Anti-Atherogenic Activity of Ethanolic Fraction of Terminalia arjuna Bark on Hypercholesterolemic Rabbits

Atherosclerosis which results from gradual deposition of lipids in medium and large arteries is a leading cause of mortality worldwide. Terminalia arjuna is a herb of Combretaceae family which contains hypolipidemic compounds and flavonoids with high antioxidative properties. This study was conducted to determine the effect of ethanolic fraction of T. arjuna on blood lipids and atherosclerosis in rabbits fed with high fat diet (HFD). Twenty New Zealand rabbits of either sex were randomly divided into five groups: the first two were normal diet group and HFD (21% fat) group and the remaining three groups received high cholesterol diet supplemented with standard drug (Atorvastatin 10 mg kg−1 body weight), T. arjuna ethanolic fraction (100 and 200 mg kg−1 body weight), respectively. The concentration of total cholesterol (TC), low density lipoprotein (LDL) cholesterol, triglycerides (TGs), very low density lipoprotein (VLDL) cholesterol and high density lipoprotein (HDL) cholesterol was determined in rabbits at the start of the experiment, at the 14th, 30th days and at the end of the study. Anti-atherogenic index was calculated from the lipid profile of the rabbits before sacrifice. At the end of the experimental period, the aorta was removed for assessment of atherosclerotic plaques. Results show that T. arjuna significantly decreases TC, LDL and TG levels and increases HDL and lessens atherosclerotic lesion in aorta (P < .05). Hence T. arjuna extract can effectively prevent the progress of atherosclerosis. This is likely due to the effect of T. arjuna on serum lipoproteins and its antioxidant and anti-inflammatory properties

Trust Based Routing to Improve Network Lifetime of Mobile Ad Hoc Networks

Mobile Ad hoc Network is an impromptu wireless network consisting of mobile, self governing independent nodes. Routing in Mobile Ad hoc Networks has been a major concern due to its dynamic topology, lossy and unreliable links. In traditional routing, a single specific node is selected in prior as the potential next-hop forwarder for a packet. Unlike traditional routing, a category of routing technique termed Opportunistic Routing exploits the broadcast nature of wireless medium to compensate the unreliability of the packet transmissions in the channel. In Opportunistic Routing, one among the set of candidate nodes is selected as the potential next-hop forwarder using metrics like number of transmissions in a link, link error probability, cost, etc., for packet transmission. For selection and prioritization of candidates that ensures minimum number of transmissions from source to destination node, whilst improving the lifetime of the network on determining the residual battery energy, a new metric is proposed. This metric helps in improving the network lifetime considering the transmission powers in terms of the fraction of residual battery powers. Further, as nodes in mobile ad hoc networks are susceptible to attacks, a trust model based on direct, as well as indirect trust degrees from similar trusted neighbours is integrated in order to overcome the vulnerability due to attacks by malicious/selfish nodes and to provide reliable packet transmissions. Fading of trust is incorporated with a perspective to ensure the uncertainty of trust with time until it is updated

Factor VII activating protease (FSAP) influences vascular remodeling in the mouse hind limb ischemia model

Background: Investigations in factor VII activating protease (FSAP)-/- mice suggest a role for FSAP in stroke, thrombosis and neointima formation. Here, we analyzed the role of FSAP in vascular remodeling processes related to arteriogenesis and angiogenesis in the mouse hind limb ischemia model. Methods and results: Femoral artery ligation was performed in mice and exogenous FSAP was injected locally to examine its effect on arteriogenesis in the adductor and angiogenesis in the gastrocnemius muscle over 21 days. Perfusion was decreased by FSAP, which was reflected in a lower arterial diameter and was associated with reduced monocyte infiltration in the adductor muscle. There was increased angiogenesis in the gastrocnemius muscle triggered indirectly by less blood supply to the lower limb. Comparison of wild-type (WT) and FSAP-/- mice showed that perfusion was not different between the genotypes but there were 2.5-fold more collateral arteries in the adductor muscle of FSAP-/- mice at day 21. This was associated with a higher infiltration of monocytes at day 3. Capillary density in the gastrocnemius muscle was not altered. Activity of the two major proteolytic pathways associated with vascular remodeling; matrix metalloprotease (MMP)-9 and urokinase-type plasminogen activator (uPA) was elevated in the gastrocnemius but not in the adductor muscle in FSAP-/- mice. Conclusions: Arteriogenesis is enhanced, and this is associated with a higher infiltration of monocytes, in the absence of endogenous FSAP but angiogenesis is unchanged. Exogenous FSAP had the opposite effect on arteriogenesis indicating a possible therapeutic potential of modulating endogenous FSAP

Foot-and-mouth disease in elephants in Kerala state of India during 2013

Foot-and-mouth disease (FMD) is a highly contagious acute vesicular disease of the cloven-hoofed animals including cattle, buffalo, sheep, goats, pigs along with more than 70 wildlife species. During the year 2013, FMD outbreaks were recorded in the southern peninsular India comprising the states of Karnataka, Tamil Nadu, Kerala and Andhra Pradesh. Besides domestic livestock, captive elephants in Kerala were also affected by FMD. The suspected FMD outbreak in six elephants occurred in Neendoor of Kottayam district, Guruvayoor and Thrissur of Thrissur district in Kerala during November - December 2013. The first clinical signs recorded in the elephants were loss of appetite and lameness with mild fever. Frank lesions were grossly evident on the tongue, palate and inner mucous membrane of trunk with exudates from nostrils. There was copious salivation often appeared to be drooling. Severe lameness led to recumbency. Erosive lesions were also noticed in foot-slipper. The foot with blisters turned to open sores making the animals difficult to stand and walk. Clinical samples (foot/oral/tongue/trunk/nasal epithelium) from the FMD-suspected elephants were collected in 50% phosphate buffered saline/glycerol medium (pH-7.5). Supernatants of the homogenized clinical samples were used in a serotype differentiating antigen detection ELISA and samples found negative were further subjected to multiplex PCR. All clinical samples were found positive for FMD virus (FMDV) serotype O in antigen detection ELISA and in mPCR. The VP1 region based phylogenetic analysis indicated the involvement of O/Middle East-South Asia/Ind2001d sub-lineage of FMDV serotype O, which was also responsible for severe disease in domestic livestock in southern states of India during 2013

Trending Advancements in Technologies Pertinent to Therapeutical Pharmacodynamics

It is omniscient that pharmacodynamics of a drug is understood as its effect on body by interacting with the structure of targets to either activate or inhibit their function/action. Based on the activity of the drug to the target binding site they have been classified into different types. Physiological, cellular, molecular, biochemical, and toxicological effects individually have a significant role in drug’s effect and response. The mechanism of action, dosage and its response, therapeutic index are some of the noteworthy parameters to be considered in drug pharmacodynamics. This chapter comprehends the above-mentioned concepts, their importance in pharmacodynamics of drug, and the impact of recently developed methods like genome-wide or transcriptome-wide sequencing, chronopharmacodynamics, systems biology, pharmacometabolomics, etc., in different stages of drug discovery process, and how the digitization of therapeutics and healthcare direct the path to personalized medicine. The integration of bioinformatics, systems biology, and big data related approaches like ML & AI with the pharmacological (PK/PD) study highly benefits the patients’ therapeutics

The Parmodulin NRD-21 is an Allosteric Inhibitor of PAR1 Gq Signaling with Improved Anti-Inflammatory Activity and Stability

Novel analogs of the allosteric, biased PAR1 ligand ML161 (parmodulin 2, PM2) were prepared in order to identify potential anti-thrombotic and anti-inflammatory compounds of the parmodulin class with improved properties. Investigations of structure-activity relationships of the western portion of the 1,3-diaminobenzene scaffold were performed using an intracellular calcium mobilization assay with endothelial cells, and several heterocycles were identified that inhibited PAR1 at sub-micromolar concentrations. The oxazole NRD-21 was profiled in additional detail, and it was confirmed to act as a selective, reversible, negative allosteric modulator of PAR1. In addition to inhibiting human platelet aggregation, it showed superior anti-inflammatory activity to ML161 in a qPCR assay measuring the expression of tissue factor in response to the cytokine TNF-alpha in endothelial cells. Additionally, NRD-21 is much more plasma stable than ML161, and is a promising lead compound for the parmodulin class for anti-thrombotic and anti-inflammatory indications

Global estimates on the number of people blind or visually impaired by cataract: a meta-analysis from 2000 to 2020

Background: To estimate global and regional trends from 2000 to 2020 of the number of persons visually impaired by cataract and their proportion of the total number of vision-impaired individuals. Methods: A systematic review and meta-analysis of published population studies and gray literature from 2000 to 2020 was carried out to estimate global and regional trends. We developed prevalence estimates based on modeled distance visual impairment and blindness due to cataract, producing location-, year-, age-, and sex-specific estimates of moderate to severe vision impairment (MSVI presenting visual acuity &lt;6/18, ≥3/60) and blindness (presenting visual acuity &lt;3/60). Estimates are age-standardized using the GBD standard population. Results: In 2020, among overall (all ages) 43.3 million blind and 295 million with MSVI, 17.0 million (39.6%) people were blind and 83.5 million (28.3%) had MSVI due to cataract blind 60% female, MSVI 59% female. From 1990 to 2020, the count of persons blind (MSVI) due to cataract increased by 29.7%(93.1%) whereas the age-standardized global prevalence of cataract-related blindness improved by −27.5% and MSVI increased by 7.2%. The contribution of cataract to the age-standardized prevalence of blindness exceeded the global figure only in South Asia (62.9%) and Southeast Asia and Oceania (47.9%). Conclusions: The number of people blind and with MSVI due to cataract has risen over the past 30 years, despite a decrease in the age-standardized prevalence of cataract. This indicates that cataract treatment programs have been beneficial, but population growth and aging have outpaced their impact. Growing numbers of cataract blind indicate that more, better-directed, resources are needed to increase global capacity for cataract surgery.</p

Global estimates on the number of people blind or visually impaired by cataract : a meta-analysis from 2000 to 2020

DATA AVAILABILITY : Data sources for the Global Vision Database are listed at the following weblink http://www.anglia.ac.uk/verigbd. Fully disaggregated data is not available publicly due to data sharing agreements with some principal investigators yet requests for summary data can be made to the corresponding author.CHANGE HISTORY 16 July 2024 : A Correction to this paper has been published: https://doi.org/10.1038/s41433-024-03161-7.BACKGROUND : To estimate global and regional trends from 2000 to 2020 of the number of persons visually impaired by cataract and their proportion of the total number of vision-impaired individuals. METHODS : A systematic review and meta-analysis of published population studies and gray literature from 2000 to 2020 was carried out to estimate global and regional trends. We developed prevalence estimates based on modeled distance visual impairment and blindness due to cataract, producing location-, year-, age-, and sex-specific estimates of moderate to severe vision impairment (MSVI presenting visual acuity <6/18, ≥3/60) and blindness (presenting visual acuity <3/60). Estimates are age-standardized using the GBD standard population. RESULTS : In 2020, among overall (all ages) 43.3 million blind and 295 million with MSVI, 17.0 million (39.6%) people were blind and 83.5 million (28.3%) had MSVI due to cataract blind 60% female, MSVI 59% female. From 1990 to 2020, the count of persons blind (MSVI) due to cataract increased by 29.7%(93.1%) whereas the age-standardized global prevalence of cataract-related blindness improved by −27.5% and MSVI increased by 7.2%. The contribution of cataract to the age-standardized prevalence of blindness exceeded the global figure only in South Asia (62.9%) and Southeast Asia and Oceania (47.9%). CONCLUSIONS : The number of people blind and with MSVI due to cataract has risen over the past 30 years, despite a decrease in the age-standardized prevalence of cataract. This indicates that cataract treatment programs have been beneficial, but population growth and aging have outpaced their impact. Growing numbers of cataract blind indicate that more, better-directed, resources are needed to increase global capacity for cataract surgery.Brien Holden Vision Institute, Fondation Thea, Fred Hollows Foundation, Bill & Melinda Gates Foundation, Lions Clubs International Foundation (LCIF), Sightsavers International, and University of Heidelberg. Open Access funding enabled and organized by CAUL and its Member Institutions.https://www.nature.com/eyehj2024School of Health Systems and Public Health (SHSPH)SDG-03:Good heatlh and well-bein

Faktor VII aktivierende Protease (FSAP) in Thrombose und Hämostase in vivo

Factor VII activating protease (FSAP), a serine protease produced in the liver (plasma conc.12 microgramm/mL) has been associated with cardiovascular diseases. In vitro studies revealed that FSAP has a dual function in the coagulation system via inhibition of tissue factor pathway inhibitor (TFPI) and activation of pro-urokinase (pro-uPA). Even though functional polymorphism in the FSAP gene is linked with cardiovascular diseases, due to contradictory clinical observations as well as its dual role in the coagulation system in vitro, the real function and mechanistic aspects of FSAP is ambiguous. To identify the actual function of FSAP in thrombosis and haemostasis, we characterized the FSAP deficient mice using various in vivo and ex-vivo mouse models. Our results showed that in pulmonary thromboembolism model FSAP-/- mice had a significantly higher survival than WT littermates (p smaller than 0.01). The carotid artery injury as well as mesenteric arteriole models revealed that the occlusion time was significantly increased in FSAP-/- mice (p smaller than 0.01). Partial venous thrombosis (PVT) showed a trend in the reduction of total thrombus content and thrombus weight in FSAP-/- mice. Western blotting analysis of plasma samples as well as immunohistochemical analysis of thrombotic carotid arteries and lung tissue extracts showed a slightly increased TFPI expression in FSAP-/- mice when compared to the WT littermates. In situ and gel-based casein zymography showed that FSAP-/- mice had more uPA than the WT littermates. Plasma samples from all these models did not show any influence of plasminogen levels. In vitro analysis of FSAP on platelet TFPI demonstrated that FSAP could inhibit not only the circulating beta form of TFPI but also the platelet derived alpha form of TFPI. Tail-bleeding assay revealed that more than 80% of FSAP-/-mice showed re-bleeding incidences compared to WT littermate controls. The clinical relevance of Marburg-I polymorphism is not well understood because of contradictory observations in various studies. Interestingly, our mice models revealed that the endogenous FSAP plays a key role in extrinsic coagulation cascade via inhibition of TFPI.Die Faktor VII aktivierende Protease (FSAP), eine in der Leber synthetisierte Serinprotease (Plasmakonzentration: 12 µg/ mL), spielt eine Rolle bei kardiovaskulären Erkrankungen. In vitro Studien zeigten, dass FSAP eine duale Rolle in der Hämostase innehat. Einerseits wirkt FSAP prokuagolatorisch durch Hemmung des Gewebsfaktor-Plasminogen Inhibitors(TFPI), andererseits fibrinolytisch durch Aktivierung der Prouro- kinase (pro-uPA). Obwohl der funktionale Polymorphismus des FSAP-Gens mit kardiovaskulären Erkrankungen verbunden ist, bleibt die Funktion und Wirkungsweise von FSAP aufgrund widersprüchlicher klinischer Untersuchungen wie auch seiner dualen Rolle im Hämostasesystem, unklar. Zur Aufklärung der Funktion von FSAP in Hinsicht auf Thrombose und Hämostase wurden FSAP-defiziente Mäuse in verschiedenen in vivo und ex vivo Modellen getestet. Unsere Ergebnisse zeigten, dass FSAP-/- Mäuse in einem Lungen-Thrombose-Embolie-Modell eine signifikant höhere Überlebensrate aufwiesen als WT-Mäuse (p < 0.01). Bei Verletzung der Karotis-Arterie oder der Mesenterial-arteriole war die Okklusionszeit bei FSAP-/- Mäusen signifikant erhöht (p < 0.01). Eine partiale Venenthrombose (PVT) zeigte tendenziell eine Verringerung des Thrombus in Größe und Gewicht. Westernblot-Analysen von Plasmaproben wie auch immunohistochemische Untersuchungen an thrombotischen Karotis-Arterien und Lungenextrakten ergaben einen leichten Anstieg der TFPI-Expression bei FSAP-/- Mäusen verglichen mit WT-Mäusen. In der In-situ-Zymographie sowie Gel basierenden Kasein-Zymographie zeigten FSAP-/- Mäuse gegnüber WT-Mäusen höhere uPA-Spiegel. Plasmaproben aus allen Modellen zeigten keinen Einfluss von FSAP auf die Plasminogenkonzentration. In vitro Untersuchungen an Plättchen-TFPI zeigten, dass FSAP nicht nur die zirkulierende ß-Form von TFPI, sondern auch die platelet-derived alpha-Form von TFPI hemmt. Bei Messungen der Blutungszeit durch Verletzung des Schwanzes der Mäuse neigten mehr als 80% der FSAP-/- Mäuse zu wiederholtem Bluten gegenüber WT-Mäusen. Die klinische Relevanz des Maburg I Polymorphismus ist aufgrund der widersprüchlichen Beobachtungen an Venenthrombose-Modellen wenig verstanden. Unsere Mausmodelle zeigten, dass endogenes FSAP eine Schlüsselrolle bei der extrinsischen Blutgerinnungskaskade durch Hemmung von TFPI innehat