Induction of bradycardia in trout by centrally administered corticotropin-releasing-hormone (CRH)

The cardiovascular effects of centrally and peripherally administered synthetic salmon corticotropin-releasing-hormone (CRH), a member of a family of stress-related neuropeptides, were investigated in the unanesthetized trout, Oncorhynchus mykiss. In group 1, trout bearing a cannula in the dorsal aorta, neither intracerebroventricular (i.c.v.) nor intra-arterial (i.a.) injections of CRH produced any significant change in mean heart rate (HR) and mean dorsal aortic blood pressure. These results stand in contrast to the previously reported hypertensive effects of i.a. and i.c.v. injections of trout urotensin-I. In group 2, non-cannulated trout bearing two subcutaneous electrocardiographic electrodes, conditions that are considered to be less stressful to the animals, the baseline level of HR was significantly reduced compared to the corresponding value for cannulated trout. In these trout, no significant change occurred in the HR after i.c.v. administration of 1 pmol of CRH. However, i.c.v. injection of 5 pmol of CRH caused a 12% (P<0.01) decrease in HR during the 20-25 min post-injection period. In addition, the heart rate variability (HRV), a marker of vagal input to the heart, was increased by 120%. The CRH antagonist, CRH-(9-41)-peptide alone had no effect on HR or HRV but blocked CRH-induced bradycardia. In the non-cannulated trout, i.c.v. injection of trout urotensin-I (5 pmol) produced no significant change in HR and HRV. In contrast, i.c.v. administration of angiotensin II (5 pmol) elicited a highly significant 33% (P<0.001) increase in the mean HR as well as inducing a marked (64%) reduction in HRV. Our results suggest that picomolar doses of CRH act centrally to evoke a bradycardia by a probable mechanism that involves enhancement of the parasympathetic drive to the heart.     

Biomimetic organization: Octapeptide self-assembly into nanotubes of viral capsid-like dimension

The controlled self-assembly of complex molecules into well defined hierarchical structures is a promising route for fabricating nanostructures. These nanoscale structures can be realized by naturally occurring proteins such as tobacco mosaic virus, capsid proteins, tubulin, actin, etc. Here, we report a simple alternative method based on self-assembling nanotubes formed by a synthetic therapeutic octapeptide, Lanreotide in water. We used a multidisciplinary approach involving optical and electron microscopies, vibrational spectroscopies, and small and wide angle x-ray scattering to elucidate the hierarchy of structures exhibited by this system. The results revealed the hexagonal packing of nanotubes, and high degree of monodispersity in the tube diameter (244 A) and wall thickness (approximately equal to 18 A). Moreover, the diameter is tunable by suitable modifications in the molecular structure. The self-assembly of the nanotubes occurs through the association of beta-sheets driven by amphiphilicity and a systematic aromatic/aliphatic side chain segregation. This original and simple system is a unique example for the study of complex self-assembling processes generated by de novo molecules or amyloid peptides.     

The vagus is inhibitory of the late postprandial insulin secretion in conscious pigs

The vagus is involved in the cephalic phase of insulin secretion but its role in the meal absorption phase of insulin release remains to be defined. The aim of this study was therefore to evaluate the role of the vagus in the early and the late meal absorption phases of insulin secretion. In six pigs, venous insulin profiles were compared in intact animals, after ventral or dorsal vagal trunk section, and after section of both vagal trunks (truncal vagotomy). Since gastric emptying could be modified by vagotomy, it was recorded concomitantly by gamma scintigraphy. Semi-solid (porridge) and liquid (glucose 10%) meals were tested. Truncal vagotomy significantly increased insulin release compare to intact animals after glucose (63.8%) and porridge (174.4%) meals in the early and the late absorption phases of insulin secretion, respectively. For the glucose meal, this effect could be explained by a vagally mediated change in gastric emptying rate, since insulin concentrations for a similar amount of nutrient propelled to the duodenum were not different in intact and truncal vagotomized animals. In contrast, after the porridge meal, truncal vagotomy was associated with a second, later occurring increase in circulating insulin, which could not be explained by changes in gastric emptying rate. These results demonstrate for the first time an inhibitory role of the vagus in the late meal absorption phase of insulin release.     

The roles of the cerebellum and basal ganglia in timing and error prediction

Recent evidence that the cerebellum and the basal ganglia are activated during the performance of cognitive and attention tasks challenges the prevailing view of their primary function in motor control. The specific roles of the basal ganglia and the cerebellum in cognition, however, have been difficult to identify. At least three functional hypotheses regarding their roles have been proposed. The first hypothesis suggests that their main function is to switch attentional set. The second hypothesis states that they provide error signals regarding stimuli or rewards. The third hypothesis is that they operate as an internal timing system, providing a precise representation of temporal information. Using functional magnetic resonance imaging, we tested these three hypotheses using a task-switching experiment with a 2 x 2 factorial design varying timing (random relative to fixed) and task order (unpredictable relative to predictable). This design allowed us to test whether switching between tasks, timing irregularity and/or task order unpredictability activate the basal ganglia and/or the cerebellum. We show that the cerebellum is primarily activated with timing irregularity while the anterior striatum is activated with task order unpredictability, supporting their distinctive roles in two forms of readjustment. Task order unpredictability alone, independent of reward delivery, is sufficient to induce striatal activation. In addition, activation of the cerebellum and basal ganglia were not specific to switching attention because these regions were both activated during switching between tasks and during the simultaneous maintenance of two tasks without switching between them.     

Matrix-directed regulation of pericellular proteolysis and tumor progression

The microenvironment of cancer cells, composed of extracellular matrix (ECM) macromolecules, plays a pivotal function in tumor progression. ECM preexisting modules or cryptic sites revealed by partial enzymatic hydrolysis positively or negatively regulate matrix metalloproteinase (MMP) expression and activation, further influencing matrix invasion by cancer cells. Pericellular activation of gelatinase A (MMP-2) proceeds via the formation of a complex involving its inhibitor, TIMP-2, its activator(s), MT-MMPs and alphavbeta3 integrin forming a docking system. This proteinase has been invariably linked to cancer cell invasive potential and is often predictive of a poor survival. MMP-2 degrades most ECM macromolecules and appears to act as a main 'decryptase'. ECM modulation of MMP-2 activation pathway thus influences angiogenesis and tumor growth. For instance the noncollagenous domain of alpha3 chain of type IV collagen, through alphavbeta3 integrin binding, inhibits both MT1-MMP and alphavbeta3 integrin expression from melanoma cells and empedes cell migration and proliferation. At the opposite, a particular module in elastin (VGVAPG) with type VIII beta turn conformation stimulates MT1-MMP and proMMP-2 activation through binding to S-gal elastin receptor, and increases the matrix invasive capacity of several cancer cell lines and endothelial cells. Endocytosis emerges as a main mechanism controlling MMP-2, and also other MMPs; it proceeds via the formation of a MMP-thrombospondin(s) complex further recognized by the LRP scavenger receptor. ECM undergoes conspicuous variations with aging linked to alterations of tissue organization and post-translational modifications of matrix constituents that modify cell-matrix interactions and MMP-2 activation pathway.     

Brachial fluoroscopically guided implantation of venous port devices in oncology patients

Access to the central venous circulation for chemotherapy infusion has traditionally been achieved surgically via the subclavian or jugular routes. With ongoing improvements in technical management, alternative means of central venous access have been developed such as arm-port or forearm-port implantation under imaging guidance. Venous arm port devices implantation was attempted in 200 cancer patients under fluoroscopic guidance, after arm venography. The 4% failure rate was due to the inability to perform the arm venogram, venous spasm or presence of a large contrast medium hematoma (rolling vein). Median follow-up was 180 days (range 4-671) and the complication rate was 13.3% (0.7/1,000 patients-day). Twenty-six complications occurred and were due to venous thrombosis (n = 3), large brachial hematoma (n = 1), local (n = 7) and systemic sepsis (n = 1), skin dehiscence (n = 4), fissuration (n = 4), dislocation (n = 2), obstruction (n = 2), and twist of the port (n = 2), leading to a 8.5% removal rate. Main indications for arm port implantation may be breast cancer, previous arm or cervical venous thrombosis, morbid obesity, respiratory insufficiency, previous surgical failure and the irradiated neck.     

Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis (AH): individual data analysis of the last three randomized placebo controlled double blind trials of corticosteroids in severe AH

BACKGROUND/AIMS: Controversy surrounding the efficacy of corticosteroids in severe alcoholic hepatitis (AH) persists. The aims of our study were: (a) to analyze individual data of patients with severe AH discriminant function (DF)> or =32 from the last three randomized controlled trials; and (b) to identify the independent prognostic factors associated with short-term survival. METHODS: Individual data were collected from the three principal investigators. Survival analysis was performed at 28 days using the Kaplan-Meier method and log-rank test. The independent prognostic values were assessed by the proportional hazards regression model. RESULTS: About 102 placebo and 113 corticosteroid patients with DF > or =32 were analyzed. At 28 days, corticosteroid patients had significantly higher survival: 84.6+/-3.4% vs. 65.1+/-4.8%, P=0.001. In univariate analysis, corticosteroid treatment, age, DF, albumin, creatinine and encephalopathy were prognostic factors. In multivariate analysis, age (P=0.0001), serum creatinine (P<0.002) and corticosteroid treatment (P=0.002) were independent prognostic variables. A more dramatic decrease of median serum bilirubin values (micromol/l) was observed at 7 and 14 days in corticosteroid patients (P<0.05) : -76.5 vs. -35 and -105 vs. -45. CONCLUSIONS: Corticosteroids improved short-term survival of patients with severe AH. Age and serum creatinine are independent prognostic factors. Corticosteroids are recommended for patients with severe AH.