Endocrine systems in juvenile anadromous and landlocked Atlantic salmon (Salmo salar): seasonal development and seawater acclimation

The present study compares developmental changes in plasma levels of growth hormone (GH), insulin-like growth factor I (IGF-I) and cortisol, and mRNA levels of their receptors and the prolactin receptor (PRLR) in the gill of anadromous and landlocked Atlantic salmon during the spring parr-smolt transformation (smoltification) period and following four days and one month seawater (SW) acclimation. Plasma GH and gill GH receptor (GHR) mRNA levels increased continuously during the spring smoltification period in the anadromous, but not in landlocked salmon. There were no differences in plasma IGF-I levels between strains, or any increase during smoltification. Gill IGF-I and IGF-I receptor (IGF-IR) mRNA levels increased in anadromous salmon during smoltification, with no changes observed in landlocked fish. Gill PRLR mRNA levels remained stable in both strains during spring. Plasma cortisol levels in anadromous salmon increased 5-fold in May and June, but not in landlocked salmon. Gill glucocorticoid receptor (GR) mRNA levels were elevated in both strains at the time of peak smoltification in anadromous salmon, while mineralocorticoid receptor (MR) mRNA levels remained stable. Only anadromous salmon showed an increase of gill 11beta-hydroxysteroid dehydrogenase type-2 (11beta-HSD2) mRNA levels in May. GH and gill GHR mRNA levels increased in both strains following four days of SW exposure in mid-May, whereas only the anadromous salmon displayed elevated plasma GH and GHR mRNA after one month in SW. Plasma IGF-I increased after four days in SW in both strains, decreasing in both strains after one month in SW. Gill IGF-I mRNA levels were only increased in landlocked salmon after 4days in SW. Gill IGF-IR mRNA levels in SW did not differ from FW levels in either strain. Gill PRLR mRNA did not change after four days of SW exposure, and decreased in both strains after one month in SW. Plasma cortisol levels did not change following SW exposure in either strain. Gill GR, 11beta-HSD2 and MR mRNA levels increased after four days in SW in both strains, whereas only the anadromous strain maintained elevated gill GR and 11beta-HSD2 mRNA levels after one month in SW. The results indicate that hormones and receptors of the GH and cortisol axes are present at significantly lower levels during spring development and SW acclimation in landlocked relative to anadromous salmon. These findings suggest that attenuation of GH and cortisol axes may, at least partially, result in reduced preparatory upregulation of key gill ion-secretory proteins, possibly a result of reduced selection pressure for marine adaptations in landlocked salmon.     

Left ventricular non-compaction: insights from cardiovascular magnetic resonance imaging

OBJECTIVES: We aimed to test the diagnostic accuracy of cardiovascular magnetic resonance (CMR) imaging in distinguishing pathological left ventricular non-compaction (LVNC) from lesser degrees of trabecular layering seen in healthy volunteers and, in those with cardiomyopathies and concentric left ventricular hypertrophy, potential differential diagnoses. We hypothesized that pathological trabeculation could be distinguished by determining the ratio of non-compacted to compacted myocardium (NC/C ratio). BACKGROUND: Left ventricular non-compaction is characterized by a non-compacted myocardial layer in the left ventricle. Cardiovascular magnetic resonance images this layer with unprecedented quality, particularly in the ventricular apex, where echocardiography has inherent difficulties. METHODS: We analyzed magnetic resonance cine images, using the 17-segment model in 45 healthy volunteers, 25 athletes, 39 patients with hypertrophic cardiomyopathy and 14 with dilated cardiomyopathy, 17 with hypertensive heart disease, and 30 with aortic stenosis, as well as images from 7 patients previously diagnosed with LVNC whose diagnoses were supported by additional features. RESULTS: Areas of non-compaction were common and occurred more frequently in all groups studied in apical and lateral, rather than in basal or septal, segments. A NC/C ratio of >2.3 in diastole distinguished pathological non-compaction, with values for sensitivity, specificity, and positive and negative predictions of 86%, 99%, 75%, and 99%, respectively. CONCLUSIONS: Left ventricular non-compaction is diagnosed accurately with CMR using the NC/C ratio in diastole.     

Influence of ventricular pacing on myocardial oxygen tension

INTRODUCTION: The influence of heart rate on cardiac output, oxygen consumption, and myocardial activity has been widely investigated. However, the influence of heart rate on myocardial oxygen tension (pO2) remains unclear. Since the introduction of flexible pO2 micro catheters to measure partial oxygen tension in a working muscle, it is possible to investigate the influence of heart rate on myocardial oxygen tension. METHODS: Intraoperatively, a flexible pO2 micro catheter was positioned in the mid-myocardium of 8 male farm pigs. The heart rate was varied via an external pacer from base rate up to fibrillation and the corresponding myocardial pO2 was measured. RESULTS: Within 2 min, the myocardial pO2 adjusted to a change in heart rate. In this animal model, an optimal myocardial pO2 was observed at 109 bpm. A further increase in heart rate led to a decrease in myocardial pO2. When the heart rate was reaching the level of a fibrillation, pO2 dropped to zero. CONCLUSION: In young healthy pigs--with a normal blood vessel regulation and the pharmacologic and experimental conditions used in this study--a significant relation between myocardial pO2 and heart rate was observed. Myocardial oxygen tension increased during cardiac pacing until a heart rate of 109 bpm. Thereafter a decline of pO2 occurred. Each change in heart rate resulted in a corresponding change of pO2 within roughly 2 min.     

Stimulation of collagenase 3 expression in synovial fibroblasts of patients with rheumatoid arthritis by contact with a three-dimensional collagen matrix or with normal cartilage when coimplanted in NOD/SCID mice

OBJECTIVE: To study the expression of collagenase 3 (matrix metalloproteinase 13 [MMP-13]) and collagenase 1 (MMP-1) in synovial fibroblasts from patients with rheumatoid arthritis (RA) when cultured within 3-dimensional collagen gels or coimplanted with normal cartilage in immunodeficient NOD/SCID mice. METHODS: Messenger RNA (mRNA) and protein expression of collagenase 3 and collagenase 1 were characterized in synovial and skin fibroblasts by Northern blot and Western blot analysis. The mRNA expression of both collagenases in cell-cartilage implants in NOD/SCID mice was investigated by in situ hybridization in combination with immunohistochemistry of human fibroblasts. RESULTS: Synovial fibroblasts coimplanted with normal cartilage in NOD/SCID mice deeply invaded adjacent cartilage tissue. In this in vivo system of cartilage destruction, collagenase 3 mRNA was induced in synovial fibroblasts at sites of cartilage erosion, while the expression of collagenase 1 mRNA could not be detected. Culture of synovial fibroblasts within 3-dimensional collagen gels was associated with a marked increase in collagenase 3 mRNA expression and proenzyme production. This stimulatory effect was 1 order of magnitude higher in comparison with a 2-4-fold increase upon treatment with interleukin-1beta or tumor necrosis factor a. In contrast, mRNA expression and proenzyme production of collagenase 1 were increased strongly, and to a similar extent, either by contact with 3-dimensional collagen or by proinflammatory cytokines. CONCLUSION: The expression of collagenase 3, in contrast to that of collagenase 1, is preferentially stimulated in synovial fibroblasts by 3-dimensional collagen rather than by proinflammatory cytokines. The induction of collagenase 3 by cell-matrix interactions represents a potential mechanism contributing to the invasive phenotype of synovial fibroblasts at sites of synovial invasion into cartilage in RA.     

Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses

The tyrosine kinase inhibitors sorafenib and sunitinib are approved for the treatment of patients with malignant diseases. To analyze the possible use of these compounds in combination with immunotherapeutic approaches, we analyzed the effects of both inhibitors on the immunostimulatory capacity of human dendritic cells (DCs) and the induction of primary immune responses in vivo. Sorafenib, but not sunitinib, inhibits function of DCs, characterized by reduced secretion of cytokines and expression of CD1a, major histocompatibility complex, and costimulatory molecules in response to TLR ligands as well as by their impaired ability to migrate and stimulate T-cell responses. These inhibitory effects are mediated by inhibition of PI3 and MAP kinases and NFB signaling. In contrast, sorafenib had no influence on the phenotype and proliferation of T cells. To analyze the effects of both TKIs on cytotoxic T-cell induction in vivo, C57BL/6 mice were pretreated with sorafenib or sunitinib and immunized with OVA_257-264 peptide. Sorafenib, but not sunitinib, application significantly reduced the induction of antigen-specific T cells. Numbers of regulatory T cells were reduced in peripheral blood mononuclear cells from mice treated with sunitinib. These results indicate that sunitinib, but not sorafenib, is suitable for combination with immunotherapeutic approaches for treatment of cancer patients.