleled by increases in the tissue levels of PGE(2) and decreases in 15d-PGJ(2). A significant inverse correlation was found between PGE(2) and 15-d-PGJ(2) (r = -0.51, p < 0.05). Significant correlations (p < 0.05) were also obtained between COX-2 and PPARgamma mRNA (inverse, r = -0.72) and between COX-2 and PGE(2) (direct, r = 0.68). Increases in COX-2 mRNA expression and levels of PGE(2) and down-regulation of PPARgamma mRNA expression and 15d-PGJ(2) levels were characterized as predictors of breast cancer risk (p < 0.05). Our results suggest that the altered expression of COX-2 and PPARgamma and the subsequent modulation in the tissue levels of PGE(2) and 15-d-PGJ(2) may influence the development of human breast cancer and its progression to metastasis.     

Deactivation of alveolar macrophages in septic neutropenic ARDS

STUDY OBJECTIVES: Neutrophils often have been involved in the pathophysiology of ARDS. However, authentic ARDS has been described in patients with severe neutropenia, suggesting the presence of other potential mechanisms that are responsible of this syndrome. Alveolar macrophages (AMs) could be involved in the development of ARDS, and so we decided to study AM activation in neutropenic patients. PATIENTS: We designed a prospective study and enrolled two subgroups of consecutive patients (group A, 18 patients; group B, 22 patients) with septic ARDS. In the first period, 7 of 18 patients were neutropenic, and in the second period 10 of 22 patients were neutropenic. All neutropenic patients were treated with granulocyte colony-stimulating factor (G-CSF). Measurements and results: In group A, BAL fluid samples were analyzed for differential and total cell counts, and alveolar activation marker expression (ie, human leukocyte antigen [HLA]-DR locus) was determined. Basal and lipopolysaccharide (LPS)-stimulated production of tumor necrosis factor, interleukin (IL)-1 beta, IL-6, and IL-10 was evaluated in group B. In neutropenic patients, the BAL fluid total cell count and the neutrophil absolute count was significantly lower compared to those in nonneutropenic patients (p = 0.029 and p = 0.046, respectively). HLA-DR expression on AMs was significantly decreased (p = 0.016), and the percentage of AMs expressing HLA-DR was also significantly lower (p = 0.041). In neutropenic patients, the mean percentage of AMs expressing HLA-DR was significantly lower in deceased patients compared to survivors (30 +/- 7 vs 43 +/- 1, respectively; p = 0.047). Basal AMs released cytokines was comparable between the two groups; however, LPS stimulation yielded a deactivation of AMs in neutropenic patients. CONCLUSION: These results suggest a deactivation and/or hypoactivation of AMs in septic ARDS patients. This deactivation/hypoactivation could be linked to the use of G-CSF as this molecule has been shown to generate a down-regulation of HLA-DR expression.