Homocysteine in Myointimal Hyperplasia

AbstractIntroduction: homocysteine, a sulphur-containing non-essential amino acid, appears to play a role in the pathophysiology of atherosclerosis. However, its role in myointimal hyperplasia, the cause of almost 30% of failures of interventional therapeutic procedures, is much less clear. Methods: a review of the published scientific data concerning the role of homocysteine in myointimal hyperplasia was performed using MEDLINE and other on-line databases. Evidence was sought from cell culture experiments, animal models and clinical studies. Results: several clinical studies have recently been published linking plasma homocysteine levels to restenosis in coronary and peripheral arterial disease. However, several contradictory studies also exist making the role of homocysteine unclear. There are currently no published randomised trials. Cell culture and animal model experiments have elucidated several potential mechanisms by which may stimulate myointimal hyperplasia. Possible mechanisms include endothelial cell activation with the enhanced release of inflammatory cytokines and growth factors and a direct effect on vascular smooth muscle cell migration and proliferation. Conclusion: further studies are required before the true role of homocysteine in the pathogenesis of myointimal hyperplasia can be clearly evaluated. If evidence does confirm a role, the ease with which homocysteine levels can be normalised makes it an attractive alternative therapeutic target for intervention

Evidence for geometry-dependent universal fluctuations of the Kardar-Parisi-Zhang interfaces in liquid-crystal turbulence

We provide a comprehensive report on scale-invariant fluctuations of growing interfaces in liquid-crystal turbulence, for which we recently found evidence that they belong to the Kardar-Parisi-Zhang (KPZ) universality class for 1+1 dimensions [Phys. Rev. Lett. 104, 230601 (2010); Sci. Rep. 1, 34 (2011)]. Here we investigate both circular and flat interfaces and report their statistics in detail. First we demonstrate that their fluctuations show not only the KPZ scaling exponents but beyond: they asymptotically share even the precise forms of the distribution function and the spatial correlation function in common with solvable models of the KPZ class, demonstrating also an intimate relation to random matrix theory. We then determine other statistical properties for which no exact theoretical predictions were made, in particular the temporal correlation function and the persistence probabilities. Experimental results on finite-time effects and extreme-value statistics are also presented. Throughout the paper, emphasis is put on how the universal statistical properties depend on the global geometry of the interfaces, i.e., whether the interfaces are circular or flat. We thereby corroborate the powerful yet geometry-dependent universality of the KPZ class, which governs growing interfaces driven out of equilibrium.Comment: 31 pages, 21 figures, 1 table; references updated (v2,v3); Fig.19 updated & minor changes in text (v3); final version (v4); J. Stat. Phys. Online First (2012

Evaluation of the mRNA-1273 Vaccine against SARS-CoV-2 in Nonhuman Primates

Background: Vaccines to prevent coronavirus disease 2019 (Covid-19) are urgently needed. The effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines on viral replication in both upper and lower airways is important to evaluate in nonhuman primates. Methods: Nonhuman primates received 10 or 100 μg of mRNA-1273, a vaccine encoding the prefusion-stabilized spike protein of SARS-CoV-2, or no vaccine. Antibody and T-cell responses were assessed before upper- and lower-airway challenge with SARS-CoV-2. Active viral replication and viral genomes in bronchoalveolar-lavage (BAL) fluid and nasal swab specimens were assessed by polymerase chain reaction, and histopathological analysis and viral quantification were performed on lung-tissue specimens. Results: The mRNA-1273 vaccine candidate induced antibody levels exceeding those in human convalescent-phase serum, with live-virus reciprocal 50% inhibitory dilution (ID50) geometric mean titers of 501 in the 10-μg dose group and 3481 in the 100-μg dose group. Vaccination induced type 1 helper T-cell (Th1)-biased CD4 T-cell responses and low or undetectable Th2 or CD8 T-cell responses. Viral replication was not detectable in BAL fluid by day 2 after challenge in seven of eight animals in both vaccinated groups. No viral replication was detectable in the nose of any of the eight animals in the 100-μg dose group by day 2 after challenge, and limited inflammation or detectable viral genome or antigen was noted in lungs of animals in either vaccine group. Conclusions: Vaccination of nonhuman primates with mRNA-1273 induced robust SARS-CoV-2 neutralizing activity, rapid protection in the upper and lower airways, and no pathologic changes in the lung. (Funded by the National Institutes of Health and others.)

Interactions between cholinergic and prostaglandin signaling elements in the urothelium: Role for muscarinic type 2 receptors

<p>Objective: To characterize the interactions between the cholinergic and prostaglandin signaling systems within the urothelium-lamina propria of the guinea pig and elucidate the role of muscarinic receptors in these interactions.</p> <p>Methods: The urothelium-lamina propria was isolated from guinea pig bladders, cut into strips (5 × 10 mm), and maintained in vitro. The tissue was either stretched or left unstretched but exposed to 2′(3′)-O-(4-benzoylbenzoyl)adenosine-5′-triphosphate tri(triethylammonium) salt, arecaidine, and prostaglandin E<sub>2</sub> (PGE<sub>2</sub>). Acetylcholine and PGE2 release was measured using a GeneBLAzer M3 CHO-K1-bla cell reporter assay and an enzyme immunoassay, respectively. The role of the muscarinic type 2 and 3 (M<sub>2</sub> and M<sub>3</sub>, respectively) receptors and nitric oxide in mediating PGE<sub>2</sub> release was determined in the presence of the muscarinic antagonists 11-[(2-[(diethylamino)methyl]-1-piperidinyl)acetyl]-5,11-dihydro-6H-pyrido[2,3b][1,4] benzodiazepin-6-one and darafenicin and a nitric oxide donor (NONOate).</p> <p>Results: Acetylcholine release was detected in response to stretch and in the unstretched preparations exposed to PGE<sub>2</sub> or the adenosine triphosphate analog 2′(3′)-O-(4-benzoylbenzoyl)adenosine-5′-triphosphate tri(triethylammonium) salt. The cholinergic agonist arecaidine induced a concentration-dependent production of PGE<sub>2</sub> (half-maximal concentration 75 nM). The arecaidine stimulation of PGE<sub>2</sub> production was inhibited in a dose-dependent manner by the antagonist AFDX-116 (M<sub>2</sub> > M<sub>3</sub>; half-maximal inhibition 110 nM) but not darifenacin (M<sub>3</sub> > > M<sub>2</sub>). Finally, in the presence of the nitric oxide donor, NONOate, arecaidine-stimulated PGE<sub>2</sub> production was inhibited.</p> <p>Conclusion: These observations demonstrate that complex signal interactions occur within the urothelium involving acetylcholine, adenosine triphosphate, nitric oxide, and PGE<sub>2</sub>. In addition, the data have demonstrated a role for muscarinic M<sub>2</sub> receptors and nitric oxide in the cholinergic regulation of PGE<sub>2</sub> production in the bladder wall.</p&gt

Stretch independent regulation of prostaglandin E₂ production within the isolated guinea-pig lamina propria

<p>Objective: To use an isolated preparation of the guinea-pig bladder lamina propria (LP) to investigate the effects of adenosine tri-phosphate (ATP) and nitric oxide (NO) on the release of prostaglandin E<sub>2</sub> (PGE<sub>2</sub>).</p> <p>Materials and Methods: The bladders of female guinea-pigs (200–400 g) were isolated and opened to expose the urothelial surface. The LP was dissected free of the underlying detrusor muscle and cut into strips from the dome to base. Strips were then incubated in Krebs buffer at 37 °C. Each tissue piece was then exposed to the stable ATP analogue, BzATP, and a NO donor, diethylamine-NONOate (DEANO), and the effect on PGE<sub>2</sub> output into the supernatant determined using the Parameter <sup>TM</sup> PGE<sub>2</sub> enzyme immunoassay kit (R & D Systems, Abingdon, UK). Experiments were repeated in the presence of purinergic receptor and cyclooxygenase (COX) enzymes, COX I and COX II, antagonists. The cellular location of COX I, COX II and neuronal NO synthase (nNOS) within the bladder LP was also determined by immunohistochemistry.</p> <p>Results: PGE<sub>2</sub> production was significantly increased by BzATP. Antagonist studies showed the purinergic stimulation involved both P2X and P2Y receptors. The BzATP response was inhibited by the COX inhibitor indomethacin (COX I >COX II) but not by DUP 697 (COX II >COX I). Thus, BzATP stimulation occurs because of COX I stimulation. NO had no effect on PGE<sub>2</sub> production over the initial 10 min of an exposure. However, PGE<sub>2</sub> output was increased 100 min after exposure to the NO donor. In the presence of NO, the BzATP stimulation was abolished. Immunohistochemistry was used to confirm the location of COX I to the basal and inner intermediate urothelial layers and to cells within the diffuse layer of LP interstitial cells. In addition, nNOS was also located in the basal urothelial layers whilst COX II was found in the interstitial cell layers.</p> <p>Conclusion: There is complex interaction between ATP and NO to modulate PGE<sub>2</sub> release from the bladder LP in the un-stretched preparation. Such interactions suggest a complex interrelationship of signals derived from this region of the bladder wall. The importance of these interactions in relation to the physiology of the LP remains to be determined.</p&gt

"Focused Introspection" During Naturally Increased Diuresis: Description and Repeatability of a Method to Study Bladder Sensation Non-Invasively

Objective To present and describe a non-invasive method to study the origin and development of bladder filling sensation and to evaluate the repeatability of the method. Method Eighteen volunteers participated in the study and were given a water loading protocol consisting of 1,000ml water intake 1hr before the session and 200ml every 10min during the session. Protocol 1: To evaluate diuresis rate, seven participants were asked to void every 15min and the voided volume was measured. Protocol 2: Eleven volunteers graded bladder sensation on regular time points, on an empty graph with time on the X-axis and intensity of sensation on the Y-axis. The protocol ended at absolute need to void (maximal intensity) and voided volumes were measured. This protocol was conducted three times with a 10 days interval. Results Protocol 1: The diuresis rate was not different during the sessions and showed no variation over the studied time period (P=0.2). Protocol 2: For an individual, the diuresis rate was not different between the sessions. The curves in all patients showed a continuously increasing bladder intensity. In seven participants the curve was convex, in the other four, the curve was sigmoidal. For each individual the pattern was constant during the three sessions. Conclusion A strict water loading protocol induces a constant diuresis. This allows individuals to draw an introspection bladder sensation curve with a specific shape, which can be used as a method to study the development of bladder sensation non-invasively. Neurourol. Urodynam. 33:502-506, 2014. (c) 2013 Wiley Periodicals, Inc