Search

Background:Oral propranolol reduces retinopathy of prematurity (ROP) progression, although not safely. This study evaluated safety and efficacy of propranolol eye micro-drops in preterm newborns with ROP.Methods:A multicenter open-label trial, planned according to the Simon optimal two-stage design, was performed to analyze safety and efficacy of propranolol micro-drops in newborns with stage 2 ROP. To this end, hemodynamic and respiratory parameters were monitored, and blood samples were collected weekly, for 3 wk. Propranolol plasma levels were also monitored. The progression of the disease was evaluated with serial ophthalmologic examinations.Results:Twenty-three newborns were enrolled. Since the fourth of the first 19 newborns enrolled in the first stage of the study showed a progression to stage 2 or 3 with plus, the second stage was prematurely discontinued. Even though the objective to complete the second stage was not achieved, the percentage of ROP progression (26%) was similar to that obtained previously with oral propranolol administration. However, no adverse effects were observed and propranolol plasma levels were significantly lower than those measured after oral administration.Conclusion:Propranolol 0.1% eye micro-drops are well tolerated, but not sufficiently effective. Further studies are required to identify the optimal dose and administration schedule.

To date, the study of the sympathetic regulation of renal function has been restricted to the important contribution of β1- and β2-adrenergic receptors (ARs). Here we investigate the expression and the possible physiologic role of β3-adrenergic receptor (β3-AR) in mouse kidney. The β3-AR is expressed in most of the nephron segments that also express the type 2 vasopressin receptor (AVPR2), including the thick ascending limb and the cortical and outer medullary collecting duct. Ex vivoexperiments in mouse kidney tubules showed that β3-AR stimulation with the selective agonist BRL37344 increased intracellular cAMP levels and promoted 2 key processes in the urine concentrating mechanism. These are accumulation of the water channel aquaporin 2 at the apical plasma membrane in the collecting duct and activation of the Na-K-2Cl symporter in the thick ascending limb. Both effects were prevented by the β3-AR antagonist L748,337 or by the protein kinase A inhibitor H89. Interestingly, genetic inactivation of β3-AR in mice was associated with significantly increased urine excretion of water, sodium, potassium, and chloride. Stimulation of β3-AR significantly reduced urine excretion of water and the same electrolytes. Moreover, BRL37344 promoted a potent antidiuretic effect in AVPR2-null mice. Thus, our findings are of potential physiologic importance as they uncover the antidiuretic effect of β3-AR stimulation in the kidney. Hence, β3-AR agonism might be useful to bypass AVPR2-inactivating mutations.

Purpose Only mechanical and biological heart valve prostheses are currently commercially available. The former show longer durability but require anticoagulant therapy; the latter display better fluid dynamic behavior but do not have adequate durability. New Polymeric Heart Valves (PHVs) could potentially combine the hemodynamic properties of biological valves with the durability of mechanical valves. This work presents a hydrodynamic evaluation of 2 groups of newly developed supra-annular, trileaflet prosthetic heart valves made from styrenic block copolymers (SBC): Poli-Valves.Methods 2 types of Poli-Valves made of SBC and differing in polystyrene fraction content were tested under continuous and pulsatile flow conditions as prescribed by ISO 5840 Standard. A pulse duplicator designed ad hoc allowed the valve prototypes to be tested at different flow rates and frequencies. Pressure and flow were recorded; pressure drops, effective orifice area (EOA), and regurgitant volume were computed to assess the behavior of the valve.Results Both types of Poli-Valves met the minimum requirements in terms of regurgitation and EOA as specified by the ISO 5840 Standard. Results were compared with 5 mechanical heart valves (MHVs) and 5 tissue heart valves (THVs), currently available on the market.Conclusions Based on these results, PHVs based on styrenic block copolymers, as are Poli-Valves, can be considered a promising alternative for heart valve replacement in the near future.

Purpose A novel finite-element model of ventricular torsion for the analysis of the twisting behavior of the left human ventricle was developed, in order to investigate the influence of various biomechanical parameters on cardiac kinematics.Methods The ventricle was simulated as a thick-walled ellipsoid composed of nine concentric layers. Arrays of reinforcement bars were embedded in each layer to mimic physiological myocardial anisotropy. The reinforcement bars were activated through an artificial combination of thermal and mechanical effects in order to obtain a contractile behavior which is similar to that of myocardial fibers. The presence of an incompressible fluid inside the ventricular cavity was also simulated and the ventricle was combined with simple lumped-parameter hydraulic circuits reproducing preload and afterload. Changes to a number of cardiac parameters, such as preload, afterload and fiber angle orientation were introduced, in order to study the effects of these changes on cardiac torsion.Results The model is able to reproduce a similar torsional behavior to that of a physiological heart. The results of the simulations showed that there was sound correspondence between the model outcomes and available data from the literature. Results confirmed the importance of symmetric transmural patterns for fiber orientation.Conclusions This model represents an important step on the path towards unveiling the complexity of cardiac torsion. It proves to be a practical and versatile tool which could assist clinicians and researchers by providing them with easily-accessible, detailed data on cardiac kinematics for future diagnostic and surgical purposes.

Aim of this study is to develop a mechanical simulator (MS) reproducing cardiac wall kinematics i.e., radial (R), longitudinal (L) and rotational (RT) motions to test piezoelectric gyroscopic sensors (GS) that are able to measure cardiac torsion that has proved to be a sensitive index of cardiac performance. The MS consists of three brushless motors controlled by a dedicated software either separately or simultaneously reproducing the three main cardiac wall movements (R, L, RT) obtained by implementing different physiologic or pathologic velocity profiles derived from in vivodata. GS accuracy (max % error) was experimentally tested by connecting it to the MS driven in velocity in different working conditions i.e., cardiac period (515–1030 ms), RT angle (4–16 degrees), GS axis inclination (0–90 degrees) with respect to the cardiac rotation axis. The MS reproduced the tested velocity profiles well. The GS showed high accuracy in measuring both physiologic and pathologic RT velocity profiles, whereas they proved insensitive to R and L motions. GS axis inclination influenced measurements; however, it was possible to correct this taking the inclination angle cosine into account. The MS proved to be a useful tool to study cardiac wall kinematics and test GS reliability with a view to in vivoapplication.

Somatostatin (SRIF)‐14 is recognized as an important mediator between the nervous and the immune system, although the functional role of its receptors (sst1–sst5) is poorly understood in humans. In our study, we demonstrate that human macrophages, differentiated from PBMC‐derived monocytes, express sst1and sst2mRNAs. sst1and sst2are mostly localized at the cell surface and display active binding sites. In particular, sst1/sst2activation results in a weak internalization of sst1, and the sst2internalization appears more efficient. At the functional level, the activation of SRIF receptors by the multiligand analogs SOM230 and KE108, but not by SRIF‐14 or cortistatin‐14, reduces macrophage viability. Their effects are mimicked by the selective activation of sst1and sst2using CH‐275 and SMS 201‐995/L‐779,976, respectively. Further, sst1‐ and sst2‐mediated effects are reversed by the sst1antagonist SRA‐880 or the sst2antagonist CYN 154806, respectively. CH‐275, SMS 201‐995, and L‐779,976, but not SRIF‐14, decrease mRNA expression and secretion of the MCP‐1. In addition, SRIF‐14, CH‐275, SMS 201‐995, and L‐779,976 decrease IL‐8 secretion, and they do not affect IL‐8 mRNA expression. In contrast, SRIF‐14 and sst1/sst2agonists do not affect the secretion of matrix metalloproteinase‐9. Collectively, our results suggest that the SRIF system, through sst1and sst2, exerts mainly an immunosuppressive effect in human macrophages and may, therefore, represent a therapeutic window that can be exploited for the development of new strategies in pharmacological therapy of inflammation.

Somatostatin (SRIF) is a cyclic peptide widely distributed throughout the body with important physiological effects (mostly inhibitory) on several organ systems. SRIF may act as a neurohormone, neurotransmitter, neuromodulator or as a local factor, and exhibits potent antiproliferative activity. SRIF effects have formed the basis for the clinical use of SRIF analogues in the treatment of endocrine tumours, acromegaly and gastrointestinal disorders. Several data suggest that SRIF may also be a therapeutic target in a number of different diseases. The binding of SRIF to its five G-protein coupled receptors leads to modulation of multiple transduction pathways, including adenylyl cyclase, guanylyl cyclase, phospholipase C, K and Ca2 channels, phospholipase A2, nitric oxide, Na/H exchanger, protein phosphatases and MAP kinases. The diversity of the transduction pathways reflects the pleiotropic actions of SRIF. However, our current understanding depicts a rather complicated picture and conflicting results have also been reported. Data are mostly based on in vitro experiments, and parallels with the real in vivo conditions are not so obvious. Due to the clinical relevance of the SRIF system, the elucidation of the intracellular role of endogenous SRIF receptors may offer new therapeutic perspectives. These will enable development of specific pharmacological signalling modulators which can be incorporated into the therapeutic arsenal. The present review represents a detailed and exhaustive summary which covers the latest advances in the transduction pathways of SRIF receptors.

This study analyzes the structure and mechanical properties of the trachea of the striped dolphin Stenella coeruleoalba, one of the most common cetacean species. The cetacean trachea is made up of closed or semiclosed cartilaginous rings without a paries membranaceus. Our results indicate that the inner lining of the trachea contains erectile tissue in which several venous lacunae permeate the mucosa. We also observed and described the presence of peripheral neurons containing nitric oxide along the rim of the venous lacunae. Data obtained from compression and tensile tests and comparison with the pig and goat tracheas indicate a higher stiffness and a different, higher breaking point for the dolphin trachea. On the whole, our data suggest that the trachea of the striped dolphin possesses structural properties that allow rapid filling with blood, possibly in relation to dive activities, and also allow modifications due to increased pressure and immediate return to the original shape without risks of permanent bending or rupture, as would happen in a terrestrial mammal. As the organ undergoes intense pressure difference during descent to optimal foraging depth and subsequent rapid ascent to surface, especially in deep dives of hundreds of meters, the specific structural and biomechanical peculiarities of the trachea of the striped dolphin may represent an evolutionary adaptation to life in the water and to diving. © 2005 Wiley-Liss, Inc.

In rat pituitary tumour cells (GC cells), spontaneous oscillations of the intracellular concentration of Ca2+([Ca2+]i) induce growth hormone (GH) secretion that is inhibited by octreotide, a somatostatin (SRIF) agonist which binds to SRIF subtype (sst) receptor 2. The effects of its functional activation on the control of [Ca2+]iwere investigated using fluorimetric measurements of [Ca2+]i.SRIF decreases the basal [Ca2+]iand the [Ca2+]irise in response to forskolin (FSK) through the inhibition of L‐type voltage‐dependent Ca2+channels.Pretreatment with octreotide or with L‐Tyr8Cyanamid 154806, a sst2receptor antagonist, abolishes the SRIF‐induced inhibition of [Ca2+]i. Octreotide is known to operate through agonist‐induced desensitization, while the antagonist operates through receptor blockade.sst1and sst2receptor‐immunoreactivities (‐IRs) are localized to cell membranes. sst2, but not sst1receptor‐IR, internalizes after cell exposure to octreotide.SRIF‐induced inhibition of basal [Ca2+]ior FSK‐induced Ca2+entry is blocked by pertussis toxin (PTX).FSK‐induced cyclic AMP accumulation is only partially decreased by SRIF or octreotide, indicating that sst2receptors are coupled to intracellular pathways other than adenylyl cyclase (AC) inhibition.In the presence of H‐89, an inhibitor of cyclic AMP‐dependent protein kinase (PKA), SRIF‐induced inhibition of basal [Ca2+]iis still present, although reduced in amplitude.SRIF inhibits [Ca2+]iby activating sst2receptors. Inhibition of AC activity is only partly responsible for this effect, and other transduction pathways may be involved.

In PC12 cells, somatostatin (SRIF) decreases the Ca2+influx in response to high K+through the inhibition of voltage-dependent Ca2+channels. In the present study, we measured the intracellular Ca2+concentration ( [Ca2+]i) following the application of SRIF-14 or its analogues which bind to different SRIF subtype (sst) receptors. Their application differentially reduces [Ca2+]i(octreotide>SRIF-14>CGP23996>BIM23056) in a dose-dependent manner. Pretreatment with a SRIF antagonist prevents the SRIF-induced inhibition of [Ca2+]i. These results suggest the involvement of specific membrane receptors and are in line with recent findings indicating the presence of receptor mRNAs on PC12 cells. Our results also exclude the possibility that SRIF interacts with opioid receptors and suggest that the SRIF-induced inhibition of [Ca2+]iis mediated by mechanisms involving PTX-sensitive G-proteins and PK-dependent pathways.

Significant amounts of endogenous serotonin have been detected in the retina of many nonmammalian vertebrates. In the pigeon retina, serotonin-like immunoreactivity has been localized within a subpopulation of bipolar and amacrine cells, and serotonin-containing terminals have been found to be segregated in different laminae of the inner plexiform layer. In the current experiments 5,7-dihydroxytryptamine was injected intravitreally in the pigeon eye in order to examine the effect of serotonin depletion on the functional activity of the retina. The physiological modifications induced by the serotonin depletion were examined by recording electroretinographic responses to light flashes of different intensity under conditions of light and dark adaptation. Our results show that 5,7-dihydroxytryptamine treatment selectively increases b-wave amplitude and modifies the function relating b-wave amplitude to Log flash intensity without affecting the peak latency and the amplitude of oscillatory potentials. These results can be interpreted in terms of a possible inhibitory role of serotonin on b-wave generators.

Homing pigeons were subjected to either hippocampal or control anterior forebrain ablations to examine what role the hippocampus and related structures may play in homing behavior. One year after surgery, the test birds were released from five locations where they had never been before. Both groups were successful in orienting homeward from the release sites, indicating that the hippocampus is not necessary for the neural regulation of a pigeon's map and compass system. Nonetheless, hippocampal ablated pigeons were significantly poorer with respect to the time required to return home, indicating a homing performance impairment. Alternative hypotheses are discussed to explain this result, the most parsimonious being impaired ability on the part of the hippocampal ablated birds to direct a course homeward.