El COVID-19 también Afecta el Sistema Nervioso por una de sus Compuertas: El Órgano Vascular de la Lámina Terminal y el Nervio Olfatorio. Alerta Neurológica, Prueba de Disosmia o Anosmia Puede Ayudar a Un Diagnóstico Rápido / COVID-19 also Affects the Nervous System by One of its Gates: The Vascular Organ of Lamina Terminalis and the Olfactory Nerve. Neurological Alert, Dysosmia or Anosmia Test Can Help to A Quick Diagnosis

Se presenta una breve revisión de órgano vascular de la lámina terminal (organum vasculosum laminae terminalis) y el nervio olfatorio, el primero un elemento neuroanatómico hipotalámico relacionado con la producción de hormona antidiurética y su asociación como una vía potencial de invasión del COVID-19 al sistema nervioso central, afectando la regulación fisiológica de liberación de hormonas relacionadas con la homeostásis del sodio. También se vincula el neurotropismo de este virus al asociarse con el nervio olfatorio, una evaginación del cerebro en la que se altera su funcionalidad por generación de disosmia entre otras características neurosemiológicas. Se plantea la necesidad de advertir a los profesionales de la salud en general y a los neurólogos en especial, sobre las potenciales alteraciones neurológicas relacionadas con esta pandemia antes y después del contagio de este virus e implementar una prueba olfatoria rápida con ácido acético, incluso antes de otras valoraciones como hipertérmia, tos y cefalalgia.

Effect of Chemical Denture Disinfectants and Tree Extracts on Biofilm-forming Staphylococcus aureus and Viridans Streptococcus Species Isolated from Complete Denture.

AIMS: The present study aims at recording the antibacterial efficacy of various disinfectants used at different time periods against Staphylococcus aureus and viridans streptococcal species of bacteria isolated from complete dentures. MATERIALS AND METHODS: Fifty complete denture patients were selected for the study and swabs were collected from their complete denture surfaces. The isolated bacteria were subjected to six experimental groups which includes four groups of chemical denture disinfectants and two tree extracts groups. Isolation of the bacteria S. aureus and viridians streptococcal species was done by means of selective media and confirmed by means of biochemical tests. The bacteria were subjected to biofilm assays. The biofilm-forming bacteria with optical density (O.D.) values of more than 1.5 were selected for the study. About 150 acrylic specimens were fabricated and were contaminated by the 2 isolated bacteria mentioned above. The contaminated samples were disinfected by immersion for 10, 20, and 30 minutes in six disinfectants, namely: (1) 1% sodium hypochlorite, (2) 2% chlorhexidine, (3) 2% glutaraldehyde, (4) 3.8% sodium perborate, (5) 2% aalam extract, and (6) 2% neem extract. RESULTS: ANOVA test was performed for both S. aureus and viridans streptococcal species with regard to various synthetic and tree extracts as well as time duration of disinfection. F values for disinfection vs S. aureus is 205.4 (p < 0.001) and the relevant Scheffe post hoc test values is in the following order: 3 < 1, 4 < 6, 2 < 5. F values for disinfection vs viridans streptococcal species is 364.7 (p < 0.001) and the relevant Scheffe post hoc test values is in the following order: 3 < 4 < 1, 6, 2 < 5. CONCLUSION: For biofilm-forming S. aureus, 2% glutaraldehyde showed best antibacterial efficacy which was followed by 1% sodium hypochlorite and 3.8% sodium perborate. When it comes to biofilm-forming viridans streptococcal species, 2% glutaraldehyde showed best antibacterial efficacy. Next to 2% glutaraldehyde, 3.8% sodium perborate exhibited good disinfection potential. CLINICAL SIGNIFICANCE: Complete denture patients have a plethora of microorganisms habitating their complete dentures. Some bacteria are capable of causing systemic illness such as aspiration pneumonia and endocarditis. Hence, constant removal and disinfection of biofilms from the denture surface is vital to the local and systemic wellness of the patient. The most common bacteria capable of causing pneumonia and endocarditis that are isolated from complete dentures include S. aureus and viridans streptococcal species. The present study evaluates antibacterial efficacy of different disinfection agents especially against these biofilm-forming bacteria for different time periods. How to cite this article: Andonissamy L, Karthigeyan S, Ali SA, et al. Effect of Chemical Denture Disinfectants and Tree Extracts on Biofilm-forming Staphylococcus aureus and Viridans Streptococcus Species Isolated from Complete Denture. J Contemp Dent Pract 2019;20(11):1307-1314.

The design and synthesis of novel spirocyclic heterocyclic sulfone ROMK inhibitors as diuretics.

A spirocyclic class of ROMK inhibitors was developed containing a structurally diverse heterocyclic sulfone moiety and spirocyclic core starting from lead 1. These compounds not only displayed exquisite ROMK potency but significantly improved selectivity over hERG. The lead compounds were found to have favorable pharmacokinetic properties and displayed robust diuretic, natriuretic and blood pressure lowering effects in spontaneously hypertensive rats.

Discovery of a potent and selective ROMK inhibitor with improved pharmacokinetic properties based on an octahydropyrazino[2,1-c][1,4]oxazine scaffold.

Following the discovery of small molecule acyl piperazine ROMK inhibitors, the acyl octahydropyrazino[2,1-c][1,4]oxazine series was identified. This series displays improved ROMK/hERG selectivity, and as a consequence, the resulting ROMK inhibitors do not evoke QTc prolongation in an in vivo cardiovascular dog model. Further efforts in this series led to the discovery of analogs with improved pharmacokinetic profiles. This new series also retained comparable ROMK potency compared to earlier leads.

Discovery of MK-7145, an Oral Small Molecule ROMK Inhibitor for the Treatment of Hypertension and Heart Failure.

ROMK, the renal outer medullary potassium channel, is involved in potassium recycling at the thick ascending loop of Henle and potassium secretion at the cortical collecting duct in the kidney nephron. Because of this dual site of action, selective inhibitors of ROMK are expected to represent a new class of diuretics/natriuretics with superior efficacy and reduced urinary loss of potassium compared to standard-of-care loop and thiazide diuretics. Following our earlier work, this communication will detail subsequent medicinal chemistry endeavors to further improve lead selectivity against the hERG channel and preclinical pharmacokinetic properties. Pharmacological assessment of highlighted inhibitors will be described, including pharmacodynamic studies in both an acute rat diuresis/natriuresis model and a subchronic blood pressure model in spontaneous hypertensive rats. These proof-of-biology studies established for the first time that the human and rodent genetics accurately predict the in vivo pharmacology of ROMK inhibitors and supported identification of the first small molecule ROMK inhibitor clinical candidate, MK-7145.

The Renal Outer Medullary Potassium Channel Inhibitor, MK-7145, Lowers Blood Pressure, and Manifests Features of Bartter's Syndrome Type II Phenotype.

The renal outer medullary potassium (ROMK) channel, located at the apical surface of epithelial cells in the thick ascending loop of Henle and cortical collecting duct, contributes to salt reabsorption and potassium secretion, and represents a target for the development of new mechanism of action diuretics. This idea is supported by the phenotype of antenatal Bartter's syndrome type II associated with loss-of-function mutations in the human ROMK channel, as well as, by cardiovascular studies of heterozygous carriers of channel mutations associated with type II Bartter's syndrome. Although the pharmacology of ROMK channels is still being developed, channel inhibitors have been identified and shown to cause natriuresis and diuresis, in the absence of any significant kaliuresis, on acute oral dosing to rats or dogs. Improvements in potency and selectivity have led to the discovery of MK-7145 [5,5'-((1R,1'R)-piperazine-1,4-diylbis(1-hydroxyethane-2,1-diyl))bis(4-methylisobenzofuran-1(3H)-one)], a potential clinical development candidate. In spontaneously hypertensive rats, oral dosing of MK-7145 causes dose-dependent lowering of blood pressure that is maintained during the entire treatment period, and that displays additive/synergistic effects when administered in combination with hydrochlorothiazide or candesartan, respectively. Acute or chronic oral administration of MK-7145 to normotensive dogs led to dose-dependent diuresis and natriuresis, without any significant urinary potassium losses or changes in plasma electrolyte levels. Elevations in bicarbonate and aldosterone were found after 6 days of dosing. These data indicate that pharmacological inhibition of ROMK has potential as a new mechanism for the treatment of hypertension and/or congestive heart failure. In addition, Bartter's syndrome type II features are manifested on exposure to ROMK inhibitors.

Differentiation of ROMK potency from hERG potency in the phenacetyl piperazine series through heterocycle incorporation.

Following the discovery of small molecule acyl piperazine ROMK inhibitors and their initial preclinical validation as a novel diuretic agent, our group set out to discover new ROMK inhibitors with reduced risk for QT effects, suitable for further pharmacological experiments in additional species. Several strategies for decreasing hERG affinity while maintaining ROMK inhibition were investigated and are described herein. The most promising candidate, derived from the newly discovered 4-N-heteroaryl acetyl series, improved functional hERG/ROMK ratio by >10× over the previous lead. In vivo evaluation demonstrated comparable diuretic effects in rat with no detectable QT effects at the doses evaluated in an in vivo dog model.

Discovery of a Potent and Selective ROMK Inhibitor with Pharmacokinetic Properties Suitable for Preclinical Evaluation.

A new subseries of ROMK inhibitors exemplified by 28 has been developed from the initial screening hit 1. The excellent selectivity for ROMK inhibition over related ion channels and pharmacokinetic properties across preclinical species support further preclinical evaluation of 28 as a new mechanism diuretic. Robust pharmacodynamic effects in both SD rats and dogs have been demonstrated.

pSnakes: a new radial active contour model and its application in the segmentation of the left ventricle from echocardiographic images.

Active contours are image segmentation methods that minimize the total energy of the contour to be segmented. Among the active contour methods, the radial methods have lower computational complexity and can be applied in real time. This work aims to present a new radial active contour technique, called pSnakes, using the 1D Hilbert transform as external energy. The pSnakes method is based on the fact that the beams in ultrasound equipment diverge from a single point of the probe, thus enabling the use of polar coordinates in the segmentation. The control points or nodes of the active contour are obtained in pairs and are called twin nodes. The internal energies as well as the external one, Hilbertian energy, are redefined. The results showed that pSnakes can be used in image segmentation of short-axis echocardiogram images and that they were effective in image segmentation of the left ventricle. The echo-cardiologist's golden standard showed that the pSnakes was the best method when compared with other methods. The main contributions of this work are the use of pSnakes and Hilbertian energy, as the external energy, in image segmentation. The Hilbertian energy is calculated by the 1D Hilbert transform. Compared with traditional methods, the pSnakes method is more suitable for ultrasound images because it is not affected by variations in image contrast, such as noise. The experimental results obtained by the left ventricle segmentation of echocardiographic images demonstrated the advantages of the proposed model. The results presented in this paper are justified due to an improved performance of the Hilbert energy in the presence of speckle noise.

Genetic analysis of Porphyromonas gingivalis (fimA), Aggregatibacter actinomycetemcomitans, and red complex in coronary plaque.

AIM: The objective of the present study was to detect the presence of Porphyromonas gingivalis (fimA), Aggregatibacter actinomycetemcomitans, and red complex in the coronary plaque of patients with coronary artery disease. METHODS: The study population consisted of 51 patients with chronic periodontitis undergoing coronary artery bypass grafting. DNA was extracted from subgingival and coronary atherosclerotic plaque samples. Polymerase chain reaction was used to amplify the part of 16S rRNA gene to detect the presence of Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis (fimA), Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola. RESULTS: Aggregatibacter actinomycetemcomitans, Tannerella forsythia, Porphyromonas gingivalis, Porphyromonas gingivalis (fimA), and Treponema denticola were detected in 0%, 31.4%, 45.1%, 39.2%, and 51% of the atherosclerotic plaque samples, respectively. In both subgingival and coronary atherosclerotic plaque samples, Tannerella forsythia was detected in 19.6%, Porphyromonas gingivalis in 39.2%, Porphyromonas gingivalis (fimA) in 33.3%, and Treponema denticola in 35.3% of the samples. CONCLUSION: The study confirmed the detection of red complex bacteria in coronary plaque samples. However Aggregatibacter actinomycetemcomitans could not be detected in these samples.

Pharmacologic inhibition of the renal outer medullary potassium channel causes diuresis and natriuresis in the absence of kaliuresis.

The renal outer medullary potassium (ROMK) channel, which is located at the apical membrane of epithelial cells lining the thick ascending loop of Henle and cortical collecting duct, plays an important role in kidney physiology by regulating salt reabsorption. Loss-of-function mutations in the human ROMK channel are associated with antenatal type II Bartter's syndrome, an autosomal recessive life-threatening salt-wasting disorder with mild hypokalemia. Similar observations have been reported from studies with ROMK knockout mice and rats. It is noteworthy that heterozygous carriers of Kir1.1 mutations associated with antenatal Bartter's syndrome have reduced blood pressure and a decreased risk of developing hypertension by age 60. Although selective ROMK inhibitors would be expected to represent a new class of diuretics, this hypothesis has not been pharmacologically tested. Compound A [5-(2-(4-(2-(4-(1H-tetrazol-1-yl)phenyl)acetyl)piperazin-1-yl)ethyl)isobenzofuran-1(3H)-one)], a potent ROMK inhibitor with appropriate selectivity and characteristics for in vivo testing, has been identified. Compound A accesses the channel through the cytoplasmic side and binds to residues lining the pore within the transmembrane region below the selectivity filter. In normotensive rats and dogs, short-term oral administration of compound A caused concentration-dependent diuresis and natriuresis that were comparable to hydrochlorothiazide. Unlike hydrochlorothiazide, however, compound A did not cause any significant urinary potassium losses or changes in plasma electrolyte levels. These data indicate that pharmacologic inhibition of ROMK has the potential for affording diuretic/natriuretic efficacy similar to that of clinically used diuretics but without the dose-limiting hypokalemia associated with the use of loop and thiazide-like diuretics.

Modelo de Contorno Ativo Crisp Adaptativo 2D aplicado na segmentação dos pulmões em imagens de TC do tórax de voluntários sadios e pacientes com enfisema pulmonar / Adaptive 2D Crisp Active Contour Model applied to lung segmentation in CT images of the thorax of healthy volunteers and patients with pulmonary emphysema

INTRODUÇÃO: Dentre as doenças que afetam a população mundial, destaca-se a preocupação com a Doença Pulmonar Obstrutiva Crônica (DPOC), que, segundo a Organização Mundial de Saúde, pode se constituir na terceira causa de morte mais importante em todo mundo no ano de 2030. Visando contribuir com o auxílio ao diagnóstico médico, esta pesquisa centraliza seus esforços na etapa de segmentação dos pulmões, visto que esta é a etapa básica de sistema de Visão Computacional na area de pneumologia. MÉTODOS: Este trabalho propõe um novo método de segmentação dos pulmões em imagens de Tomografia Computadorizada (TC) do tórax chamado de Método de Contorno Ativo (MCA) Crisp Adaptativo 2D. Este MCA consiste em traçar automaticamente uma curva inicial dentro dos pulmões, que se deforma por iterações sucessivas, minimizando energias que atuam sobre a mesma, deslocando-a até as bordas do objeto. O MCA proposto é o resultado do aperfeiçoamento do MCA Crisp desenvolvido previamente, visando aumentar a sua exatidão, diminuindo o tempo de análise e reduzindo a subjetividade na segmentação e análise dos pulmões dessas imagens pelos médicos especialistas. Este método por iterações sucessivas de minimização de sua energia, segmenta de forma automática os pulmões em imagens de TC do tórax. RESULTADOS: Para sua validação, o MCA Crisp Adaptativo é comparado com os MCAs THRMulti, THRMod, GVF, VFC, Crisp e também com o sistema SISDEP, sendo esta avaliação realizada utilizando como referência 24 imagens, sendo 12 de pacientes com DPOC e 12 de voluntários sadios, segmentadas manualmente por um pneumologista. Os resultados obtidos demonstram que o método proposto é superior aos demais. CONCLUSÃO: Diante dos resultados obtidos, pode-se concluir que este método pode integrar sistemas de auxílio ao diagnóstico médico na área de Pneumologia.

INTRODUCTION: Among the diseases that affect the world's population, there is concern about Chronic Obstructive Pulmonary Disease (COPD), that, according to the World Health Organization, could be the leading cause of death worldwide by the year 2030. Aiming to contribute to aid medical diagnosis, this research focuses its efforts on the segmentation of the lungs, since this is the basic step system in the area of Computer Vision pulmonology. METHODS: This paper proposes a new method for segmentation of lung images in Computed Tomography (CT) of the chest called Active Contour Method (MCA) Crisp Adaptive 2D. This MCA is to draw a curve starting inside an object of interest. This curve is deformed by successive iterations, minimizing energies that act on it, moving it to the edges of the object. The MCA is the improvement of the proposed MCA Crisp previously developed, aiming to increase the accuracy, decreasing analysis time and reducing the subjectivity in the segmentation and analysis of the lungs of these images by pulmonologists. This method is automatically initialized in the lungs and on successive iterations to minimize this energy, this MCA automatically targets the lungs in chest CT images. RESULTS: To evaluate the proposed method, the MCA Adaptive Crisp is compared with MCAs THRMulti, THRMod, GVF, VFC, Crisp and also with the system SISDEP, this assessment is performed using reference images 24, 12 COPD patients and 12 volunteers healthy, manually segmented by a pulmonologist. The results show that the proposed method is superior to the others. CONCLUSION: Based on the results, it can be concluded that this method can integrate systems aid in the medical diagnosis of Pulmonology.

Segmentação automática 2D de vias aéreas em imagens de tomografia computadorizada do tórax / Automatic 2D segmentation of airways in thorax computed tomography images

INTRODUÇÃO: Grande parte da população mundial é afetada por doenças pulmonares, como é o caso das broncopatias constituídas pela asma, bronquiectasia e a bronquite. O diagnóstico de broncopatias é baseado no estado das vias aéreas. Neste sentido, a segmentação automática das vias aéreas em imagens de Tomografia Computadorizada (TC) do tórax é uma etapa fundamental para auxílio ao diagnóstico dessas doenças. MÉTODOS: O presente trabalho avalia algoritmos e desenvolve métodos de segmentação automática das vias aéreas 2D. Tais métodos são compostos por algoritmos de detecção de vias aéreas, sendo estes rede neural Multilayer Perceptron (MLP) e Análise de Densidades Pulmonares (ADP), e por algoritmos de segmentação de vias aéreas, sendo estes Crescimento de Região (CR), Método de Contornos Ativos (MCA) Balão e Topológico Adaptativo. RESULTADOS: Os resultados foram obtidos em três etapas: análise comparativa entre os algoritmos de detecção MLP e ADP, com um padrão-ouro adquirido por três médicos com expertise em imagens de TC do tórax; análise comparativa entre algoritmos de segmentação MCA balão, MCA topológico adaptativo, MLP e CR; e avaliação das possíveis combinações entre os algoritmos de detecção e segmentação, resultando no método completo para segmentação automática das vias aéreas em 2D. CONCLUSÃO: A baixa incidência de falso-negativo e a redução significativa de falso-positivo, resulta em coeficiente de similaridade e sensibilidade superior a 91% e 87% respectivamente, para uma combinação dos algoritmos, com qualidade de segmentação satisfatória.

INTRODUCTION: Much of the world population is affected by pulmonary diseases, such as the bronchial asthma, bronchitis and bronchiectasis. The bronchial diagnosis is based on the airways state. In this sense, the automatic segmentation of the airways in Computed Tomography (CT) scans is a critical step in the aid to diagnosis of these diseases. METHODS: This paper evaluates algorithms for airway automatic segmentation, using Neural Network Multilayer Perceptron (MLP) and Lung Densities Analysis (LDA) for detecting airways, along with Region Growing (RG), Active Contour Method (ACM) Balloon and Topology Adaptive to segment them. RESULTS: We obtained results in three stages: comparative analysis of the detection algorithms MLP and LDA, with a gold standard acquired by three physicians with expertise in CT imaging of the chest; comparative analysis of segmentation algorithms ACM Balloon, ACM Topology Adaptive, MLP and RG; and evaluation of possible combinations between segmentation and detection algorithms, resulting in the complete method for automatic segmentation of the airways in 2D. CONCLUSION: The low incidence of false negative and the significant reduction of false positive, results in similarity coefficient and sensitivity exceeding 91% and 87% respectively, for a combination of algorithms with satisfactory segmentation quality.

Discovery of a novel sub-class of ROMK channel inhibitors typified by 5-(2-(4-(2-(4-(1H-Tetrazol-1-yl)phenyl)acetyl)piperazin-1-yl)ethyl)isobenzofuran-1(3H)-one.

A sub-class of distinct small molecule ROMK inhibitors were developed from the original lead 1. Medicinal chemistry endeavors led to novel ROMK inhibitors with good ROMK functional potency and improved hERG selectivity. Two of the described ROMK inhibitors were characterized for the first in vivo proof-of-concept biology studies, and results from an acute rat diuresis model confirmed the hypothesis that ROMK inhibitors represent new mechanism diuretic and natriuretic agents.

A novel benzazepinone sodium channel blocker with oral efficacy in a rat model of neuropathic pain.

A series of benzazepinones were synthesized and evaluated for block of Nav1.7 sodium channels. Compound 30 from this series displayed potent channel block, good selectivity versus other targets, and dose-dependent oral efficacy in a rat model of neuropathic pain.

Protective effect of glutathione against isoproterenol induced myocardial injury in rats.

Though there are studies to show protective effect of glutathione against neurotoxicity and nephrotoxicity, the present study was designed to investigate the cardio protective effect of glutathione against isoproterenol induced myocardial infarction in rats by demonstrating the changes in serum cardiac markers, antioxidant enzymes and ECG changes. Wistar male rats were randomly divided into four groups namely control (GI), glutathione (GII), isoproterenol (GIII) and glutathione + isoproterenol treated (GIV). Glutathione treated group-received glutathione (200 mg/kg body wt) orally for 30 days. Myocardial infarction was induced in rats by isoproterenol administration (100 mg/kg) subcutaneously (sc) at an interval of 24 hrs on 31st and 32nd day cardiac marker enzymes, ECG, lipid peroxidation and antioxidant enzymes were assessed 24 hrs after the last dose of isoproterenol. Isoproterenol showed changes in ECG pattern, increase in serum level of cardiac marker, increased lipid per oxidation and decreased antioxidant defense system in heart. Glutathione pretreatment brings almost all the parameters to near normal level in isoproterenol-induced myocardial infarction in rats. The present study revealed that glutathione ameliorates cardiac damage in isoproterenol induced myocardial infarction in rats due to potent antioxidant, free radical scavenging effect, myocardial adaptation at cellular and organ levels.

Prevelance of periodontopathogenic bacteria in subgingival biofilm and atherosclerotic plaques of patients undergoing coronary revascularization surgery.

AIM: The objective of the present study was to detect the presence of specific periodontopathogenic bacteria in the coronary plaque of patients with coronary artery disease and to find out the significant association between the periodontal status and the presence of pathogenic bacteria in the coronary plaque. MATERIALS AND METHODS: The study population consisted of 51 patients with chronic generalized periodontitis undergoing coronary artery bypass grafting. Periodontal parameters were recorded and deoxyribonucleic acid was extracted from the subgingival plaque and coronary atherosclerotic plaque samples of the same patients. Polymerase chain reaction was used to amplify the part of 16S ribosomal ribonucleic acid (rRNA) gene to detect the presence of Aggregatibacter actinomycetemcomitans (Aa), Tannerella forsythia (Tf), Porphyromonas gingivali (Pg), Porphyromonas gingivalis (fimA) gene and Treponema denticola (Td). RESULTS: Aa, Tf, Pg, Pg (fimA) gene and Td were detected in 0%, 31.4%, 45.1% 39.2% and 51% of atherosclerotic plaque samples, respectively. Tf was detected in 19.6%, Pg in 39.2%, Pg (fimA) gene in 33.3% and Td in 35.3% of both, subgingival plaque and atherosclerotic plaque samples. Periodontal parameters correlated with the presence of bacteria in coronary plaque. Aa could not be detected in coronary plaque samples. CONCLUSIONS: The study confirmed the detection of Red complex bacteria in coronary plaque samples and these bacteria correlated with the severity of periodontal destruction.

The inwardly rectifying potassium channel Kir1.1: development of functional assays to identify and characterize channel inhibitors.

The renal outer medullary potassium (ROMK) channel is a member of the inwardly rectifying family of potassium (Kir) channels. ROMK (Kir1.1) is predominantly expressed in kidney where it plays a major role in the salt reabsorption process. Loss-of-function mutations in the human Kir1.1 channel are associated with antenatal Bartter's syndrome type II, a life-threatening salt and water balance disorder. Heterozygous carriers of Kir1.1 mutations associated with antenatal Bartter's syndrome have reduced blood pressure and a decreased risk of developing hypertension by age 60. These data suggest that Kir1.1 inhibitors could represent novel diuretics for the treatment of hypertension. Because little is known about the molecular pharmacology of Kir1.1 channels, assays that provide a robust, reliable readout of channel activity-while operating in high-capacity mode-are needed. In the present study, we describe high-capacity, 384- and 1,536-well plate, functional thallium flux, and IonWorks electrophysiology assays for the Kir1.1 channel that fulfill these criteria. In addition, 96-well (86)Rb(+) flux assays were established that can operate in the presence of 100% serum, and can provide an indication of the effect of a serum shift on compound potencies. The ability to grow Madin-Darby canine kidney cells expressing Kir1.1 in Transwell supports provides a polarized cell system that can be used to study the mechanism of Kir1.1 inhibition by different agents. All these functional Kir1.1 assays together can play an important role in supporting different aspects of drug development efforts during lead identification and/or optimization.

Discovery of Selective Small Molecule ROMK Inhibitors as Potential New Mechanism Diuretics.

The renal outer medullary potassium channel (ROMK or Kir1.1) is a putative drug target for a novel class of diuretics that could be used for the treatment of hypertension and edematous states such as heart failure. An internal high-throughput screening campaign identified 1,4-bis(4-nitrophenethyl)piperazine (5) as a potent ROMK inhibitor. It is worth noting that this compound was identified as a minor impurity in a screening hit that was responsible for all of the initially observed ROMK activity. Structure-activity studies resulted in analogues with improved rat pharmacokinetic properties and selectivity over the hERG channel, providing tool compounds that can be used for in vivo pharmacological assessment. The featured ROMK inhibitors were also selective against other members of the inward rectifier family of potassium channels.

Santiago Felipe Ramón y Cajal, ¿Padre de la neurociencia o pionero de la ciencia neural? / Santiago Felipe Ramón y Cajal, ¿Neuroscience father or pioneer of neural science?

El objetivo de este trabajo es demostrar, con base en referentes de la literatura neurocientífica, que Santiago Ramón y Cajal no fue padre de la Neurociencia, pero sí uno de los pioneros de la ciencia neural. Para corroborar dicha aseveración se consultó información variada sobre Ramón y Cajal en la que se indicara que él es uno de los pioneros de la Neurociencia y se contrastó con el tiempo en que se instauró la Neurociencia como disciplina; luego se comparó dicha información con aspectos variados de otros personajes que pudieron no ser llamados fundadores de la Neurociencia. Se concluye que Santiago Felipe Ramón y Cajal no es el padre de la Neurociencia, aunque sí se resalta el que es considerado uno de los pioneros de la ciencia neural.

The present work on Santiago Ramón y Cajal aims to demonstrate on the basis of neuroscientist literature, that Santiago Ramón y Cajal was not the father or founder of Neuroscience, but is considered a neural science pioneer. In order to corroborate this statement, varied information on Ramón y Cajal was consulted within Neuroscience to determine if Ramón Y Cajal is one of the Neuroscience pioneers, and contrast that information with the beginnings of neuroscience as a discipline. Subsequently this information was compared with various aspects of other important figures who were not named Neuroscience founders. In conclusion Santiago Felipe Ramón and Cajal if not the father of Neuroscience, though it should be noted he is considered one of the pioneers of neural science.