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• A single bout of exercise is likely to induce small to large increases in myokine expression immediately after and up to 60 min post-exercise, while myokine responses typically revert to baseline levels from 180 min to 24 h post-exercise. • Both aerobic exercise and resistance exercise lead to notable changes in the expression of myokines; however, the magnitude of these changes varies according to the specific myokine type. • This meta-analysis expands our knowledge of the overall effects of myokine expression in relation to exercise modes; however, substantial variation is evident, indicating that the response to exercise mode is myokine-specific. • Some exercise modes and time points have not been investigated for certain myokines and, thus, should be considered for future research. The benefits of exercise are well known; however, many of the underlying molecular mechanisms are not fully understood. Skeletal muscle secretes myokines, which mediate muscle–organ crosstalk. Myokines regulate satellite-cell proliferation and migration, inflammatory cascade, insulin secretion, angiogenesis, fatty oxidation, and cancer suppression. To date, the effects of different exercise modes (namely, aerobic and resistance exercise) on myokine response remain to be elucidated. This is crucial considering the clinical implementation of exercise to enhance general health and wellbeing and as a medical treatment. A systematic search was undertaken in PubMed, MEDLINE, CINAHL, Embase, SPORTDiscus, and Web of Science in April 2023. Eligible studies examining the effects of a single bout of exercise on interleukin15 (IL-15), irisin, secreted protein acidic and rich in cysteine (SPARC), oncostatin M (OSM), and decorin were included. A random-effects meta-analysis was also undertaken to quantify the magnitude of change. Sixty-two studies were included (n = 1193). Overall, exercise appeared to induce small to large increases in myokine expression, with effects observed immediately after to 60 min post-exercise, although these were mostly not statistically significant. Both aerobic and resistance exercise resulted in changes in myokine levels, without any significant difference between training modes, and with the magnitude of change differing across myokines. Myokine levels returned to baseline levels within 180 min to 24 h post-exercise. However, owing to potential sources of heterogeneity, most changes were not statistically significant, indicating that precise conclusions cannot be drawn. Knowledge is limited but expanding with respect to the impact of overall and specific effects of exercise on myokine expression at different time points in the systemic circulation. Further research is required to investigate the effects of different exercise modes at multiple time points on myokine response. [Display omitted] [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is characterized by an increase of a pressure in the pulmonary circulation; PAH is accompanied by activation of the sympathetic (SNS) and the renin-angiotensin-aldosterone system (RAAS). However, PAH-associated changes in baroreceptor regulation of systemic circulation, which is tightly interwoven with SNS and RAAS, have not been studied. The baroreceptor response (BRR) was studied in a chronic monocrotaline (MCT) model of PAH in rats (Wistar, 290 ± 30 g, 2–4 months). Phenylephrine as an agonist of α1-adrenergic receptor and sodium nitroprusside as NO donor were gradually administered to chronically catheterized, non-anesthetized control animals and animals with PAH (4 weeks after MCT administration) to induce vasomotor responses. Mean arterial pressure and heart rate (HR) were recorded under the action of vasoactive compounds alone or under the action of vasoactive compounds in presence of angiotensin-II (ATII), atropine. The parameters characterizing baroreceptor change in HR including maximal and minimal heart rate (HRmax, HRmin), reflex tachycardia (TBRR) and bradycardia (BBRR), range (ABRR) and the baroreceptor response sensitivity index (SIBRR) were calculated. A significant decrease in HRmax, TBRR, ABBR (but not BBRR), as well as the sensitivity index of BRR was observed in rats with PAH. ATII induces significant and different changes in the BRR parameters in control rats and in rats with PAH if administered 4 weeks after the start of the experiment. In rats with PAH, ATII causes less pronounced changes in HRmax, TBRR, and BBRR than in control animals. ATII insignificantly affects parasympathetic component of the baroreceptor reflex in rats with PAH. Thus, at least in the MCT-mediated model in rats, PAH significantly deteriorates the baroreceptor regulation of HR. This effect manifests in a decrease in the range and sensitivity of the baroreceptor response. Also, PAH unequally affects the sympathetic and parasympathetic control of the baroreceptor regulation of HR. On the other hand, ATII exhibits weak ability to alter BRR in rats with HAP. In conclusion, PAH leads to a disfunction of immediate, reflex mechanisms HR and systemic circulation control. [ABSTRACT FROM AUTHOR]

Background: The benefits of exercise are well known; however, many of the underlying molecular mechanisms are not fully understood. Skeletal muscle secretes myokines, which mediate muscle–organ crosstalk. Myokines regulate satellite-cell proliferation and migration, inflammatory cascade, insulin secretion, angiogenesis, fatty oxidation, and cancer suppression. To date, the effects of different exercise modes (namely, aerobic and resistance exercise) on myokine response remain to be elucidated. This is crucial considering the clinical implementation of exercise to enhance general health and wellbeing and as a medical treatment. Methods: A systematic search was undertaken in PubMed, MEDLINE, CINAHL, Embase, SPORTDiscus, and Web of Science in April 2023. Eligible studies examining the effects of a single bout of exercise on interleukin15 (IL-15), irisin, secreted protein acidic and rich in cysteine (SPARC), oncostatin M (OSM), and decorin were included. A random-effects meta-analysis was also undertaken to quantify the magnitude of change. Results: Sixty-two studies were included (n = 1193). Overall, exercise appeared to induce small to large increases in myokine expression, with effects observed immediately after to 60 min post-exercise, although these were mostly not statistically significant. Both aerobic and resistance exercise resulted in changes in myokine levels, without any significant difference between training modes, and with the magnitude of change differing across myokines. Myokine levels returned to baseline levels within 180 min to 24 h post-exercise. However, owing to potential sources of heterogeneity, most changes were not statistically significant, indicating that precise conclusions cannot be drawn. Conclusion: Knowledge is limited but expanding with respect to the impact of overall and specific effects of exercise on myokine expression at different time points in the systemic circulation. Further research is required to investigate the effects of different exercise modes at multiple time points on myokine response.

Patients with hypoplastic left heart syndrome (HLHS) are born with an underdeveloped left heart. They typically receive a sequence of surgeries that result in a single ventricle physiology called the Fontan circulation. While these patients usually survive into early adulthood, they are at risk for medical complications, partially due to their lower than normal cardiac output, which leads to insufficient cerebral and gut perfusion. While clinical imaging data can provide detailed insight into cardiovascular function within the imaged region, it is difficult to use these data for assessing deficiencies in the rest of the body and for deriving blood pressure dynamics. Data from patients used in this paper include three-dimensional, magnetic resonance angiograms (MRA), time-resolved phase contrast cardiac magnetic resonance images (4D-MRI) and sphygmomanometer blood pressure measurements. The 4D-MRI images provide detailed insight into velocity and flow in vessels within the imaged region, but they cannot predict flow in the rest of the body, nor do they provide values of blood pressure. To remedy these limitations, this study combines the MRA, 4D-MRI, and pressure data with 1D fluid dynamics models to predict hemodynamics in the major systemic arteries, including the cerebral and gut vasculature. A specific focus is placed on studying the impact of aortic reconstruction occurring during the first surgery that results in abnormal vessel morphology. To study these effects, we compare simulations for an HLHS patient with simulations for a matched control patient that has double outlet right ventricle (DORV) physiology with a native aorta. Our results show that the HLHS patient has hypertensive pressures in the brain as well as reduced flow to the gut. Wave intensity analysis suggests that the HLHS patient has irregular circulatory function during light upright exercise conditions and that predicted wall shear stresses are lower than normal, suggesting the HLHS patient may have hypertension.

Reactive oxygen species (ROS) produced by NADPH oxidases (NOX, a key source of ROS in vascular cells) are involved in the regulation of vascular tone, but this has been explored mainly for adult organisms. Importantly, the mechanisms of vascular tone regulation differ significantly in early postnatal ontogenesis and adulthood, while the vasomotor role of ROS in immature systemic arteries is poorly understood. We tested the hypothesis that the functional contribution of NADPH oxidase-derived ROS to the regulation of peripheral arterial tone is higher in the early postnatal period than in adulthood. We studied saphenous arteries from 10‐ to 15‐day‐old ("young") and 3‐ to 4-month-old ("adult") male rats using lucigenin-enhanced chemiluminescence, quantitative PCR, Western blotting, and isometric myography. We demonstrated that both basal and NADPH-stimulated superoxide anion radical (O 2 •−) production was significantly higher in the arteries from young in comparison to adult rats. Importantly, pan-inhibitor of NADPH oxidase VAS2870 (10 μM) reduced NADPH-induced O 2 •− production in arteries of young rats. Saphenous arteries of both young and adult rats demonstrated high levels of Nox2 and Nox4 mRNAs, while Nox1 and Nox3 mRNAs were not detected. The protein contents of NOX2 and NOX4 were significantly higher in arterial tissue of young compared to adult animals. Moreover, VAS2870 (10 μM) had no effect on methoxamine-induced contractile responses of adult arteries but decreased them significantly in young arteries; such effect of VAS2870 persisted after removal of the endothelium. Finally, NOX2 inhibitor GSK2795039 (10 μM), but not NOX1/4 inhibitor GKT137831 (10 μM) weakened methoxamine-induced contractile responses of arteries from young rats. Thus, ROS produced by NOX2 have a pronounced contractile influence in saphenous artery smooth muscle cells of young, but not adult rats, which is associated with the increased vascular content of NOX2 protein at this age. [Display omitted] • O 2.•− production is higher in saphenous artery of young compared to adult rats • NADPH-oxidases are important source of O 2.•− in saphenous artery of young rats • NOX2 and NOX4 contents are higher in arteries of young compared to adult rats. • O 2.•− produced by NOX2 promotes arterial contraction in young, but not adult rats [ABSTRACT FROM AUTHOR]

Transdermal administration offers the benefit of avoiding the first-pass impact and enabling continuous medication release. The largest obstacle to transdermal distribution, however, is the fact that only a small number of strong medications with optimal physicochemical characteristics can pass through skin barriers, intercellularly penetrate, and attain therapeutic concentration through this mechanism. One strategy for achieving high patient compliance is microneedle medication administration. The use of microneedles improves medication administration by this method and helps to solve a number of issues with traditional formulations. One of the microscale physical enhancement techniques that significantly broadens the range of medications available for transdermal and intradermal administration is the use of microneedles. The main idea is that the skin layer is disrupted, which opens up micron-sized passageways that carry the medication straight to the upper dermis or epidermis, where it can enter the systemic circulation without having to pass through the barrier. The design of the microneedles and the drug compositions can regulate the dosage, rate of distribution, and effectiveness of the medications. The types of microneedles, their designs, the materials utilised in their construction, and their production processes are all introduced in this review. [ABSTRACT FROM AUTHOR]

Pathophysiology of portal vein thrombosis (PVT) in cirrhosis is still not entirely understood. Elevated levels of lipopolysaccharides (LPS) in portal circulation are significantly associated with hypercoagulation, increased platelet activation and endothelial dysfunction. The aim of the study was to investigate if LPS was associated with reduced portal venous flow, the third component of Virchow's triad, and the underlying mechanism. Serum nitrite/nitrate, as a marker of nitric oxide (NO) generation, and LPS were measured in the portal and systemic circulation of 20 patients with cirrhosis undergoing transjugular intrahepatic portosystemic shunt (TIPS) procedure; portal venous flow velocity (PVV) was also measured in each patient and correlated with NO and LPS levels. Serum nitrite/nitrate and LPS were significantly higher in the portal compared to systemic circulation; a significant correlation was found between LPS and serum nitrite/nitrate (R = 0.421; p < 0.01). Median PVV before and after TIPS was 15 cm/s (6–40) and 31 cm/s (14–79), respectively. Correlation analysis of PVV with NO and LPS showed a statistically significant negative correlation of PVV with portal venous NO concentration (R = – 0.576; p = 0.020), but not with LPS. In vitro study with endothelial cells showed that LPS enhanced endothelial NO biosynthesis, which was inhibited by L-NAME, an inhibitor of NO synthase, or TAK-242, an inhibitor of TLR4, the LPS receptor; this effect was accomplished by up-regulation of eNOS and iNOS. The study shows that in cirrhosis, endotoxemia may be responsible for reduced portal venous flow via overgeneration of NO and, therefore, contribute to the development of PVT. [ABSTRACT FROM AUTHOR]

Functional polysaccharides are characterized by functional and structural biomolecules, which play a dual role, both as nutrient molecules providing energy and as signaling molecules involved in intercellular communications. There are increasing evidences showing that functional polysaccharides possess beneficial effects for treating chronic diseases, such as cancer, cardiovascular disease, etc., but its mechanism of action remains imprecision. Additionally, due to the limitations of precision detection methods and the complexity of their structures, the metabolic kinetics behaviours or bioavailability of functional polysaccharides, and the interaction between it entering the systemic circulation and target cells of action have been a conundrum faced by researcher. This review summarized the latest advances in the efficacy of functional polysaccharides in chronic diseases and their structure-activity relationship, absorption and metabolic behaviours, and specific cellular receptors so as to understand the mechanisms of their bioactivities. This review is expected to provide new insights of functional polysaccharides and paves the way for their application.

Objectives: To measure the Doppler velocimetry parameters in the anterior cerebral artery (ACA), superior mesenteric artery (SMA), and main renal artery (RA) in neonates with late-onset sepsis and correlate it with associated clinical morbidities. Methodology: Prospective observational study carried out at a tertiary-level neonatal intensive care unit in India in 2022, enrolling 20 neonates with late-onset neonatal sepsis (LONS). Baseline characteristics and sepsis parameters obtained. Serial ultrasound performed on days 1, 3, and 7 from the day of clinical sepsis in the ACA, SMA, and RA and velocimetry measurements obtained. The findings were compared with 20 gestational age (GA) matched neonates in the control arm. Results: The mean GA of neonates with LONS was 31.03 ± 2.79 weeks and their mean birthweight was 1474 ± 509.99 g. The peak systolic velocity, resistive and pulsatility indices were significantly higher in ACA, SMA, and RA and the end-diastolic velocity was significantly lower in ACA and RA (P < 0.05) in LONS. The incidences of intraventricular hemorrhage (IVH), necrotising enterocolitis (NEC), and acute kidney injury (AKI) in neonates with LONS were 45%, 50%, and 10% respectively. A subgroup analysis of the Doppler velocimetry parameters in the neonates with LONS and for neonates with and without clinical outcomes did not suggest a significant difference. Conclusion: LONS is associated with alterations in cerebral, splanchnic, and renal perfusion seen as abnormal blood flow velocimetry and vascular resistance which may predispose to IVH, NEC, and AKI. [ABSTRACT FROM AUTHOR]

Abstract Background Helicobacter pylori infection is a well-recognized cause of gastric diseases, including chronic gastritis, peptic ulcer, and gastric cancer. Vacuolating cytotoxin-A (VacA) and cytotoxin-associated gene A protein (CagA) play a role in the pathogenesis of H. pylori-related gastric diseases. Also, extragastric disorders are frequent morbid complications in patients with H. pylori infection. However, the direct pathologic implication of these virulence factors in extragastric manifestations remains unclear. Our hypothesis in the present study is that VacA and CagA released by H. pylori in the gastric mucosa leak into the systemic circulation, and therefore they can be measured in serum. Results Sixty-two subjects were enrolled. They were allocated into the H. pylori-positive and H. pylori-negative groups. VacA and CagA were measured by immunoassays. The serum levels of VacA and CagA above an upper limit cut-off (mean plus two standard deviations of the mean in patients without H. pylori infection) were considered positive for antigen circulating level. Five out of 25 H. pylori-positive patients were positive for both serum VacA and serum CagA. The serum levels of VacA and CagA were significantly correlated with the serum levels of anti- H. pylori antibody and interleukin-12p70 among all H. pylori-positive and H. pylori-negative patients. Conclusions This study suggests that spill-over of VacA and CagA antigens in the systemic circulation may occur in some patients with H. pylori infection.

Background: Helicobacter pylori infection is a well-recognized cause of gastric diseases, including chronic gastritis, peptic ulcer, and gastric cancer. Vacuolating cytotoxin-A (VacA) and cytotoxin-associated gene A protein (CagA) play a role in the pathogenesis of H. pylori-related gastric diseases. Also, extragastric disorders are frequent morbid complications in patients with H. pylori infection. However, the direct pathologic implication of these virulence factors in extragastric manifestations remains unclear. Our hypothesis in the present study is that VacA and CagA released by H. pylori in the gastric mucosa leak into the systemic circulation, and therefore they can be measured in serum. Results: Sixty-two subjects were enrolled. They were allocated into the H. pylori-positive and H. pylori-negative groups. VacA and CagA were measured by immunoassays. The serum levels of VacA and CagA above an upper limit cut-off (mean plus two standard deviations of the mean in patients without H. pylori infection) were considered positive for antigen circulating level. Five out of 25 H. pylori-positive patients were positive for both serum VacA and serum CagA. The serum levels of VacA and CagA were significantly correlated with the serum levels of anti- H. pylori antibody and interleukin-12p70 among all H. pylori-positive and H. pylori-negative patients. Conclusions: This study suggests that spill-over of VacA and CagA antigens in the systemic circulation may occur in some patients with H. pylori infection. [ABSTRACT FROM AUTHOR]

• GC–MS method was optimized to quantify SCFA concentrations in human plasma or serum. • SCFA were derivatized with 2,4-difluoroaniline and extracted in ethyl acetate. • The method was validated according to the FDA guidelines. • The method was effectively applied with analysis of human plasma from dietary study. Fermentation-derived short-chain fatty acids (SCFA) 4 4 SCFA: short-chain fatty acids. are potential mediators of the health benefits associated with dietary fiber intake. SCFA affect physiological processes locally in the gut and on distant organs via the systemic circulation. Since SCFA are used as energy source for colonocytes and substrate for the liver metabolism, their concentrations in the systemic circulation are low. Therefore, quantification of systemic SCFA requires sensitive analytical techniques. This article covers the optimization and validation of a gas chromatography-mass spectrometry method to measure systemic SCFA concentrations following derivatization with 2,4-difluoroaniline (DFA) 5 5 DFA: 2,4-difluoroaniline. and extraction in ethyl acetate. Sample preparation was optimized by varying the amount of DFA, coupling agent 1,3-dicyclohexylcarbodiimide, ethyl acetate and sodium bicarbonate, which is used to quench derivatization. In addition, evaporation of the samples using a vacuum concentrator resulted in less contamination, notably of acetate, compared to drying with N 2 gas. The method showed excellent linearity with coefficient of variation (R2) > 0.99 and a good precision (relative standard deviation < 20 %) and accuracy. Finally, systemic concentrations of SCFA in human plasma samples could successfully be determined. [ABSTRACT FROM AUTHOR]

The cardiovascular system, consisting of the heart as the 'pump' and the vascular network of blood vessels, is responsible for the distribution of blood around the body. Oxygen molecules attach to haemoglobin in red blood cells and are transported around the body where the oxygen aids cellular metabolism. Any blockage in the blood vessels as a result of build-up of plaques in the endothelium layer would result in an interruption in blood supply and therefore oxygen deprivation (ischaemia). This would lead to necrosis of the distal area of the affected vessel and is known as an infarct. This article aims to describe the normal anatomy and physiology of the cardiovascular system and to explain some of the common associated disorders, with a brief guide to the management of a common heart disorder, myocardial infarction. A case study is included to enhance the knowledge of management of myocardial infarction. An in-depth knowledge and understanding of the cardiovascular system and its associated disorders will enable the nurse to safely assess a patient, recognise a deteriorating patient and seek early intervention. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) is the most common clinical tachyarrhythmia, posing a significant burden to patients, physicians, and healthcare systems worldwide. With the advent of more effective rhythm control strategies, such as AF catheter ablation, an early rhythm control strategy is progressively demonstrating its superiority not only in symptoms control but also in prognostic terms, over a standard strategy (rate control, with rhythm control reserved only to patients with refractory symptoms). This review summarizes the different impacts exerted by AF on heart mechanics and systemic circulation, as well as on cerebral and coronary vascular beds, providing computational modeling-based hemodynamic insights in favor of pursuing sinus rhythm maintenance in AF patients.

Simple Summary: Pulmonary hypertension is a potentially life-threatening disease among dogs that is characterized by increased pulmonary arterial pressure and pulmonary vascular resistance. In veterinary medicine, a phosphodiesterase-5 inhibitor such as sildenafil is the most common drug used to treat pulmonary hypertension. However, the availability of sildenafil is limited because of its high cost, difficulty in obtaining the drug in some areas, and potential inter-individual variability in the response to sildenafil therapy. Beraprost sodium is one of the most common drugs used to treat pulmonary hypertension in humans. However, little is known about its efficacy in dogs with pulmonary hypertension. In this study, beraprost sodium showed significant pulmonary and systemic vasodilation without any adverse effects in sixteen dogs with pulmonary hypertension. Additionally, echocardiographic improvements in cardiac function and pulmonary and systemic circulation were observed. These results emphasize the potential efficacy of beraprost sodium in treating canine pulmonary hypertension. Pulmonary hypertension (PH) is a fatal condition that affects many dogs. In humans, PH is often treated with beraprost sodium (BPS). However, the effectiveness of BPS for canine PH has not been established. This study aimed to evaluate the clinical and cardiovascular response of BPS in canine patients with PH of various causes. Sixteen dogs with PH (post-capillary PH, n = 8; pre-capillary PH, n = 8) were included. BPS was continuously administered twice daily at 15 µg/kg. All dogs underwent echocardiography, including speckle-tracking analysis and blood pressure measurement, before and after BPS administration. Continuous BPS administration (range: 13.2–22.0 µg/kg) significantly decreased the pulmonary and systemic vascular impedance and increased left and right ventricular myocardial strain. In dogs with post-capillary PH, BPS administration caused no significant worsening of the left atrial pressure indicators. No side effects of BPS were observed in any dog. BPS also improved cardiac function and pulmonary circulation through pulmonary vasodilation, suggesting that BPS may be an additional treatment option for canine PH of various causes. Particularly, BPS increased left ventricular function and systemic circulation without worsening the left heart loading condition in dogs with post-capillary PH. [ABSTRACT FROM AUTHOR]

Gentamicin sulphate is an antibiotic belonging to the aminoglycosides and to class III of the Biopharmaceutical Classification System (BCS). Gentamicin sulphate is highly water soluble, but has very low intestinal permeability. The wide use is because of its broad spectrum of activity. In the current study, the suitability of administering gentamicin sulphate orally for local action against susceptible gastrointestinal tract (GIT) bacteria was investigated. The possibility of the drug escaping into the systemic circulation even in the presence of some permeation enhancers was ascertained. Representatives of potential GIT bacteria pathogens were evaluated for their susceptibility to the drug at concentrations obtainable in the GIT using standard microbiological methods. Dose levels that will inhibit these potential bacteria pathogens were also established, as well as the frequency of their administration. Different batches of oral capsules of 250 mg gentamicin sulphate were formulated and their release profiles ascertained using standard methods. The results showed that the selected representatives of the GIT potential pathogenic bacteria were all susceptible to gentamicin sulphate. The drug at its plausible dosage levels of 14.28 mg/kg (1,000 mg/70 kg), 10.71 mg/kg (750 mg/70 kg) and 7.14 mg/kg (500 mg/70 kg) did not cross the mucosal barrier into the systemic circulation even in the presence of some permeation enhancers. The drug's frequency of administration were found to be on 8-hourly bases. Gentamicin sulphate (250 mg) granules formulated with polyethylene glycol (PEG 4000) as granulating aid were quick drying because the granules were not hygroscopic. The formulated gentamicin sulphate capsule batch released enough concentration of the drug that inhibits the test organism within 2 min of dissolution. The above stated doses are acceptable in the dosage form design; it is possible to formulate non-absorbable oral gentamicin sulphate dosage form for local activity in the GIT using existing conventional solid dosage formulating equipment.

• Zebrafish are an alternative model for preclinical investigation of nanomedicines. • Their optical transparency facilitates investigation of mechanistic insights of nanomedicines. • Their role in PK/PD investigation of nanomedicines is discussed. • The model is cheap and can quickly screen nanomedicines under in vivo conditions. Zebrafish (Danio rerio) have emerged as a promising model for assessing nanomedicines because of their fecundity, physiological and anatomically similarity to mammals, optical transparency and genetic malleability. Zebrafish can be used to predict the toxicity, systemic circulation, biodistribution and therapeutic efficacy of nanomedicines, therefore can act as an efficient alternative vertebrate screening model to decrease the number of experiments in higher vertebrates. In addition, the model is proven to be cheap and can quickly screen nanomedicines under in vivo conditions thus bridging the gap between in vitro and rodent studies. In this review, we highlight the potential of utilizing zebrafish as a model organism for preclinical investigation of nanomedicines with respect to toxicology, pharmacokinetics and therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Aim a comprehensive study of disorders of the biomechanics of blood circulation for early diagnostics of atherosclerosis. Material and methods. The study included 120 people having one of the following risk factors for cardiovascular diseases: smoking, hypertension, Type 1 or Type 2 diabetes. All subjects underwent computer-assisted rheopulmonography, rheovasography, apexcardiography, and direct sphygmography of the major arteries. The functioning of the heart, the arterial wall, the vascular bed of the pulmonary and systemic circulation was evaluated. Results. Smoking patients mainly had violations of the pulmonary circulation hemodynamics and the biomechanics of the arterial wall of the peripheral arteries due, obviously, to direct damage by nicotine. In patients with arterial hypertension, there was an increase in the work of the myocardium, obviously as a result of the formation of a hyperkinetic type of blood circulation in this disease. Patients with type 1 and type 2 diabetes mellitus were characterized primarily by the development of systolic-diastolic vascular dysfunction, which may be a predictor of the development of angiopathies in the future. In addition, the study of the kinetics of the major arteries revealed violations of the biomechanics of the wall of all vessels under study with risk factors for atherosclerosis. At the same time, it should be noted that more pronounced changes were found in the distal arteries of the muscular type than in the arteries of the muscular-elastic type, which is obviously associated with hemodynamic overloads experienced by peripheral vessels, both as a result of the hydraulic shock that occurs with hyperkinetic type of blood circulation, and the effect of hydrodynamic forces on the vessel wall under the influence of gravity. Conclusion. Each factor contributes to the development of disorders of cardiovascular biomechanics and hemodynamics. It is necessary to consider changes in the biomechanics of the heart and vascular bed as early manifestations of the circulatory system malfunction with present risk factors for cardiovascular diseases.

Gentamicin sulphate is an antibiotic belonging to the aminoglycosides and to class III of the Biopharmaceutical Classification System (BCS). Gentamicin sulphate is highly water soluble, but has very low intestinal permeability. The wide use is because of its broad spectrum of activity. In the current study, the suitability of administering gentamicin sulphate orally for local action against susceptible gastrointestinal tract (GIT) bacteria was investigated. The possibility of the drug escaping into the systemic circulation even in the presence of some permeation enhancers was ascertained. Representatives of potential GIT bacteria pathogens were evaluated for their susceptibility to the drug at concentrations obtainable in the GIT using standard microbiological methods. Dose levels that will inhibit these potential bacteria pathogens were also established, as well as the frequency of their administration. Different batches of oral capsules of 250 mg gentamicin sulphate were formulated and their release profiles ascertained using standard methods. The results showed that the selected representatives of the GIT potential pathogenic bacteria were all susceptible to gentamicin sulphate. The drug at its plausible dosage levels of 14.28 mg/kg (1,000 mg/70 kg), 10.71 mg/kg (750 mg/70 kg) and 7.14 mg/kg (500 mg/70 kg) did not cross the mucosal barrier into the systemic circulation even in the presence of some permeation enhancers. The drug's frequency of administration were found to be on 8-hourly bases. Gentamicin sulphate (250 mg) granules formulated with polyethylene glycol (PEG 4000) as granulating aid were quick drying because the granules were not hygroscopic. The formulated gentamicin sulphate capsule batch released enough concentration of the drug that inhibits the test organism within 2 min of dissolution. The above stated doses are acceptable in the dosage form design; it is possible to formulate non-absorbable oral gentamicin sulphate dosage form for local activity in the GIT using existing conventional solid dosage formulating equipment. [ABSTRACT FROM AUTHOR]

Background: Sepsis is common in cirrhosis and is often a result of immune dysregulation. Specific stimuli and pathways of inter‐cellular communications between immune cells in cirrhosis and sepsis are incompletely understood. Immune cell‐derived extracellular vesicles (EV) were studied to understand mechanisms of sepsis in cirrhosis. Methods: Immune cell‐derived EV were measured in cirrhosis patients [Child‐Turcotte‐Pugh (Child) score A, n = 15; B n = 16; C n = 43 and Child‐C with sepsis (n = 38)], and healthy controls (HC, n = 11). In vitro and in vivo functional relevance of EV in cirrhosis and associated sepsis was investigated. Results: Monocyte, neutrophil and hematopoietic stem cells associated EV progressively increased with higher Child score (P <.001)and correlated with liver disease severity indices (r2 > 0.3, P <.001), which further increased in Child C sepsis than without sepsis(P <.001); monocyte EV showing the highest association with disease stage [P =.013; Odds ratio‐4.14(1.34‐12.42)]. A threshold level of monocyte EV of 53/µl predicted mortality in patients of Child C with sepsis [Odds ratio‐6.2 (2.4‐15.9), AUROC = 0.76, P <.01]. In vitro EV from cirrhotic with sepsis compared without sepsis, induced mobilization arrest in healthy monocytes within 4 hours (P =.004), reduced basal oxygen consumption rate (P <.001) and induced pro‐inflammatory genes (P <.05). The septic‐EV on adoptive transfer to C57/BL6J mice, induced sepsis‐like condition within 24 h with leukocytopenia (P =.005), intrahepatic inflammation with increased CD11b + cells (P =.03) and bone marrow hyperplasia (P <.01). Conclusion: Extracellular vesicles induce functional impairment in circulating monocytes and contribute to the development and perpetuation of sepsis. High levels of monocyte EV correlate with mortality and can help early stratification of sicker patients. [ABSTRACT FROM AUTHOR]

An exponential rise in patient data provides an excellent opportunity to improve the existing health care infrastructure. In the present work, a method to enable cardiovascular digital twin is proposed using inverse analysis. Conventionally, accurate analytical solutions for inverse analysis in linear problems have been proposed and used. However, these methods fail or are not efficient for nonlinear systems, such as blood flow in the cardiovascular system (systemic circulation) that involves high degree of nonlinearity. To address this, a methodology for inverse analysis using recurrent neural network for the cardiovascular system is proposed in this work, using a virtual patient database. Blood pressure waveforms in various vessels of the body are inversely calculated with the help of long short-term memory (LSTM) cells by inputting pressure waveforms from three non-invasively accessible blood vessels (carotid, femoral and brachial arteries). The inverse analysis system built this way is applied to the detection of abdominal aortic aneurysm (AAA) and its severity using neural networks. [ABSTRACT FROM AUTHOR]

Clinical Impact: On needs-based ex vivo monitoring of implantable devices or tissues/organs in cardiovascular simulators provides new insights and paves new paths for device prototypes. The insights gained could not only support the needs of patients, but also inform engineers, scientists and clinicians about undiscovered aspects of diseases (during routine monitoring). We analyze seminal and current work and highlight a variety of opportunities for developing preclinical tools that would improve strategies for future implantable devices. Holistically, mock circulation loop studies can bridge the gap between in vivo and in vitro approaches, as well as clinical and laboratory settings, in a mutually beneficial manner., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Mechanical dyssynchrony affects left ventricular (LV) mechanics and coronary perfusion. Due to the confounding effects of their bi-directional interactions, the mechanisms behind these changes are difficult to isolate from experimental and clinical studies alone. Here, we develop and calibrate a closed-loop computational model that couples the systemic circulation, LV mechanics, and coronary perfusion. The model is applied to simulate the impact of mechanical dyssynchrony on coronary flow in the left anterior descending artery (LAD) and left circumflex artery (LCX) territories caused by regional alterations in perfusion pressure and intramyocardial pressure (IMP). We also investigate the effects of regional coronary flow alterations on regional LV contractility in mechanical dyssynchrony based on prescribed contractility-flow relationships without considering autoregulation. The model predicts that LCX and LAD flows are reduced by 7.2%, and increased by 17.1%, respectively, in mechanical dyssynchrony with a systolic dyssynchrony index of 10% when the LAD's IMP is synchronous with the arterial pressure. The LAD flow is reduced by 11.6% only when its IMP is delayed with respect to the arterial pressure by 0.07 s. When contractility is sensitive to coronary flow, mechanical dyssynchrony can affect global LV mechanics, IMPs and contractility that in turn, further affect the coronary flow in a feedback loop that results in a substantial reduction of dPLV/dt, indicative of ischemia. Taken together, these findings imply that regional IMPs play a significant role in affecting regional coronary flows in mechanical dyssynchrony and the changes in regional coronary flow may produce ischemia when contractility is sensitive to the changes in coronary flow.

Pressure–velocity-based analysis of arterial wave intensity gives clinically relevant information about the performance of the heart and vessels, but its utility is limited because accurate pressure measurements can only be obtained invasively. Diameter–velocity-based wave intensity can be obtained noninvasively using ultrasound; however, due to the nonlinear relationship between blood pressure and arterial diameter, the two wave intensities might give disparate clinical indications. To test the magnitude of the disagreement, we have generated an age-stratified virtual population to investigate how the two dominant nonlinearities viscoelasticity and strain-stiffening cause the two formulations to differ. We found strong agreement between the pressure–velocity and diameter–velocity methods, particularly for the systolic wave energy, the ratio between systolic and diastolic wave heights, and older subjects. The results are promising regarding the introduction of noninvasive wave intensities in the clinic. [ABSTRACT FROM AUTHOR]

Mechanical dyssynchrony affects left ventricular (LV) mechanics and coronary perfusion. Due to the confounding effects of their bi-directional interactions, the mechanisms behind these changes are difficult to isolate from experimental and clinical studies alone. Here, we develop and calibrate a closed-loop computational model that couples the systemic circulation, LV mechanics, and coronary perfusion. The model is applied to simulate the impact of mechanical dyssynchrony on coronary flow in the left anterior descending artery (LAD) and left circumflex artery (LCX) territories caused by regional alterations in perfusion pressure and intramyocardial pressure (IMP). We also investigate the effects of regional coronary flow alterations on regional LV contractility in mechanical dyssynchrony based on prescribed contractility-flow relationships without considering autoregulation. The model predicts that LCX and LAD flows are reduced by 7.2%, and increased by 17.1%, respectively, in mechanical dyssynchrony with a systolic dyssynchrony index of 10% when the LAD's IMP is synchronous with the arterial pressure. The LAD flow is reduced by 11.6% only when its IMP is delayed with respect to the arterial pressure by 0.07 s. When contractility is sensitive to coronary flow, mechanical dyssynchrony can affect global LV mechanics, IMP s and contractility that in turn, further affect the coronary flow in a feedback loop that results in a substantial reduction of dP LV / dt , indicative of ischemia. Taken together, these findings imply that regional IMP s play a significant role in affecting regional coronary flows in mechanical dyssynchrony and the changes in regional coronary flow may produce ischemia when contractility is sensitive to the changes in coronary flow. [ABSTRACT FROM AUTHOR]

In current drug delivery technology, the Transdermal drug delivery system (TDDS) is an innovative milestone system that delivers the drug into systemic circulation by avoiding the hurdles related to pure drug characteristics like molecular size, lipophilicity, permeability, through physical or chemical enhancers. At present, more than 100 kinds of medicated transdermal patches are available in the current market worth of 5 Billion USD Sales. Based on the comparative risk study with other conventional formulations, TDDS has very less risk factors and shows better patient compliance. The ongoing patent application and continuous search on TDDS show that there is a phenomenal growth in cosmetic, topical, and Pharmaceutical Industry. This review intends to render rich information on TDDS as a ready reference to the upcoming researchers on TDDS. [ABSTRACT FROM AUTHOR]

The development of fast dissolving dosage form consisted in film form and the rapid disintegrating properties were obtained through a special procedure or formulation modification, recently fast dissolving film are gaining as an alternative to fast dissolving film rapid absorbed. The present work aimed at preparing mouth dissolving film of Sumatriptan Succinate with the purpose of developing a dosage form a very quick onset of action. Sumatriptan Succinate is a 5-HT1B/1D receptor agonist used in the treatment of migraine. The bioavailability of Sumatriptan is approximately 15% so by delivering the drug through sublingual route will enhance bioavailability of the drug and provide quick onset of action to treat acute migraine attack. It allows the drug to directly enter into the systemic circulation and bypass the first pass metabolism. The main purpose of doing this study is to enhance the bioavailability and efficacy of sumatriptan because according to literature review this drug comes under the category of low efficacy drug used in management of acute attack of migraine due to its limitation to achieve pain free response within 2 hours of administration of oral dosage form of drug. This route by passes the first pass effect and due to this drug degradation will also not take place and it proves to be better option for dysphagic patients, pediatric, geriatric patients. The fast dissolving films are more beneficial in comparison to the tablet and capsules because sublingual films tend to dissolve within a minutes/second safter placing below the tongue. [ABSTRACT FROM AUTHOR]

Mesenchymal stromal cells (MSCs) are adult multipotent stem cells residing as pericytes in various tissues and organs where they can differentiate into specialized cells to replace dying cells and damaged tissues. These cells are commonly found at injury sites and in tumors that are known to behave like “wounds that do not heal.” In this article, we discuss the mechanisms of MSCs in migrating, homing, and repairing injured tissues. We also review a number of reports showing that tumor microenvironment triggers plasticity mechanisms in MSCs to induce malignant neoplastic tissue formation, maintenance, and chemoresistance, as well as tumor growth. The antitumor properties and therapeutic potential of MSCs are also discussed.

Purpose: This study aimed to assess the course of changes in choroidal morphology after immersion of the foot in warm water at 40°C using enhanced depth imaging optical coherence tomography (EDI-OCT)., Methods: Forty-three right eyes of 43 healthy participants were included. Changes in choroidal morphology were determined using EDI-OCT to evaluate subfoveal choroidal thickness (SCT). Systolic, diastolic, and mean blood pressures (SBP, DBP, and MBP, respectively) were also measured to determine systemic circulatory dynamics at baseline, immediately after immersion (0 min), and 10, 20, and 30 min after immersion., Results: Immediately after immersion, SBP, DBP, and MBP were significantly declined versus baseline. In contrast, the SCT was significantly increased after warm water immersion. However, all these parameters did not change significantly compared to the baseline within 30 min., Conclusion: In the normal eye, parasympathetic nerve activity induced by warming stimuli increases choroidal morphology in response to a decrease in systemic circulatory activity, which normalizes within 30 min. The findings of this study may provide basic data for the prevention and treatment of various choroidal diseases in which sympathetic hyperactivity is involved in the pathogenesis., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2024, Toh et al.)

In this paper we introduce a novel method for prescribing terminal boundary conditions in one-dimensional arterial flow networks. This is carried out by coupling the terminal arterial vessel with a poro-elastic tube, representing the flow resistance offered by microcirculation. The performance of the proposed porous media-based model has been investigated through several different numerical examples. First, we investigate model parameters that have a profound influence on the flow and pressure distributions of the system. The simulation results have been compared against the waveforms generated by three elements (RCR) Windkessel model. The proposed model is also integrated into a realistic arterial tree, and the results obtained have been compared against experimental data at different locations of the network. The accuracy and simplicity of the proposed model demonstrates that it can be an excellent alternative for the existing models. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Changes in gravity or body position provoke changes in hydrostatic pressure in the arterial system and in venous return. Potential asymmetries between left (̇LV) and right ventricular (̇RV) cardiac output during transient gravity changes were investigated. It was hypothesized that blood volume is temporarily stored in the pulmonary vessels, with amount and duration depending on the level and directions of gravity. METHODS: Eight healthy, male subjects (32 ± 3 yr, 182 ± 7 cm, 82 ± 6 kg) were tested on a tilt seat (TS), in a long arm human centrifuge (laHC), and during parabolic flights (PF). The gravitational changes during PF were reconstructed by changing gravity in a laHC and different body positions on a TS. All participants were tested in the seated, resting position. Heart rate and blood pressure were recorded continuously and ̇LV was calculated, applying the Modelflow Algorithm. Gas exchange was measured breath-by-breath. ̇RV was calculated from these data according to the Fick Principle. Four sequences were superimposed and analyzed by ANOVA with the factors Time, Ventricle (̇RV, ̇LV), and Mode (TS, PF, laHC). RESULTS: After reductions in gravity ̇RV and ̇LV were transiently desynchronized. ANOVA showed no main effect for Mode, but significant changes were found for Time and Ventricle and all interactions. DISCUSSION: Phases of reduced gravity seem to lead to transiently increased storage of blood volume inside the pulmonary vascular system. A more detailed understanding of these mechanisms might help to describe the compliance of the pulmonary vascular system in diseases of the pulmonary circulation. [ABSTRACT FROM AUTHOR]

In 2015, oncolytic virotherapy was approved for clinical use, and in 2017, recombinant adeno-associated virus (AAV) delivery was also approved. However, systemic administration remains challenging due to the limited number of viruses that successfully reach the target site. Although the US Food and Drug Administration (FDA) permits the use of higher doses of AAV to achieve greater rates of transduction, most AAV still accumulates in the liver, potentially leading to toxicity there and elsewhere. Targeting the tumor microenvironment is a promising strategy for cancer treatment due to the critical role of the tumor microenvironment in controlling tumor progression and influencing the response to therapies. Newly discovered evidence indicates that administration routes focusing on the tumor microenvironment can promote delivery specificity and transduction efficacy within the tumor. Here, we review approaches that involve modifying viral surface features, modulating the immune system, and targeting the physicochemical characteristics in tumor microenvironment to regulate therapeutic delivery. Targeting tumor acidosis presents advantages that can be leveraged to enhance virotherapy outcomes and to develop new therapeutic approaches that can be integrated with standard treatments. [Display omitted] [ABSTRACT FROM AUTHOR]

While it has long been recognized that bi-directional interaction between the heart and the vasculature plays a critical role in the proper functioning of the cardiovascular system, a comprehensive study of this interaction has largely been hampered by a lack of modeling framework capable of simultaneously accommodating high-resolution models of the heart and vasculature. Here, we address this issue and present a computational modeling framework that couples finite element (FE) models of the left ventricle (LV) and aorta to elucidate ventricular—arterial coupling in the systemic circulation. We show in a baseline simulation that the framework predictions of (1) LV pressure—volume loop, (2) aorta pressure—diameter relationship, (3) pressure—waveforms of the aorta, LV, and left atrium (LA) over the cardiac cycle are consistent with the physiological measurements found in healthy human. To develop insights of ventricular-arterial interactions, the framework was then used to simulate how alterations in the geometrical or, material parameter(s) of the aorta affect the LV and vice versa. We show that changing the geometry and microstructure of the aorta model in the framework led to changes in the functional behaviors of both LV and aorta that are consistent with experimental observations. On the other hand, changing contractility and passive stiffness of the LV model in the framework also produced changes in both the LV and aorta functional behaviors that are consistent with physiology principles.

Purpose: Changes in systemic circulatory dynamics and choroidal thickness are poorly understood. This study aimed to investigate the time course of changes in choroidal morphology during normal menstrual cycles in healthy women using enhanced depth imaging optical coherence tomography (EDI-OCT)., Materials and Methods: This prospective study included 15 left eyes of 15 healthy Japanese women (mean age, 20.2 ± 0.8 years) with a normal menstrual cycle. Using EDI-OCT, the subfoveal choroidal thickness (SCT) was manually measured during the late follicular and mid-luteal phases. Intraocular pressure (IOP), systolic, diastolic, and mean blood pressure (SBP, DBP, and MBP), and heart rate (HR) were also evaluated during these phases., Results: SBP, DBP, and MBP were significantly elevated in the mid-luteal phase. The average SCT was significantly decreased in the mid-luteal phase. In contrast, there were no significant changes in IOP or HR., Conclusion: These findings indicate that choroidal thickness decreases during the mid-luteal phase in healthy Japanese women with normal menstrual cycles depending on systemic circulatory dynamics. However, since the difference in the SCT values between the late follicular and the mid-luteal phase is not large (7 μm), the menstrual cycle may have little influence on the interpretation of choroidal thickness data in clinical practice., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2023, Kurahashi et al.)