Miracle-dz/UniFAR-FTUs huggingface dataset:
Adenosine Receptors Modulate [Ca2+]i in Hippocampal Astrocytes In Situ

Abstract: Cultured astroglia express both adenosine and ATP purinergic receptors that are coupled to increases in intracellular calcium concentration ([Ca2+]i). Currently, there is little evidence that such purinergic receptors exist on astrocytes in vivo. To address this issue, calcium‐sensitive fluorescent dyes were used in conjunction with confocal microscopy and immunocytochemistry to examine the responsiveness of astrocytes in acutely isolated hippocampal slices to purinergic neuroligands. Both ATP and adenosine induced dynamic increases in astrocytic [Ca2+]i that were blocked by the adenosine receptor antagonist 8‐(p‐sulfophenyl)theophylline. The responses to adenosine were not blocked by tetrodotoxin, 8‐cyclopentyltheophylline, 8‐(3‐chlorostyryl)caffeine, dipyridamole, or removal of extracellular calcium. The P2Y‐selective agonist 2‐methylthioadenosine triphosphate was unable to induce increases in astrocytic [Ca2+]i, whereas the P2 agonist adenosine 5′‐O‐(2‐thiodiphosphate) induced astrocytic responses in a low percentage of astrocytes. These results indicate that the majority of hippocampal astrocytes in situ contain P1 purinergic receptors coupled to increases in [Ca2+]i, whereas a small minority appear to contain P2 purinergic receptors. Furthermore, individual hippocampal astrocytes responded to adenosine, glutamate, and depolarization with increases in [Ca2+]i. The existence of both purinergic and glutamatergic receptors on individual astrocytes in situ suggests that astrocytes in vivo are able to integrate information derived from glutamate and adenosine receptor stimulation.
Noninvasive Tests for Fibrosis Predict 5-Year Mortality and Hepatocellular Carcinoma in Patients With Chronic Hepatitis B

Goals: To evaluate the degree of liver fibrosis as a predictor of mortality and hepatocellular carcinoma (HCC) development among patients with chronic hepatitis B. Background: The level of fibrosis predicts mortality and liver-related complications. Study: A total of 542 patients over 18 years old with chronic hepatitis B who visited the Konkuk University Hospital between the years 2005 and 2006 were enrolled. We performed noninvasive tests of fibrosis (APRI, FIB-4) and hepatitis B virus (HBV) DNA levels. The data on mortality and newly developed HCC collected during a 5-year follow-up were analyzed. Results: In 5 years, 40 patients died and 68 patients developed HCC. The area under the receiver operator characteristic (AUROC) curve of APRI, FIB-4, and HBV DNA levels for mortality was 0.760, 0.789, and 0.463, with cut-off points at 0.766, 2.671, and 3.150, respectively. The AUROC curve of APRI, FIB-4, and HBV DNA levels for HCC was 0.731, 0.803, and 0.523, with cut-off points at 0.766, 2.225, and 4.245, respectively. APRI and FIB-4 were predictors of mortality and HCC development, where patients with APRI over 0.766 had a greater risk of death [odds ratio (OR)=3.214, 95% confidence interval (CI), 1.009-10.238] and HCC development (OR=4.245, 95% CI, 1.723-10.456). Patients with FIB-4>2.671 had a higher risk of death (OR=4.431, 95% CI, 1.512-12.986) and those over 2.225 had a greater risk of developing HCC (OR=3.607, 95% CI, 1.622-8.021). Conclusions: APRI and FIB-4 may be more useful than HBV DNA level in predicting 5-year mortality and development of HCC.
Ligand Specificity and Evolution of Mammalian Musk Odor Receptors: Effect of Single Receptor Deletion on Odor Detection

Musk odors have been used widely for fragrance and medicine for >2000 years because of their fascinating scent and physiological effects. Therefore, fragrance manufacturers have been eager to develop high-quality musk compounds that are safe and easily synthesized. We recently identified muscone-responsive olfactory receptors (ORs) MOR215-1 and OR5AN1 in mice and humans, respectively (Shirasu et al., 2014). In this study, we identified musk ORs that are evolutionarily closely related to MOR215-1 or OR5AN1 in various primates and investigated structure–activity relationships for various musk odorants and related compounds. We found that each species has one or two functional musk ORs that exhibit specific ligand spectra to musk compounds. Some of them, including the human OR5AN1, responded to nitro musks with chemical properties distinct from muscone. The ligand specificity of OR5AN1 reflects the perception of musk odors in humans. Genetic deletion of MOR215-1 in mice resulted in drastic reduction of sensitivity to muscone, suggesting that MOR215-1 plays a critical role in muscone perception. Therefore, the current study reveals a clear link between the identified OR and muscone perception. Moreover, the strategy established for screening ligands for the muscone OR may facilitate the development of novel and commercially useful musk odors. SIGNIFICANCE STATEMENT The long-sought musk odor receptor family in mammals was discovered and found to be well conserved and narrowly tuned to musk odors. In mice, deletion of the most sensitive musk receptor resulted in drastic reduction in sensitivity to muscone, demonstrating a strong link between receptor and odor perception. In humans, we found one musk receptor that recognized both macrocyclic and nitro musks that had distinct chemical structures. The structure–activity relationships were in a good agreement with human sensory perception and therefore may be used to develop novel musk aroma in fragrance fields. Finally, identification of a natural ligand(s) for musk receptors in mammals other than musk deer would reveal an evolutionarily pivotal role in each species in the future.
Effect of soybean meal particle size on amino acid and energy digestibility in grower-finisher swine.

A study was conducted using the ileal digestibility technique with grower-finisher pigs to evaluate the effects of particle size reduction of soybean meal (SBM) on amino acid and energy digestibility. Soybean meal was processed through a hammer mill to achieve average particle sizes of 900, 600, 300, and 150 microm. The treatments included the use of two soybean meal sources and soy protein concentrate. One source of SBM was ground to four different particle sizes (i.e., 949, 600, 389, 185); a second source was a common SBM source used in other trials (i.e., 800 microm). The soy protein concentrate had an average particle size of 385 microm. A low-protein (5% casein) diet was fed to determine endogenous amino acid losses. This experiment was conducted in a 7 x 7 Latin Square design in two replicates using 14 crossbred barrows ([Landrace x Yorkshire] x Duroc) that averaged 28 kg BW and 60 d of age. Animals were surgically fitted with a T-cannula at the distal ileum. Treatment diets were fed in meal form, initially at 0.09 kg BW(0.75) and at graded increases at each subsequent period. Pigs within replicate were fed a constant quantity of their treatment diet for a 5-d adjustment period followed by a 2-d collection of ileal digesta samples. Apparent and true digestibility of amino acids was calculated by use of chromic oxide (0.5%) as an indigestible marker. Apparent digestibility of isoleucine, methionine, phenylalanine, and valine increased linearly (P < 0.05) as particle size decreased. True digestibility of isoleucine, methionine, phenylalanine, and valine increased linearly (P < 0.05) as particle size decreased. When the essential amino acids were averaged, apparent digestibility increased (P < 0.10) from 83.5% to 84.9% as particle size decreased, whereas, nonessential amino acid digestibility increased only slightly (P > 0.15). Essential amino acid true digestibility increased numerically from 91.0% to 92.4% as particle size decreased. Energy digestibility was not affected by particle size (P > 0.15). These results suggest that a reduction in particle size of soybean meal resulted in a small increase in the digestibility of its amino acids with the essential amino acids being affected more than the nonessential amino acids. The largest improvement in digestibility, however, was obtained when the particle size was reduced to 600 microm.
Flow-Diverting Stent for Ruptured Intracranial Dissecting Aneurysm of Vertebral Artery

BACKGROUND: The treatment of ruptured dissecting aneurysms of the intracranial vertebral artery (VA) with parent vessel preservation is a challenge for neurosurgeons and interventional neuroradiologists. OBJECTIVE: To propose an indication for flow-diverting treatment for reconstruction of a dissecting VA with acute subarachnoid hemorrhage. METHODS: Two male patients transferred after acute subarachnoid hemorrhage and dissecting aneurysm on the V4 segment of the dominant VA. An occlusion test was not performed because of their poor clinical state. A flow-diverting stent represented by the Pipeline embolization device was suggested to both patients. RESULTS: Three Pipeline embolization devices were deployed in each VA. One dissecting aneurysm was excluded immediately after 3 stents, and 1 patient had complete exclusion demonstrated at the 48-hour control. No morbidity directly related to the procedure was observed. No recanalization and no rebleeding occurred during the 3 months of follow-up. CONCLUSION: A flow-diverting stent may be considered an option to treat ruptured dissecting aneurysms of the VA, providing remodeling of the parent vessel and complete exclusion of the aneurysm.
Lithium pretreatment reduces brain injury after intracerebral hemorrhage in rats

Abstract Objective: In addition to the mood-stabilizing effects of lithium in patients with bipolar disorder, recent in vitro and in vivo studies in rodents increasingly implicate that lithium may be useful for treating acute cerebral ischemia, neuroinflammatory conditions, and chronic neurodegenerative diseases. However, whether lithium has a protective effect against hemorrhagic stroke is yet unknown. To test this possibility, we attempted to determine lithium’s effect on experimental intracerebral hemorrhage (ICH). Methods: We treated adult rats with either lithium (2 mEq/kg) or saline for 3 days before inducing ICH via a stereotaxic infusion of collagenase into the left basal ganglia. Hematoma volumes, hemispheric swelling, long-term hemispheric atrophy, microglial activation, cell death, cyclooxygenase-2 expression, and behavioral outcomes were assessed. Results: Per behavioral tests 2 days after ICH, the lithium-treated group recovered better than did the saline-treated group. Three days after ICH, the hematoma volumes did not differ between the groups, but hemispheric swelling was less in the lithium-treated group. Forty-two days after ICH, hemispheric atrophy was less in the lithium-treated group. Lithium reduced cell death, cyclooxygenase-2 expression, and reactive microglia in the perihematomal regions. Conclusion: The present study shows that lithium, via anti-inflammation, reduces the perihematomal cell death, which is associated with sensorimotor recovery after experimental ICH.
Mortalités estivales de l'huître Crassostrea gigas dans le bassin d'Arcachon : facteurs du milieu, aspects biochimiques et histologiques

En l'absence d'elements permettant d'avancer une etiologie infectieuse des mortalites estivales de Crassostrea gigas dans le bassin d'Arcachon, une etude comparative d'un site a haut risque de mortalite (Taussat) et d'un site a bas risque (Cap Ferret), a ete entreprise au cours de l'ete 1983 sur des Huitres de 1 an. 30 % de mortalites affectaient des lots experimentaux a Taussat et 3 % au Cap Ferret. Hormis des differences de temperature, maxima: 27°C a Taussat et 22°C au Cap Ferret, aucune desoxygenation du milieu n'a ete mise en evidence. Sur le plan nutritif les deux sites sont similaires. Les mortalites s'observent a la suite d'une decroissance progressive des poids secs relatifs et des index de condition des Mollusques et apres epuisement des reserves glucidiques (0,7 % du poids sec). Les examens histologiques ont reveles une alteration de l'epithelium digestif consecutive a une activite autophagique caracteristique d'un etat de stress. Il est suggere que l'augmentation des besoins energetiques des Huitres due a des fortes temperatures a la maturation et a la ponte, au moment ou les reserves glycogenees sont au plus bas, entraine, un desequilibre metabolique qui peut dans ces cas aigus, representer un etat pathologique. [OCR NON CONTROLE] Actes du 1er colloque international Pathologie en aquaculture marine (11-14 Septembre 1984), Montpellier, France. European Aquaculture Society. Dimensions: 16 x 23.5 cm, XVII + 428 p. ISBN-774-0689.
Le point de vue du cardiologue

L’hypertension artérielle (HTA) est une réalité épidémiologique ancienne. Dès les années 1950, on définissait déjà le niveau pressionnel pour une population. Ce niveau n’était pas fixe et se répartissait selon une courbe gaussienne avec à peu près 25 % de la population au dessus de 90 mmHg de pression diastolique (fig. 1) [1]. L’histoire de l’hypertension a réellement commencé dans les années 1907-1910. La mesure de la pression artérielle auscultatoire a débuté en 1905 et, très rapidement, on s’est aperçu qu’en fonction du niveau pressionnel, le taux de mortalité était différent. Ce sont notamment les assureurs de Philadelphie qui se sont rendus compte que parmi leurs assurés, entre ceux qui avaient une pression systolique entre 150 et 160 mmHg et ceux entre 160 et 170 mmHg, le taux de mortalité variait considérablement (tableau I) [2]. Ces assureurs ont montré qu’un phénomène mesuré dans la population générale était associé à un plus fort taux de mortalité : plus le niveau tensionnel était élevé plus le taux de mortalité était élevé. L’autre réalité essentielle de santé publique est que le plus grand nombre de morts attribué à l’HTA n’est pas lié aux patients à la tension artérielle la plus élevée, car peu de gens ont une tension très élevée, mais chez les High blood pressure-low ocular pressure: the parallels The cardiologist’s point of view
Efficacy of Intrathecal Liposomal Fasudil for Experimental Cerebral Vasospasm after Subarachnoid Hemorrhage

OBJECTIVETo investigate the safety and efficacy of liposomal fasudil in a sustained-release form for the prevention of cerebral vasospasm after subarachnoid hemorrhage (SAH). METHODSEighteen rats were divided into three groups, each of which received 2.5 mg/kg of liposomal fasudil, 5 mg/kg of liposomal fasudil, or drug-free liposomes after SAH. Next, experimental SAH was induced in 15 dogs by injection of autologous arterial blood into the cisterna magna twice after baseline vertebral angiography. In six dogs, 0.94 mg/kg of liposomal fasudil was injected into the cisterna magna (treatment group). In four dogs, drug-free liposomes were similarly injected (placebo group), and the remaining five dogs were not treated with liposomal injection after SAH (control group). Angiography was repeated on Day 7, and cerebrospinal fluid was collected before the dogs were killed. RESULTSA high dose of liposomal fasudil caused no significant changes in mean arterial blood pressure and did not induce seizures during the observation period. Gross and microscopic examination of the brains revealed no abnormalities, but severe vasospasm was noted in the rat basilar artery, mainly in the group treated with drug-free liposomes. Likewise, in the canine placebo and control groups, significant vasospasm occurred in the basilar artery on Day 7. In the treatment group, vasospasm in the basilar artery was significantly ameliorated (P < 0.01). In vivo, 90% of fasudil was released from liposomes in the cerebrospinal fluid. CONCLUSIONA single injection of intrathecal liposomal fasudil is safe and effective for the prevention of vasospasm in experimental SAH.
EspG, a Novel Type III System-Secreted Protein from Enteropathogenic Escherichia coli with Similarities to VirA of Shigella flexneri

ABSTRACT The function of the rorf2 gene located on the locus of enterocyte effacement (LEE) pathogenicity island of enteropathogenicEscherichia coli (EPEC) has not been described. We report that rorf2 encodes a novel protein, named EspG, which is secreted by the type III secretory system and which is translocated into host epithelial cells. EspG is homologous withShigella flexneri protein VirA, and the clonedespG (rorf2) gene can rescue invasion in a Shigella virA mutant, indicating that these proteins are functionally equivalent in Shigella. An EPECespG mutant had no apparent defects in in vitro assays of virulence phenotypes, but a rabbit diarrheagenic E. coli strain carrying a mutant espG showed diminished intestinal colonization and yet diarrheal attack rates similar to those of the wild type. A second EspG homolog, Orf3, is encoded on the EspC pathogenicity islet. The clonedorf3 gene could also rescue invasion in aShigella virA mutant, but an EPEC espG orf3 double mutant was not diminished in any tested in vitro assays for EPEC virulence factors. Our results indicate that EspG plays an accessory but as yet undefined role in EPEC virulence that may involve intestinal colonization.
ACTIVATION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-&bgr;/&dgr; ATTENUATES MYOCARDIAL ISCHEMIA/REPERFUSION INJURY IN THE RAT

Peroxisome proliferator-activated receptor-&bgr;/&dgr; (PPAR-&bgr;/&dgr;) is a transcription factor that belongs to the PPAR nuclear hormone receptor family. There is little information about the effects of the immediate administration of specific ligands of PPAR-&bgr;/&dgr; (e.g., GW0742) in animal models of myocardial I/R injury. Using a rat model of regional myocardial I/R in vivo, we have investigated the effects of immediate administration of GW0742 on myocardial infarct size. Male Wistar rats were subjected to 25 min of regional ischemia followed by 2 h of reperfusion and treated with GW0742 (3, 30, or 300&mgr;g/kg i.v. given at 30 min before ischemia and again at the start of reperfusion). Higher doses (30 or 300 &mgr;g/kg i.v.) of GW0742 caused a reduction in infarct size, whereas the lowest dose used was not effective. The degree of cardioprotection was similar when GW0742 (30 &mgr;g/kg i.v.) was given on reperfusion alone. The reduction in infarct size afforded by GW0742 was not reduced by the competitive irreversible PPAR-&agr; antagonist GW6471 (1 mg/kg i.v., 15 min before ischemia). GW0742 (30 &mgr;g/kg i.v.) reduced the I/R-induced (a) decrease in the phosphorylation of Akt and glycogen synthase kinase-3&bgr;, (b) nuclear translocation of the p65 subunit of nuclear factor-&kgr;B (activation of nuclear factor-&kgr;B), and (c) increase in the expression of iNOS and cyclooxygenase-2. Thus, immediate administration of the PPAR-&bgr;/&dgr; ligand GW0742 during reperfusion reduces myocardial infarct size in the rat by a mechanism that may involve inhibition of the activity of glycogen synthase kinase-3&bgr; secondary to activation of the Akt pathway.
Controlled-release injectable microemulsions: recent advances and potential opportunities

Introduction: Controlled-release injectable (CRI) formulations hold significant value for several indications. However, there have been very few successful developments and approvals due to various challenges that include limited polymer options, drug–excipient process incompatibility and complex scale-up/validation processes. Microemulsion technology, as reviewed in this article, promises to resolve many of these challenges. Areas covered: In addition to its development and manufacturing advantages, feasibility to engineer microemulsion formulations by choosing its constituents and nature of formulation vis-à-vis drug candidate demonstrates capability of microemulsion to modulate in-vivo drug release and thereby optimize drug pharmacokinetics and pharmacodynamics. This potential of microemulsion has been used in a few studies to prolong in vivo drug residence time resulting in a more favorable benefit/risk profile for various drugs. Virtues of injectable microemulsion, results related to prolonged-release injectable microemulsion, impact on drug safety and efficacy and possible opportunities have been discussed. A detailed review of research work on microemulsions as well as other parenteral controlled-release formulations was conducted using PubMed, Science Direct and Google Scholar. Expert opinion: The fact that microemulsion formulations administered through subcutaneous or intramuscular route would undergo significantly prolonged elimination should be leveraged to develop novel CRI drug products. Such products will find enormous application for several drug candidates which have poor oral pharmacokinetics resulting into poor treatment outcome.
S-nitrosylation Inhibits Protein Kinase C–mediated Contraction in Mouse Aorta

S-nitrosylation is a ubiquitous protein modification in redox-based signaling and forms S-nitrosothiol from nitric oxide (NO) on cysteine residues. Dysregulation of (S)NO signaling (nitrosative stress) leads to impairment of cellular function. Protein kinase C (PKC) is an important signaling protein that plays a role in the regulation of vascular function, and it is not known whether (S)NO affects PKC's role in vascular reactivity. We hypothesized that S-nitrosylation of PKC in vascular smooth muscle would inhibit its contractile activity. Aortic rings from male C57BL/6 mice were treated with auranofin or 1-chloro-2,4-dinitrobenzene (DNCB) as pharmacological tools, which lead to stabilize S-nitrosylation, and propylamine propylamine NONOate (PANOate) or S-nitrosocysteine (CysNO) as NO donors. Contractile responses of aorta to phorbol-12,13-dibutyrate, a PKC activator, were attenuated by auranofin, DNCB, PANOate, and CysNO. S-nitrosylation of PKCα was increased by auranofin or DNCB and CysNO as compared with control protein. Augmented S-nitrosylation inhibited PKCα activity and subsequently downstream signal transduction. These data suggest that PKC is inactivated by S-nitrosylation, and this modification inhibits PKC-dependent contractile responses. Because S-nitrosylation of PKC inhibits phosphorylation and activation of target proteins related to contraction, this posttranslational modification may be a key player in conditions of decreased vascular reactivity.
Pathogenic Nematodes Suppress Humoral Responses to Third-Party Antigens In Vivo by IL-10–Mediated Interference with Th Cell Function

One third of the human population is infected with helminth parasites. To promote their longevity and to limit pathology, helminths have developed several strategies to suppress the immune response of their host. As this immune suppression also acts on unrelated third-party Ags, a preexisting helminth infection may interfere with vaccination efficacy. In this study, we show that natural infection with Litomosoides sigmodontis suppressed the humoral response to thymus-dependent but not to thymus-independent model Ags in C57BL/6 mice. Thereby, we provide evidence that reduced humoral responses were mediated by interference with Th cell function rather than by direct suppression of B cells in L. sigmodontis-infected mice. We directly demonstrate suppression of Ag-specific proliferation in OVA-specific Th cells after adoptive transfer into L. sigmodontis-infected mice that led to equally reduced production of OVA-specific IgG. Transferred Th cells displayed increased frequencies of Foxp3+ after in vivo stimulation within infected but not within naive mice. Helminth-mediated suppression was induced by established L. sigmodontis infections but was completely independent of the individual worm burden. Using DEREG mice, we rule out a central role for host-derived regulatory T cells in the suppression of transferred Th cell proliferation. In contrast, we show that L. sigmodontis-induced, host-derived IL-10 mediated Foxp3 induction in transferred Th cells and significantly contributed to the observed Th cell hypoproliferation within infected mice.