Miracle-dz/UniFAR-FTUs huggingface dataset:
Inhibition of Muscarinic Potassium Current by the Class III Antiarrhythmic Drug RP58866 in Guinea‐Pig Atrial Myocytes

RP58866 is a potent antiarrhythmic drug that maintains its antiarrhythmic properties during ischemia. Since interstitial concentrations of adenosine increase during ischemia, we examined the properties of the drug with respect to the muscarinic K+ current [Ik(ach)], with a main emphasis on the adenosine (Ado) ‐induced current [Ik(ado)]. Using different Gj‐coupled receptors (M2, A1, sphingolipid), we studied the effect of RP58866 in isolated guinea‐pig atrial myocytes by the whole‐cell voltage clamp technique. Application of 50 μM RP58866 resulted in complete inhibition of the muscarinic K+ current. Inhibition was observed during activation of IK(ACh) by each of the three receptors. IC50 was ∼2.0 μM. GTP‐γ‐S induced IK(ACh) was reduced by RP58866. The drug was active from the outside only, and its intracellular application via the patch pipet had no inhibitory effect. Despite the structural homologies between inward rectifying K+ channels, the adenosine triphosphate‐sensitive K+ current [Ik(atp)] was not inhibited by the compound. It is concluded that muscarinic K+ current is inhibited by RP58866, an inhibition not limited to IK1, Ito, and IKr. High interstitial adenosine concentrations during ischemia are expected to increase the participation of IK(Ado) on repolarization. RP58866‐induced inhibition of Ik(ado) would, therefore, be of particular relevance during ischemia. The high sensitivity of Ik(ado) to RP58866 may partially explain the unique properties of the drug toward arrhythmias developing in the ischemic myocardium.
Salmonella typhimurium contains an anion-selective outer membrane porin induced by phosphate starvation

A mutant of Salmonella typhimurium was selected that is constitutive for the pho regulon. It exhibited constitutive glycerol-3-phosphate transport activity and synthesized a new outer membrane porin. Upon measurement of porin activity in black lipid films, it exhibited anion selectivity. It therefore appears analogous to the Escherichia coli PhoE porin.
Genomic Alterations Are Enhanced in Placentas from Pregnancies with Fetal Growth Restriction and Preeclampsia: Preliminary Results

Fetal growth restriction (FGR) secondary to placental insufficiency and preeclampsia (PE) are associated with substantially increased childhood and adult morbidity and mortality. The long-term outcomes are related to placental aberrations and intrauterine programming. Advances in microarray technology allow high-resolution, genome-wide evaluation for DNA copy number variations - deletions and duplications. The aim of our study was to demonstrate the usefulness of microarray testing in FGR placentas. Using Affymetrix GeneChip for chromosomal microarray (CMA), we analyzed 10 placentas from pregnancies with FGR attributed to placental insufficiency; 5 with FGR below the 5th percentile and 5 from the 5th to <10th percentiles. All fetuses had normal anomaly scans and karyotypes. We also analyzed 5 third-trimester placentas from pregnancies complicated by PE with severe features and 5 from PE without severe features, all with appropriately grown fetuses. The results were compared to 10 placentas from uncomplicated pregnancies with healthy neonates. CMA analysis identified more genomic alterations in FGR (p < 0.05) and in PE (p < 0.05) placentas than in healthy controls. There was a correlation to the severity of FGR and PE. The genomic alterations were below the resolution of normal karyotyping. The altered genes are related to adult human height, stress reactions and to cellular migration, differentiation and adhesion. Though very preliminary, our data support evaluating FGR and PE placentas using CMA. Larger data sets are needed for further evaluation of the findings and their clinical implications.
Heparanase inhibition reduces proteinuria in a model of accelerated anti‐glomerular basement membrane antibody disease

Background: The β‐ d‐endoglycosidase, heparanase, is emerging as an important contributor to the pathogenesis of proteinuria. The purpose of the present study therefore was to examine the role of heparanase in a model of accelerated anti‐glomerular basement disease (anti‐GBM).
Attitude of Nigerian women to contraceptive use by men

Summary This study was aimed at finding the attitude of Nigerian women to contraceptive use by their male partners. A total of 417 women received the questionnaire; 71% of these were sexually active and 34.8% were not aware of any male contraceptive method. Only 1.7% reported regular use of condoms by their spouses, however this was significantly higher if the women were better educated. Most of the women had a positive attitude to contraceptive use by their spouses, as 54% (225/417) of them showed preference to male dependant contraceptives in their relationship. However, only 32.3% (135/417) of the women had ever-requested their spouse to use a condom and in just 18.5% (25/135) was such a request regularly complied with. Significantly more Muslim women prefer their partners to use a contraceptive rather than themselves (p = 0.001), but the condom usage by their spouses is significantly lower than their Christian counterparts (p = 0.000). There is a need to offer counselling on male contraceptives to both genders so that they can make an informed choice, especially with the dual protection offered by the use of condoms.
On the system level performance of cellular FBMC-based wideband PMR network

New physical layer solutions are required for the next generation professional mobile radio (PMR) networks. Filter bank based multi-carrier (FBMC) technique is one of the promising candidates for beyond OFDM 5G wireless communication systems. This paper presents the simulation framework and models necessary for the study of the FBMC-based networks on the system level. PMR-specific 450 MHz frequency band is considered in the study. Special attention is devoted to the implementation of link-to-system interface model, which is sensitive to FBMC intrinsic interference. We demonstrate that even with simple one tap equalizer the performance of OFDM and FBMC systems are very close in the same baseline configuration. Moreover, implementation of advanced receivers together with more flexible and efficient spectrum utilization renders FBMC as the superior technology.
Safety and efficacy of the oral direct renin inhibitor aliskiren in elderly patients with hypertension

Objectives. To evaluate the efficacy, safety and tolerability of aliskiren in elderly patients (⩾65 years old) with essential hypertension. Methods. In this double‐blind, multicenter study, 355 elderly patients with hypertension [office mean sitting systolic blood pressure (msSBP) ⩾145–<180 mmHg and mean 24‐h ambulatory systolic BP (ASBP) ⩾135 mmHg] were randomized to once‐daily treatment for 8 weeks with aliskiren 75 mg (n = 91), 150 mg (n = 84), 300 mg (n = 94) or the comparator lisinopril 10 mg (n = 86). The primary efficacy variable was change in mean 24‐h ASBP. Results. At endpoint, aliskiren 75 mg, 150 mg, 300 mg and lisinopril 10 mg lowered mean 24‐h ASBP (least‐squares mean±SEM) by 8.4±0.8, 7.1±0.8, 8.7±0.8 and 10.2±0.9 mmHg, and mean 24‐h ambulatory diastolic BP by 4.5±0.5, 3.6±0.5, 3.9±0.5 and 6.3±0.5 mmHg, respectively, with no significant difference between aliskiren doses. The trough‐to‐peak ratio for ASBP reduction with aliskiren 75 mg, 150 mg, 300 mg and lisinopril 10 mg was 0.77, 0.64, 0.79 and 0.87, respectively. All treatments lowered office msSBP and mean sitting diastolic BP (msDBP) compared with baseline. A significantly greater proportion of patients receiving aliskiren 300 mg achieved BP control (msSBP/msDBP <140/90 mmHg) compared with those receiving aliskiren 75 mg (36.2% vs 24.2%, p = 0.033). There was no evidence of dose‐related increases in the rate of adverse events with aliskiren treatment. Conclusions. Aliskiren, a novel direct renin inhibitor, provides effective 24‐h BP lowering with no evidence of dose‐related increases in the incidence of adverse events in elderly patients with hypertension. Trial registration: ClinicalTrials.gov identifier: NCT00219167.
Higher blood vessel density in comparison to the lymphatic vessels in oral squamous cell carcinoma.

INTRODUCTION Oral squamous cell carcinoma (OSCC) is characterized by local invasion and the development of cervical metastasis. In the tongue, an association between the invasion of the lymphatic vessels and the development of metastasis in the regional lymph nodes has been demonstrated. Moreover, invasion of the blood vessels is associated with greater recurrence and poorer prognoses. Therefore, the presence and density of lymphatic and blood vessels in intra- and peritumoral tissues should play an important role in the progression, dissemination and metastasis of carcinomas. However, the evidence regarding OSCC is inconclusive. The aim of this study was to determine the comparison and association between the lymphatic (D2-40) and blood vessel (CD34) densities in intratumoral OSCC tissue. MATERIALS AND METHODS Thirty-seven cases diagnosed as OSCC between the years 2000 and 2008 were obtained from the Anatomic Pathology Service of the School of Dentistry, University of Chile. The immunohistochemical markers D2-40 and CD34 were used, and the densities (mm(2)) of lymphatic vessels (LVD) and blood vessels (BVD) in the intratumoral region were determined. The relationship between LVD and BVD values was evaluated. RESULTS There were significant association between the CD34 and D2-40 expression (rho=0.4, P<0.05) and between the LVD and the location in the tongue (P=0.019). The BVD was greater (128.0 vessels/mm(2)) than the LVD (42.9 vessels/mm(2)), and there was a positive correlation between the LVD and BVD. CONCLUSIONS In OSCC, the BVD is greater than the LVD, and there is a moderate correlation between the two quantities.
Distribution of 37 mucosotropic HPV types in women with cytologically normal cervical smears: The age‐related patterns for high‐risk and low‐risk types

Before guidelines can be set for the use of high‐risk human papillomavirus (HR HPV) testing in cervical cancer screening and vaccine preparation, age‐related prevalence of HR HPV types in cytologically normal smears has to be known. Therefore, in a cross‐sectional study the prevalence of 37 different HPV genotypes and putatively unidentified HPV types was determined in 3,305 cytologically normal cervical smears from the general female population (15–69 years of age) using an HPV general primer GP5+/bioGP6+ mediated PCR assay. Subsequently, HPV‐positive cervical smears were typed for 19 HR and 18 low‐risk (LR) HPVs with an enzyme immunoassay using HPV type‐specific oligoprobes in cocktails and individually, respectively. Overall, −HR and −LR HPV prevalences appeared to be of 4.6%, 3.3%, and 1.0%, respectively. Twenty‐six different HPV types were detected in the 152 HPV‐positive samples, the most prevalent types being HPV 16, 31, and 18. With regard to age, a peak prevalence of 19.6% for all HPVs was found in women 25–29 years of age, which declined to a mean of 4.3% in women over 30 years. With regard cytologically normal cervical smears (n = 3,011) of women participating in the population‐based screening program in the Netherlands (30 to 60 years), all HR HPVs showed decreased occurrence with increasing age, whereas the prevalence of LR HPV types remained constant. We suggest that screening for abnormal cytology implies screening for HR HPV infections and the subsequent treatment results in a decline of HR HPV prevalence in contrast to LR HPV prevalence during the years of screening. Int. J. Cancer 87:221–227, 2000. © 2000 Wiley‐Liss, Inc.
Molecular modeling studies on CNG channel from bovine retinal rod: A structural model of the cyclic nucleotide‐binding domain

A dimeric model of the cyclic nucleotide‐binding domain of the all‐α homomeric cyclic nucleotide‐gated channel from bovine retinal rod is constructed. The model, based on the structure of the fairly homologous catabolite gene activator protein (Weber and Steitz, J Mol Biol 1987;198:311–326), is obtained by use of comparative modeling and molecular dynamics simulations. Our model provides a structural basis for the experimentally measured difference in activity between cAMP and cGMP, as well as the different solvent accessibilities of GLY597 in the complex with cGMP, with cAMP and in the protein in free state. In addition, it provides support for the rearrangement of the domain C helix on ligand binding and releasing proposed by Matulef et al. (Neuron 1999;24:443–452). Proteins 2003;52:332–338. © 2003 Wiley‐Liss, Inc.
Advances in treatment of pulmonary arterial hypertension: patent review

ABSTRACT Introduction: Current therapeutic approaches for pulmonary arterial hypertension (PAH) commonly include use of prostacyclins, endothelin pathway antagonists or NO (nitric oxide) pathway modulators. These agents are non-specific and suffer from several important shortcomings including short half-lives, invasive routes of administration, higher dose and frequency requirements, and several dose-related systemic side effects. Hence, discovery of novel agents with improved therapeutic efficacy with respect to survival benefits and the development of non-invasive routes of administration are in critical need. Current research aimed at developing more selective therapies for PAH are focused both on agents acting on novel molecular targets, as well as, novel compounds acting on conventional pathways with improved characteristics. Area covered: The present review covers recently filed (issued/application) patents (2010–2016) describing novel agents acting on investigational targets as well as novel compounds with improved characteristics acting on established targets. Patents describing combinations of conventional and investigational compounds are also discussed. Expert opinion: PAH has recently been considered as cancer-like disease with over-proliferation of pulmonary arterial smooth muscle cells and endothelial cells. New cellular and molecular biological advances have revealed novel target/pathways involved in the pathogenesis and progression of PAH. Thus, discovery of agents that act on these novel pathways provides a promising avenue of research for improving therapeutic approaches for PAH.
Advances in pharmacotherapy for wet age-related macular degeneration

Introduction: In developed countries, neovascular age-related macular degeneration (AMD) is the leading cause of irreversible central blindness. Although AMD pathogenesis is complex and still not fully understood, many involved mechanisms are already partially known and could be promising targets for future therapies. Currently, anti-VEGF drugs are the standard care of this condition. Areas covered: This review summarizes both the current available and the emerging pharmacological therapies for the management of neovascular AMD. At first, we briefly focused on anti-VEGF compounds that are commonly used. Then, we reviewed the mechanisms of action and potential advantages of new candidate drugs that are being evaluated in clinical trials. Expert opinion: Although anti-VEGF drugs have shown mild-term good efficacy and safety profile in the treatment of neovascular AMD, they are far away from being a perfect therapy. Pharmacological research should focus on finding new molecular targets in the AMD pathogenetical pathway and on developing longer lasting agents or new drug delivery systems. Besides the development of new drugs, a better characterization of patients is also needed, taking into account variables such as choroidal neovascularization subtypes and genetic factors, in order to identify a tailored treatment for each patient.
Stability of cognitive performance in older patients with schizophrenia: an 8-week test-retest study.

OBJECTIVE It is important to understand the stability of cognitive performance in schizophrenia in order to understand 1) the potential improvements in performance associated with the beneficial effects of cognitive-enhancing medications and 2) the potential variation in performance on cognitive measures that are components of neuroimaging studies. There are several factors that could lead to spurious improvements in cognitive test scores, including practice effects and random test-retest errors. METHOD Forty-five older patients with schizophrenia who were receiving conventional antipsychotic medications participated in the study. All subjects completed a comprehensive neuropsychological test battery at baseline and again at an 8-week follow-up evaluation. RESULTS Performance on all of the cognitive measures was stable over time, as evidenced by significant test-retest correlations, and practice effects were generally absent or minimal. Tests administered with alternate forms were no more temporally stable than tests administered twice with the same form. Very few individual cases had substantial variation at retest across the 22 test scores. From these data, "norms for evaluating change" were developed and described using the reliable change index method. CONCLUSIONS The data suggest that the findings of modest cognitive improvements seen in some prior studies of schizophrenia patients when treated with second-generation antipsychotic medications were probably not due to simple retesting artifacts. At the same time, because of the variance in some of these test-retest performances, relatively substantial changes in performance on the part of individual patients would be required to be clearly interpretable.
In Vivo Assessment of Dopamine and Norepinephrine Release in Rat Neocortex: Gas Chromatography‐Mass Spectrometry Measurement of 3‐Methoxytyramine and Normetanephrine

Abstract: A new method with the sensitivity and specificity required to measure regional levels of 3‐methoxytyramine (3‐MT) and normetanephrine (NMN) in the rat cortex is described. The method utilizes a liquid ion exchanger to isolate the parent amines, dopamine (DA) and norepinephrine (NE), along with their methylated metabolites. These samples are derivatized and analyzed by negative ion gas chro‐matography‐mass spectrometry. Using this method, we examined a number of drug actions on steady‐state levels as well as pargyline‐induced increases in 3‐MT and NMN. In the prefrontal cortex, cingulate cortex, striatum, and olfactory tubercle, nomifensine was found to increase 3‐MT steady‐state levels and accumulation rates. Similar actions of this drug were observed in the cingulate and prefrontal cortices with NMN. In contrast, clonidine decreased cortical NMN levels and accumulation. A unique action was observed with haloperidol, in that both 3‐MT levels and accumulation after pargyline were increased in the nigrostriatal and mesolimbic dopaminergic projections, whereas only the accumulation rates were accelerated in the mesocortical projections. In summary, our data indicate that this new assay is a useful approach for the in vivo evaluation of DA and NE release in cortical regions of the rat. This approach is unique in that no surgery, restraint, or anesthetic is required, thereby permitting more complicated experimental paradigms to be utilized.
Etude de mécanismes moléculaires et de lois physiques qui régissent l'auto-organisation des microtubules en réseaux ordonnés et complexes in vitro

Le cytosquelette de microtubule (MT) est essentiel dans de nombreux processus cellulaire. Il est notamment implique dans le trafic intracellulaire, la division cellulaire, la modification et le maintien de la forme de la cellule. En fonction du type cellulaire ou de son etat de differenciation, les reseaux de MTs vont adopter des architectures differentes. Ces organisations sont definies par des contraintes geometriques intracellulaires et l'activite moleculaire de nombreuses proteines associees aux MTs (MAPs). Parmi ces proteines, des membres de la famille des MAP65s ont ete identifies. In vitro, elles forment des ponts entre les MTs pour les organiser en faisceaux. Le but de mon travail de these a ete d'etudier in vitro le role de MAP65s dans l'auto-organisation d'un reseau de faisceaux de MTs. Dans un premier temps, j'ai mis au point un systeme biomimetique utilisant la technique de « micro-patterning » qui imposent une geometrie d'assemblage pour les MTs dans des limites qui se rapprochent de celles observees dans les cellules. Cette methode permet de controler precisement l'assemblage des MTs a partir de zones dont les formes, la taille et la distribution des unes par rapport aux autres sont definies. Pour valider cette technique, j'ai reconstitue des reseaux qui miment des architectures cellulaires (i.e modules du fuseau mitotique). Dans un deuxieme temps j'ai etudie le role de MAP65s dans l'auto-organisation de reseaux de faisceaux de MTs, et plus particulierement l'etape de co-alignement entre MTs dynamiques et disperses. J'ai montre que MAP65-1 de plante et son orthologue chez la levure, Ase1, diminuent fortement la longueur de persistance de MTs isoles ou organises en faisceaux. Cet assouplissement leur permet de se deformer et donc de se co-aligner pour former des faisceaux lorsqu'ils se rencontrent a des angles de rencontre eleves. L'augmentation de flexibilite est du a l'interaction du domaine de liaison de MAP65-1/Ase1 avec la lattice des MTs. Ces resultats suggerent que la diminution de la rigidite des MTs controle dans les cellules l'issue des evenements des rencontres entre MTs. De facon plus generale, la modulation des proprietes mecaniques des MTs par des MAPs represente un nouveau mecanisme pour reguler la plasticite des reseaux de MTs dans les cellules eucaryotes.
Trafficking of host- and donor-derived dendritic cells in rat cardiac transplantation: allosensitization in the spleen and hepatic nodes.

BACKGROUND Kinetics and role of host and donor dendritic cells (DCs) in transplantation immunity are still ill-defined. Using a rat cardiac transplantation model, we studied DC trafficking and sites for allosensitization. METHODS Host and donor DCs were defined as host- or donor-type class II major histocompatibility complex antigen single-positive cells by double-immunostaining. Proliferative response of both donor and host cells were also analyzed. RESULTS Host DCs were recruited to the graft soon after transplantation. These cells represented definitive precursors because of high labeling index by a continuous bromodeoxyuridine infusion, their small round shape, and their putative bone marrow origin. Donor interstitial DCs showed a significant self-replicating capability. Both recruited host DCs in a regraft experiment and donor DCs preferentially performed blood-borne migration to the T-cell area of host spleen. Furthermore, they also migrated to the T-cell area of hepatic lymph nodes after executing the sinusoids-lymph translocation as a novel pathway for these DCs. Selectively at their migration sites, a strong T-cell proliferative response occurred, which preceded that in the graft tissues. Removal of spleen and hepatic lymph nodes significantly prolonged the mean graft survival time. CONCLUSION We conclude that allogeneic heart transplantation induces the recruitment of host DC precursors to the graft tissues and the blood-borne migration of both recruited host and donor DCs to the host spleen and hepatic nodes where effector cells are predominantly sensitized.