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Fermentation-derived short-chain fatty acids (SCFA)4 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 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 N2 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.

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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.

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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.

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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.

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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 (O2•-) 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 O2•- 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.

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Objective: The study aimed to assess the transfer of merotocin from systemic circulation to breast milk in early postpartum women and women with established lactation. Methods: This was a two-part, multicenter, open-label, parallel-group study. Merotocin was administered as a single 90-minute intravenous (iv) infusion mimicking the intranasal pharmacokinetic profile. In Part A, 12 early postpartum women received doses of either 4 µg (n = 6) or 16 µg (n = 6) of merotocin within 4 days of delivery. In Part B, six women with established lactation received 20 µg of merotocin. The total concentration of merotocin in plasma and breast milk and its metabolites excreted in breast milk were measured at various time points. Adverse events (AEs) were also assessed for both parts of the study. Results: In both early postpartum and established lactation groups (mean age, 26.3 years; 83.3% Caucasian), merotocin and its metabolites in breast milk were below the limit of quantification (25.0 pg/mL) at all time points. Sixteen treatment-emergent AEs occurred in early postpartum women only, including seven events of uterine spasm and three of breast engorgement. There was one moderate event, whereas all the other events were considered mild. Conclusion: Merotocin was undetectable in breast milk after single iv administration of up to 20 µg in early postpartum women and women with established lactation.

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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.

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OBJECTIVE: To assess the effect of cardiovascular medications on the neurodevelopment of preterm infants, as measured by calculated cumulative time of vasoactive-inotropic score (VISct). METHODS: A retrospective study was conducted on preterm infants who developed significant hypotension defined as a mean BP more than 2SDs below the mean for GA and received treatment with duration > 6 hours for each hypotensive episode, we calculated the vasoactive inotropic score (VIS) and cumulative exposure to cardiovascular medications over time (VISct). The composite Bayley III was reported from the high-risk follow-up clinic for the surviving infants between 18 to 21 months corrected age. RESULTS: VISct was significantly higher in infants with abnormal neurodevelopment. Cognitive Bayley was the most affected component with median (IQR) VISct 882.5(249,2047) versus 309(143,471) (p-value 0.012), followed by language function with VISct 786(261,1563.5), versus 343(106.75,473.75) (p-value 0.016) when those with Bayley III <85 were compared with those with normal Bayley IIIs. CONCLUSION: High VISct scores may have negative effect on cognitive and language neurodevelopmental outcomes.

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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.

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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.

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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.

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The intestinal lymphatics are considered one of the most specialized pathways, which promote the absorption of various agents such as vitamins, lipids, xenobiotics, and lipophilic substances. The intestinal lymphatics have provided various advantages like bypassing first-pass effects, and improved bioavailability. The oral delivery of poor hydrophilic drugs can be improved by employing a lipid-based formulation strategy. Self-micro emulsifying drug delivery systems (SMEDDS) are one of the vivacious strategies based on lipid-based drug delivery that have shown their effects by improving the solubility and bioavailability of the therapeutic agents. This review is an insight into the functions, targets, mechanisms, and carriers involved in intestinal lymphatics. Also, the review illustrates the types, formulation requirements, and mechanism of action of SMEDDS in detail. In addition, it describes the targeting, types, physicochemical properties, biological barriers, and benefits of lymphatic targeting in therapy. Finally, the marketed formulations and future aspects of SMEDDS formulations are addressed.

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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.

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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.

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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.

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BACKGROUND AND AIM: The study was to extend systemic circulation and biological half-life (t1/2) of trans-resveratrol (RSV) using solid lipid nanoparticles (RSV-SLN) to improve its anti-cancer potential. METHODS: RSV-SLN was prepared by solvent emulsification evaporation technique and proceeded for evaluation like particle size, PDI, zeta potential, in vitro release, in vitro cytotoxicity, cellular internalisation, haemolysis and erythrocyte membrane integrity, platelet aggregation and pharmacokinetic studies in rats. Moreover, cancer cells accumulation of RSV-SLN also needs to be evaluated for proving their targeting ability. RESULT: Prepared SLN showed 126.85 ± 12.09 nm particle size, -24.23 ± 3.27 mV Zeta potential and 74.67 ± 4.76%. release at 48 h and haemocompatible. The cellular internalisation image showed the SLN reach in a cytoplasm and nucleus of PC3 prostate cells. RSV-SLN exhibited high t1/2 (8.22 ± 1.36 h) and 7.19 ± 0.69 h MRT (Mean residence time) and lower clearance i.e. 286.42 ± 13.64 mL/min/kg. The bio-distribution of RSV-SLN was found to be extremely high in prostate cells and accumulate 7.56 times greater than that of RSV solution. CONCLUSION: The developed RSV-SLN can be applied as potential carrier for delivery of drug of chemotherapeutics at an extend systemic circulation and targeting efficiency at tumour site.

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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.

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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.

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Despite recent preclinical progress with oncolytic bacteria in cancer therapy, dose-limiting toxicity has been a long-standing challenge for clinical application. Genetic and chemical modifications for enhancing the bacterial tumor-targeting ability have been unable to establish a balance between increasing its specificity and effectiveness while decreasing side effects. Herein, we report a simple, highly efficient method for rapidly self-assembling a clinically used lipid on bacterium and for reducing its minimum effective dose and toxicity to normal organs. The resultant bacteria present the ability to reverse-charge between neutral and acidic solutions, thus enabling weak interactions with the negatively charged normal cells, hence increasing their biocompatibility with blood cells and with the immune system. Additionally, the lipid-coated bacteria exhibit a longer blood circulation lifetime and low tissue trapping compared with the wild-type strains. Thereby, the engineered bacteria show enhanced tumor specificity and effectiveness even at low doses. Multiple visualization techniques are used for vividly demonstrating the time course of bacterial circulation in the blood and normal organs after intravenous administration. We believe that these methods for biointerfacial lipid self-assembly and evaluation of bacterial systemic circulation possess vast potential in exquisitely fabricating engineered bacteria for cancer therapy in the future.

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OBJECTIVE: To validate the vasoactive inotropic score as a predictor of the severity of compromised systemic circulation and mortality in preterm infants. METHODS: A retrospective study was conducted on preterm infants with Compromised systemic circulation [hypotension±lactic acidosis±oliguria] who received a cardiovascular support, we calculated the vasoactive inotropic score (VIS) and cumulative exposure to cardiovascular medications over time (VISct). Receiver operator curve was constructed to predict the primary outcome which was death & refractory hypotension. RESULTS: VIS had an area under the curve of 0.73 (95% CI 0.85-0.98, p < 0.001). A VIS cut off of 25 has sensitivity and specificity of 66% and 92%, and positive and negative predictive values of 78.5% and 83%, respectively. CONCLUSION: High VIS predicts the severity of Compromised systemic circulation and mortality rate in preterm infants.

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