scholarly journals Vasopressin Receptor Antagonists (Vaptans) in Heart Failure

2019 ◽  
Vol 17 ◽  
Author(s):  
Piotr Lipiec ◽  
Marco Metra
Keyword(s):  
Volume Overload ◽  
Minor Role ◽  
Receptor Subtypes ◽  
Vasopressin Receptor ◽  
Receptor Antagonists ◽  
Attractive Therapeutic Target ◽  
The Usa ◽  
A Minor ◽  
Long Term Mortality

Arginine vasopressin (a peptide neuroendocrine hormone) levels are elevated in patients with HF. Acting through 3 receptor subtypes, it can cause vasoconstriction and cardiac remodelling (receptors V1a), adrenocorticotropic hormone release (receptors V1b) and water reabsorption (receptors V2), thereby increasing preload and afterload. Vasopressin-receptor antagonists (vaptans), induce hypotonic diuresis and have been proposed as a treatment option for hyponatraemia, a known complication of HF. Three vaptans have been so tested; tolvaptan, conivaptan and lixivaptan, and  two (tolvaptan and conivaptan) have been approved for clinical use in hyponatraemia (in the USA). The EVEREST trial studied tolvaptan in over 4100 patients hospitalized with an exacerbation of chronic HF with reduced LVEF. No effect was seen on long-term mortality or HF-related morbidity, but there was greater weight loss and better dyspnoea and oedema relief over the short-term.  Similar results were seen in the AQUAMARINE study. The 2016 European HF guidelines, therefore gave the limited recommendation: “Tolvaptan may be used to treat patients with volume overload and resistant hyponatraemia”. Despite targeting  an attractive  therapeutic target,  vasopressin receptor antagonists (vaptans) have to date played only a minor role in our management of HF.

NgCAM and VAMP2 Reveal that Direct Delivery and Dendritic Degradation Maintain Axonal Polarity

2021 ◽  
Author(s):  
Alec T. Nabb ◽  
Marvin Bentley
Keyword(s):  
Membrane Proteins ◽  
Molecular Mechanisms ◽  
Minor Role ◽  
Axonal Membrane ◽  
Quantitative Analyses ◽  
Direct Delivery ◽  
Novel Strategy ◽  
Extreme Scale ◽  
A Minor

Neurons are polarized cells of extreme scale and compartmentalization. To fulfill their role in electrochemical signaling, axons must maintain a specific complement of membrane proteins. Despite being subject of considerable attention, the trafficking pathway of axonal membrane proteins is not well understood. Two pathways, direct delivery and transcytosis, have been proposed. Previous studies reached contradictory conclusions about which of these mediates delivery of axonal membrane proteins to their destination, in part because they evaluated long-term distribution changes and not vesicle transport. We developed a novel strategy to selectively label vesicles in different trafficking pathways and determined the trafficking of two canonical axonal membrane proteins, NgCAM and VAMP2. Results from detailed quantitative analyses of transporting vesicles differed substantially from previous studies and found that axonal membrane proteins overwhelmingly undergo direct delivery. Transcytosis plays only a minor role in axonal delivery of these proteins. In addition, we identified a novel pathway by which wayward axonal proteins that reach the dendritic plasma membrane are targeted to lysosomes. These results redefine how axonal proteins achieve their polarized distribution, a crucial requirement for elucidating the underlying molecular mechanisms. [Media: see text] [Media: see text] [Media: see text] [Media: see text]

scholarly journals Occurrence of L1014F and L1014S mutations in insecticide resistant Culex quinquefasciatus from filariasis endemic districts of West Bengal, India

2022 ◽  
Vol 16 (1) ◽  
pp. e0010000
Author(s):  
Priyanka Rai ◽  
Dhiraj Saha
Keyword(s):  
Culex Quinquefasciatus ◽  
West Bengal ◽  
Economic Status ◽  
Minor Role ◽  
Resistance Development ◽  
Vector Population ◽  
A Minor ◽  
First Time

Introduction Lymphatic filariasis causes long term morbidity and hampers the socio-economic status. Apart from the available treatments and medication, control of vector population Culex quinquefasciatus Say through the use of chemical insecticides is a widely applied strategy. However, the unrestrained application of these insecticides over many decades has led to resistance development in the vectors. Methods In order to determine the insecticide susceptibility/resistance status of Cx. quinquefasciatus from two filariasis endemic districts of West Bengal, India, wild mosquito populations were collected and assayed against six different insecticides and presence of L1014F; L1014S kdr mutations in the voltage-gated sodium channel gene was also screened along with the use of synergists to evaluate the role of major detoxifying enzymes in resistance development. Results The collected mosquito populations showed severe resistance to insecticides and the two synergists used–PBO (piperonyl butoxide) and TPP (triphenyl phosphate), were unable to restore the susceptibility status of the vector thereupon pointing towards a minor role of metabolic enzymes. kdr mutations were present in the studied populations in varying percent with higher L1014F frequency indicating its association with the observed resistance to pyrethroids and DDT. This study reports L1014S mutation in Cx. quinquefasciatus for the first time.

scholarly journals Cervical spinal 5-HT2A and 5-HT2B receptors are both necessary for moderate acute intermittent hypoxia-induced phrenic long-term facilitation

2019 ◽  
Vol 127 (2) ◽  
pp. 432-443 ◽  
Author(s):  
Arash Tadjalli ◽  
Gordon S. Mitchell
Keyword(s):  
Receptor Antagonist ◽  
Broad Spectrum ◽  
Intermittent Hypoxia ◽  
Receptor Activation ◽  
Mapk Signaling ◽  
Receptor Subtypes ◽  
Receptor Antagonists ◽  
Erk Mapk ◽  
Long Term Facilitation

Serotonin (5-HT) is a key regulator of spinal respiratory motor plasticity. For example, spinal 5-HT receptor activation is necessary for the induction of phrenic long-term facilitation (pLTF), a form of respiratory motor plasticity triggered by moderate acute intermittent hypoxia (mAIH). mAIH-induced pLTF is blocked by cervical spinal application of the broad-spectrum 5-HT-receptor antagonist, methysergide. However, methysergide does not allow distinctions between the relative contributions of different 5-HT receptor subtypes. Intravenous administration of the Gq protein-coupled 5-HT2A/2C receptor antagonist ketanserin blocks mAIH-induced pLTF when administered before, but not after, mAIH; thus, 5-HT2 receptor activation is necessary for the induction but not maintenance of mAIH-induced pLTF. However, systemic ketanserin administration does not identify the site of the relevant 5-HT2A/2C receptors. Furthermore, this approach does not differentiate between the roles of 5-HT2A versus 5-HT2C receptors, nor does it preclude involvement of other Gq protein-coupled metabotropic 5-HT receptors capable of eliciting long-lasting phrenic motor facilitation, such as 5-HT2B receptors. Here we tested the hypothesis that mAIH-induced pLTF requires cervical spinal 5-HT2 receptor activation and determined which 5-HT2 receptor subtypes are involved. Anesthetized, paralyzed, and ventilated adult male Sprague Dawley rats were pretreated intrathecally with cervical (~C3-C5) spinal injections of subtype selective 5-HT2A/2C, 5-HT2B, or 5-HT2C receptor antagonists before mAIH. Whereas cervical spinal 5-HT2C receptor inhibition had no impact on mAIH-induced pLTF, pLTF was no longer observed after pretreatment with either 5-HT2A/2C or 5-HT2B receptor antagonists. Furthermore, spinal pretreatment with an MEK/ERK MAPK inhibitor blocked phrenic motor facilitation elicited by intrathecal injections of 5-HT2A but not 5-HT2B receptor agonists. Thus, mAIH-induced pLTF requires concurrent cervical spinal activation of both 5-HT2A and 5-HT2B receptors. However, these distinct receptor subtypes contribute to phrenic motor facilitation via distinct downstream signaling cascades that differ in their requirement for ERK MAPK signaling. The demonstration that both 5-HT2A and 5-HT2B receptors make unique contributions to mAIH-induced pLTF advances our understanding of mechanisms that underlie 5-HT-induced phrenic motor plasticity. NEW & NOTEWORTHY Moderate acute intermittent hypoxia (mAIH) triggers a persistent enhancement in phrenic motor output, an effect termed phrenic long-term facilitation (pLTF). mAIH-induced pLTF is blocked by cervical spinal application of the broad-spectrum serotonin (5-HT) receptor antagonist methysergide, demonstrating the need for spinal 5-HT receptor activation. However, the exact type of 5-HT receptors required for initiation of pLTF remains unknown. To the best of our knowledge, the present study is the first to demonstrate that 1) spinal coactivation of two distinct Gq protein-coupled 5-HT2 receptor subtypes is necessary for mAIH-induced pLTF, and 2) these receptors contribute to pLTF via cascades that differ in their requirement for ERK MAPK signaling.

scholarly journals Hyponatremia and Congestive Heart Failure: A Marker of Increased Mortality and a Target for Therapy

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Adam Romanovsky ◽  
Sean Bagshaw ◽  
Mitchell H. Rosner
Keyword(s):  
Heart Failure ◽  
Clinical Trials ◽  
Free Water ◽  
Volume Overload ◽  
Decompensated Heart Failure ◽  
Vasopressin Receptor ◽  
Receptor Antagonists ◽  
Water Excretion ◽  
Multiple Systems ◽  
Developed World

Heart failure is one of the most common chronic medical conditions in the developed world. It is characterized by neurohormonal activation of multiple systems that can lead to clinical deterioration and significant morbidity and mortality. In this regard, hyponatremia is due to inappropriate and continued vasopressin activity despite hypoosmolality and volume overload. Hyponatremia is also due to diuretic use in an attempt to manage volume overload. When hyponatremia occurs, it is a marker of heart failure severity and identifies patients with increased mortality. The recent introduction of specific vasopressin-receptor antagonists offers a targeted pharmacological approach to these pathophysiological derangements. Thus far, clinical trials with vasopressin-receptor antagonists have demonstrated an increase in free-water excretion, improvement in serum sodium, modest improvements in dyspnea but no improvement in mortality. Continued clinical trials with these agents are needed to determine their specific role in the treatment of both chronic and decompensated heart failure.

Variation in the recruitment behaviour of seagrass seeds: implications for population dynamics and resource management

1999 ◽  
Vol 5 (4) ◽  
pp. 251 ◽  
Author(s):  
Graeme J. Inglis
Keyword(s):  
Field Studies ◽  
Clonal Plants ◽  
Minor Role ◽  
Spatial And Temporal Scales ◽  
Local Populations ◽  
Seed Supply ◽  
Seed Reserves ◽  
A Minor ◽  
Effective Conservation

Effective conservation of marine organisms requires an understanding of the processes that affect the establishment, persistence and extinction of local populations. Our knowledge of the recruitment of seagrasses comes largely from studies done at small spatial and temporal scales within extant meadows. Descriptions of the demography of local populations, therefore, typically emphasize prolific ramet production and only a minor role for sexual propagules. Recent genetic and field studies, however, have shown greater variation in recruitment behaviour than previously suspected. In this paper, I review what is known about the seeds of seagrasses ? including their dormancy, dispersability and requirements for germination and establishment ? and examine the utility of recent conceptual models, developed for terrestrial clonal plants, to explain the long-term dynamics of seagrass populations. Sizable variation among species in seed size and dispersal strategy appears to be related predictably to variation in life-history and rates of recruitment. Species with small, poorly-dispersed fruits (e.g., Halophila, Halodule) are more likely to form persistent seed reserves and be rapid colonizers of disturbances within established meadows. Genera with large, buoyant fruits, capable of moderate dispersal (e.g., Thalassia, Posidonia), in contrast, appear to recruit rarely within existing meadows of conspecifics. Our ability to model long-term changes in demography and community structure is likely to benefit from a better knowledge of the importance of seed supply and microsite availability to recruitment.

scholarly journals Seasonal Changes of the Airborne Microbiome in a Large Urban Area

2020 ◽  
Author(s):  
Andrés Núñez ◽  
Diego A Moreno ◽  
Ana M García ◽  
Raul Guantes
Keyword(s):  
Disease Outbreaks ◽  
Urban Environments ◽  
Minor Role ◽  
Near Surface ◽  
Surface Atmosphere ◽  
Ecological Importance ◽  
Bacteria And Fungi ◽  
A Minor

Abstract Background Compared to soil or aquatic ecosystems, the atmosphere is still an underexplored environment for microbial diversity. Besides its ecological importance, the spatial and temporal characterization of aerosolized microorganisms is relevant for understanding allergy and disease outbreaks, especially in highly populated cities. Results In this study, we surveyed the composition, variability and sources of microbes (bacteria and fungi) in the near surface atmosphere of a highly populated area, spanning ~ 4,000 Km 2 around the city center of Madrid (Spain), in different seasonal periods along two years. We found a core of abundant bacterial genera robust across space and time, most of soil origin, while fungi were more sensitive to environmental conditions. Microbial communities showed clear seasonal patterns driven by variability of environmental factors, mainly temperature and accumulated rain, while local sources played a minor role. We also identified taxa in both kingdoms characteristic of seasonal periods, but not of specific sampling sites or plant coverage. Conclusions The present study suggests that the near surface atmosphere of urban environments constitutes a stable ecosystem, with a relatively homogenous composition, modulated by climatic variations. As such, it contributes to our understanding of the long-term changes associated to the human exposome in the air of highly populated areas.

scholarly journals Towards the Understanding of Hydrogeochemical Seismic Responses in Karst Aquifers: A Retrospective Meta-Analysis Focused on the Apennines (Italy)

Minerals ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1058
Author(s):  
Gilberto Binda ◽  
Andrea Pozzi ◽  
Alessandro M. Michetti ◽  
Paula J. Noble ◽  
Michael R. Rosen
Keyword(s):  
Meta Analysis ◽  
Monitoring Network ◽  
Solute Concentration ◽  
Minor Role ◽  
Published Data ◽  
Permeability Enhancement ◽  
Set Up ◽  
Different Response ◽  
A Minor

Earthquakes are known to affect groundwater properties, yet the mechanisms causing chemical and physical aquifer changes are still unclear. The Apennines mountain belt in Italy presents a rich literature of case studies documenting hydrogeochemical response to seismicity, due to the high frequency of seismic events and the presence of different regional aquifers in the area. In this study, we synthesize published data from the last 30 years in the Apennine region in order to shed light on the main mechanisms causing earthquake induced water changes. The results suggest the geologic and hydrologic setting specific to a given spring play an important role in spring response, as well as the timing of the observed response. In contrast to setting, the main focal mechanisms of earthquake and the distance between epicenter and the analyzed springs seems to present a minor role in defining the response. The analysis of different response variables, moreover, indicates that an important driver of change is the degassing of CO2, especially in thermal springs, whereas a rapid increase in solute concentration due to permeability enhancement is observable in different cold and shallow springs. These findings also leave open the debate regarding whether earthquake precursors can be recognized beyond site-specific responses. Such responses can be understood more comprehensively through the establishment of a regional long-term monitoring system and continuous harmonization of data and sampling strategies, achievable in the Apennine region through the set-up of a monitoring network.

scholarly journals CO2 fertilization plays a minor role in long-term carbon accumulation patterns in temperate pine forests in the southwestern Pyrenees

2019 ◽  
Vol 407 ◽  
pp. 108737 ◽  
Author(s):  
Yueh-Hsin Lo ◽  
Juan A. Blanco ◽  
Ester González de Andrés ◽  
J. Bosco Imbert ◽  
Federico J. Castillo
Keyword(s):  
Carbon Accumulation ◽  
Pine Forests ◽  
Minor Role ◽  
Co2 Fertilization ◽  
A Minor

scholarly journals Characterization of the human liver vasopressin receptor. Profound differences between human and rat vasopressin-receptor-mediated responses suggest only a minor role for vasopressin in regulating human hepatic function

1991 ◽  
Vol 276 (1) ◽  
pp. 189-195 ◽  
Author(s):  
J Howl ◽  
T Ismail ◽  
A J Strain ◽  
C J Kirk ◽  
D Anderson ◽  
...  
Keyword(s):  
Dna Synthesis ◽  
Glycogen Phosphorylase ◽  
Rat Hepatocytes ◽  
Hepatic Function ◽  
Human Hepatocytes ◽  
Minor Role ◽  
Receptor Subtype ◽  
Vasopressin Receptor ◽  
Vasopressin Receptors ◽  
A Minor

The [Arg8]vasopressin (AVP) receptor expressed by human hepatocytes was characterized, and compared with the rat hepatic V1a vasopressin receptor subtype. In addition to determining the pharmacological profile of the human receptor, the cellular responses to AVP were measured in human and rat hepatocytes by assaying glycogen phosphorylase alpha activity and DNA synthesis. Marked differences were observed between human and rat hepatocytes regarding vasopressin receptors and the intracellular consequences of stimulation by AVP. Data presented in this paper demonstrate the following, (i) Vasopressin V1a receptors are present in low abundance on human hepatocytes. (ii) Species differences exist between human and rat V1a receptors with respect to the affinity of some selective antagonists. (iii) AVP-stimulated glycogen phosphorylase a activation in human hepatocytes was approx. 5% of that observed in rat cells. (iv) In contrast with rat hepatocytes, DNA synthesis in human cells in culture was not stimulated by AVP. It is concluded that vasopressin plays only a minor role in the regulation of human hepatic function. Furthermore, conclusions drawn from observations made with AVP and its analogues on rat hepatic function cannot be directly extrapolated to the human situation.

scholarly journals Natural Competence Is a Major Mechanism for Horizontal DNA Transfer in the Oral Pathogen Porphyromonas gingivalis

mBio ◽  
2012 ◽  
Vol 3 (1) ◽  
Author(s):  
Gena D. Tribble ◽  
Todd W. Rigney ◽  
Doan-Hieu V. Dao ◽  
Cindy T. Wong ◽  
Jennifer E. Kerr ◽  
...  
Keyword(s):  
Porphyromonas Gingivalis ◽  
Dna Transfer ◽  
Extracellular Dna ◽  
Minor Role ◽  
Chromosomal Dna ◽  
Natural Competence ◽  
Content Type ◽  
A Minor ◽  
First Time

ABSTRACTPorphyromonas gingivalisis a Gram-negative anaerobe that resides exclusively in the human oral cavity. Long-term colonization byP. gingivalisrequires the bacteria to evade host immune responses while adapting to the changing host physiology and alterations in the composition of the oral microflora. The genetic diversity ofP. gingivalisappears to reflect the variability of its habitat; however, little is known about the molecular mechanisms generating this diversity. Previously, our research group established that chromosomal DNA transfer occurs betweenP. gingivalisstrains. In this study, we examine the role of putative DNA transfer genes in conjugation and transformation and demonstrate that natural competence mediated bycomFis the dominant form of chromosomal DNA transfer, with transfer by a conjugation-like mechanism playing a minor role. Our results reveal that natural competence mechanisms are present in multiple strains ofP. gingivalis, and DNA uptake is not sensitive to DNA source or modification status. Furthermore, extracellular DNA was observed for the first time inP. gingivalisbiofilms and is predicted to be the major DNA source for horizontal transfer and allelic exchange between strains. We propose that exchange of DNA in plaque biofilms by a transformation-like process is of major ecological importance in the survival and persistence ofP. gingivalisin the challenging oral environment.IMPORTANCEP. gingivaliscolonizes the oral cavities of humans worldwide. The long-term persistence of these bacteria can lead to the development of chronic periodontitis and host morbidity associated with tooth loss.P. gingivalisis a genetically diverse species, and this variability is believed to contribute to its successful colonization and survival in diverse human hosts, as well as evasion of host immune defenses and immunization strategies. We establish here that natural competence is the major driving force behindP. gingivalisDNA exchange and that conjugative DNA transfer plays a minor role. Furthermore, we reveal for the first time the presence of extracellular DNA inP. gingivalisbiofilms, which is most likely the source of DNA exchanged between strains within dental plaque. These studies expand our understanding of the mechanisms used by this important member of the human oral flora to transition its relationship with the host from a commensal to a pathogenic relationship.

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