Influence of citalopram and environmental temperature on exercise-induced changes in BDNF

Purpose: Serum brain-derived neurotrophic factor (BDNF) is known to increase with exercise. This increase is believed to originate from the brain and it is suggested that monoamines are involved in BDNF regulation. Heat exposure could influence the supposed BDNF output from the brain. Therefore, we hypothesized that administration of a selective serotonin reuptake inhibitor could influence the exercise-induced increase in BDNF, and that peripheral BDNF will be higher when exercise is performed in the heat. Methods: Eleven well-trained males performed 4 experimental trials on a cycle ergometer with citalopram or placebo treatment (20 mg in 12 h) in an environmental temperature of 18 °C or 30 °C. Blood samples (BDNF and cortisol) were taken at 4 time points: at rest, after 60 min at 55% W_max, after a time trial of 30 min at 75% W_max and following 15 min of recovery. Heart rate and core temperature were measured. Results: Performance on the time trial was 20% worse in 30 °C compared to 18 °C (p < 0.01), without influence of citalopram. Serum BDNF was found to be lower under citalopram treatment, while basal cortisol levels were increased (p < 0.05). Exercise triggered an increase in both BDNF and cortisol (p < 0.001). BDNF followed the same pattern as core temperature during exercise, with higher levels of both variables in 30 °C. Cortisol was also increased in 30 °C compared to temperate conditions (p < 0.01). Conclusion: Exercise caused a rise in serum BDNF and cortisol. This increase was enhanced with exercise in the heat. Since permeability of the blood–brain barrier increases with exercise in the heat, the hypothesis was raised that this causes a higher cerebral output of BDNF. Serotonergic stimulation did not increase peripheral BDNF, which was even lower with citalopram administration. Future research should focus on mechanisms behind BDNF increase with exercise.     

Influence of phosphodiesterases and cGMP on cAMP generation and on phosphorylation of phospholamban and troponin I by 5-HT4 receptor activation in porcine left atrium

Our objective was to investigate the role of phosphodiesterase (PDE)3 and PDE4 and cGMP in the control of cAMP metabolism and of phosphorylation of troponin I (TnI) and phospholamban (PLB) when 5-HT₄ receptors are activated in pig left atrium. Electrically paced porcine left atrial muscles, mounted in organ baths, received stimulators of particulate guanylyl cyclase (pGC) or soluble guanylyl cyclase (sGC) and/or specific PDE inhibitors followed by 5-HT or the 5-HT₄ receptor agonist prucalopride. Muscles were freeze-clamped at different moments of exposure to measure phosphorylation of the cAMP/protein kinase A targets TnI and PLB by immunoblotting and cAMP levels by enzyme immunoassay. Corresponding with the functional results, 5-HT only transiently increased cAMP content, but caused a less quickly declining phosphorylation of PLB and did not significantly change TnI phosphorylation. Under combined PDE3 and PDE4 inhibition, the 5-HT-induced increase in cAMP levels and PLB phosphorylation was enhanced and sustained, and TnI phosphorylation was now also increased. Responses to prucalopride per se and the influence thereupon of PDE3 and PDE4 inhibition were similar except that responses were generally smaller. Stimulation of pGC together with PDE4 inhibition increased 5-HT-induced PLB phosphorylation compared to 5-HT alone, consistent with functional responses. sGC stimulation hastened the fade of inotropic responses to 5-HT, while cAMP levels were not altered. PDE3 and PDE4 control the cAMP response to 5-HT₄ receptor activation, causing a dampening of downstream signalling. Stimulation of pGC is able to enhance inotropic responses to 5-HT by increasing cAMP levels, while sGC stimulation decreases contraction to 5-HT cAMP independently.     

Immunogenicity and safety of the quadrivalent meningococcal serogroups A, C, W-135 and Y tetanus toxoid conjugate vaccine (MenACWY-TT) in 2–10-year-old children: results of an open, randomised, controlled study

In Europe, the introduction of monovalent meningococcal serogroup C (MenC) conjugate vaccines has resulted in a significant decline in MenC invasive disease. However, given the potential for strain evolution and increasing travel to areas of high endemicity, protection against additional serogroups is needed. In this study, the immunogenicity, measured by a serum bactericidal activity assay using rabbit complement (rSBA), and the safety of a quadrivalent meningococcal serogroups A, C, W-135 and Y tetanus toxoid conjugate vaccine (MenACWY-TT) were compared to that of a licensed monovalent MenC conjugate vaccine (MenC-CRM₁₉₇) in children 2–10 years of age. Children were randomised (3:1) to receive a single dose of either MenACWY-TT or MenC-CRM₁₉₇. Non-inferiority of the immunogenicity of MenACWY-TT versus MenC-CRM₁₉₇ in terms of rSBA-MenC vaccine response was demonstrated. Exploratory analyses suggested that rSBA-MenC geometric mean titres adjusted for pre-vaccination titres were lower in children vaccinated with MenACWY-TT compared to MenC-CRM₁₉₇. Nevertheless, at 1 month post-vaccination, ≥99.3 % of the children who received MenACWY-TT had rSBA titres ≥1:128 for each of the four vaccine serogroups, which is the more conservative correlate of protection. The reactogenicity and safety profile of MenACWY-TT was clinically acceptable and no serious adverse events considered related to vaccination were reported throughout the study. Conclusion: When administered to European school-age children, MenACWY-TT has a clinically acceptable safety profile and, when compared with MenC-CRM₁₉₇, the potential to broaden protection against meningococcal disease caused by serogroups A, W-135 and Y while maintaining protection against MenC. This study has been registered at www.clinicaltrials.gov NCT00674583.     

Organotropism and prognostic marker discordance in distant metastases of breast carcinoma: fact or fiction? A clinicopathologic analysis

Prior studies have suggested that the type of breast cancer influences the location of distant metastases ("organotropism") and that there may be discordance of estrogen receptor and human epidermal growth factor receptor 2 (Her2) expression between primaries and metastases. Our aims were to investigate the relationship between tumor type and metastatic site and to compare biomarker expression between primary and metastatic tumors. We retrospectively reviewed 102 biopsy-proven cases of breast cancer metastatic to distant sites from 2000 to 2010 and 34 corresponding primaries for histologic subtype, grade, lymphovascular invasion, lymph node metastasis, and expression of estrogen receptor and Her2. Most metastases were of ductal (88) and lobular (11) histologic types. Available data on primaries indicated that the majority were grade III with positive lymph node metastasis and lymphovascular invasion. Biomarkers on 73 metastases showed 37 estrogen receptor positive/Her2-, 6 estrogen receptor positive/Her2+, 8 estrogen receptor negative/Her2+, and 22 estrogen receptor negative/Her2-. The most common metastatic sites were the lung (26%), bone (32%), and liver (21%). We found no association between estrogen receptor/Her2 profile and metastatic site (P = .16). When compared with ductal carcinoma, lobular carcinoma showed a unique metastatic pattern to gastrointestinal tract/gynecologic sites (P = .014). Of 34 cases with paired prognostic markers for primary and metastatic sites, 7 (20%) demonstrated discordance in estrogen receptor-positive/Her2 profile between the primary and the metastasis. Because the estrogen receptor-positive/Her2 profile of metastatic breast cancer did not always match that of the primary tumor, it is important to repeat the prognostic markers of metastasis.     

Adenocarcinoma arising in an ectopic mediastinal pancreas

Pancreatic ectopia in the mediastinum is rare, and there are no reports that it has ever given rise to malignancy. Here we report a case of adenocarcinoma arising in ectopic pancreatic tissue in the mediastinum of a 66-year-old woman. The tumor arose in a partially cystic and partially solid ectopic pancreas containing both exocrine and endocrine components. Thorough clinical examination and clinical follow-up did not reveal other primary sites. The tumor was partially resected but metastasized to the anterior sternum 6 months later and was re-excised. No other similar cases of primary mediastinal pancreatic adenocarcinoma are on record in medical literature.     

CD34-derived dendritic cells transfected ex vivo with HIV-Gag mRNA induce polyfunctional T-cell responses in nonhuman primates

The pivotal role of DCs in initiating immune responses led to their use as vaccine vectors. However, the relationship between DC subsets involved in antigen presentation and the type of elicited immune responses underlined the need for the characterization of the DCs generated in vitro. The phenotypes of tissue-derived APCs from a cynomolgus macaque model for human vaccine development were compared with ex vivo-derived DCs. Monocyte/macrophages predominated in bone marrow (BM) and blood. Myeloid DCs (mDCs) were present in all tested tissues and were more highly represented than plasmacytoid DCs (pDCs). As in human skin, Langerhans cells (LCs) resided exclusively in the macaque epidermis, expressing CD11c, high levels of CD1a and langerin (CD207). Most DC subsets were endowed with tissue-specific combinations of PRRs. DCs generated from CD34(+) BM cells (CD34-DCs) were heterogeneous in phenotype. CD34-DCs shared properties (differentiation and PRR) of dermal and epidermal DCs. After injection into macaques, CD34-DCs expressing HIV-Gag induced Gag-specific CD4(+) and CD8(+) T cells producing IFN-γ, TNF-α, MIP-1β, or IL-2. In high responding animals, the numbers of polyfunctional CD8(+) T cells increased with the number of booster injections. This DC-based vaccine strategy elicited immune responses relevant to the DC subsets generated in vitro.     

A comparison of survival with and without extracorporeal life support treatment for severe poisoning due to drug intoxication

Background

The use of extracorporeal life support (ECLS) as a treatment for severe cardiovascular impairment due to poisoning is unclear. Therefore, we conducted a retrospective cohort analysis to compare survival among critically ill poisoned patients treated with or without ECLS.

Methods

All consecutive patients admitted into 2 university hospitals in northwestern France over the past decade for persistent cardiac arrest or severe shock following poisoning due to drug intoxication were included. ECLS was preferentially performed in 1 of the 2 centers.

Results

Sixty-two patients (39 women, 23 men; mean age 48 ± 17 years) fulfilled inclusion criteria: 10 with persistent cardiac arrest and 42 with severe shock. Fourteen patients were treated with ECLS and 48 patients with conventional therapies. All subjects received vasopressor and fluid loading. Patients treated with or without ECLS at ICU admission had comparable drug ingestion histories, Simplified Acute Physiology Score (SAPS II score) (66 ± 18), Sequential Organ Failure Assessment (SOFA) score (median: 11 [IQR, 9–13]), Glasgow Coma Scale score (median: 3 [IQR, 3–11]), need for ventilator support (n = 56) and extra renal support (n = 23). Thirty-five (56%) patients survived: 12/14 (86%) ECLS patients and 23/48 (48%) non-ECLS patients (p = 0.02, by Fisher exact test). None of the patients with persistent cardiac arrest survived without ECLS support. Based on admission data, beta-blocker intoxication (p = 0.02) was also associated with lower mortality. In multivariate analysis, adjusting for SAPS II and beta-blocker intoxication, ECLS support remained associated with lower mortality [Adjusted Odds Ratio, 0.18; 95% CI, 0.03–0.96; p = 0.04].

Conclusion

In the absence of response to conventional therapies, we consider that ECLS may improve survival in critically ill poisoned patients experiencing cardiac arrest and severe shock.