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Physiological Genomics Jun 2024Short-chain fatty acids (SCFAs) produced by the gut bacteria have been associated with cardiovascular dysfunction in humans and rodents. However, studies exploring...
Short-chain fatty acids (SCFAs) produced by the gut bacteria have been associated with cardiovascular dysfunction in humans and rodents. However, studies exploring effects of SCFAs on cardiovascular parameters in the zebrafish, an increasingly popular model in cardiovascular research, remain limited. Here, we performed fecal bacterial 16S sequencing and gas chromatography/mass spectrometry (GC-MS) to determine the composition and abundance of gut microbiota and SCFAs in adult zebrafish. Following this, the acute effects of major SCFAs on heart rate and vascular tone were measured in anesthetized zebrafish larvae using fecal concentrations of butyrate, acetate, and propionate. Finally, we investigated if coincubation with butyrate may lessen the effects of angiotensin II (ANG II) and phenylephrine (PE) on vascular tone in anesthetized zebrafish larvae. We found that the abundance in , , and phyla in the adult zebrafish resembled those reported in rodents and humans. SCFA levels with highest concentration of acetate (27.43 µM), followed by butyrate (2.19 µM) and propionate (1.65 µM) were observed in the fecal samples of adult zebrafish. Immersion in butyrate and acetate produced a ∼20% decrease in heart rate (HR), respectively, with no observed effects of propionate. Butyrate alone also produced an ∼25% decrease in the cross-sectional width of the dorsal aorta (DA) at 60 min (* < 0.05), suggesting compensatory vasoconstriction, with no effects of either acetate or propionate. In addition, butyrate significantly alleviated the decrease in DA cross-sectional width produced by both ANG II and PE. We demonstrate the potential for zebrafish in investigation of host-microbiota interactions in cardiovascular health. We highlight the presence of a core gut microbiota and demonstrate in vivo short-chain fatty acid production in adult zebrafish. In addition, we show cardio-beneficial vasoactive and chronotropic properties of butyrate, and chronotropic properties of acetate in anesthetized zebrafish larvae.
Topics: Animals; Zebrafish; Gastrointestinal Microbiome; Fatty Acids, Volatile; Larva; Heart Rate; Feces; Butyrates; Angiotensin II; Bacteria; Phenylephrine; Acetates; RNA, Ribosomal, 16S
PubMed: 38557279
DOI: 10.1152/physiolgenomics.00013.2024 -
PLoS Medicine Mar 2024Prolonged labor is a common condition associated with maternal and perinatal complications. The standard treatment with oxytocin for augmentation of labor increases the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Prolonged labor is a common condition associated with maternal and perinatal complications. The standard treatment with oxytocin for augmentation of labor increases the risk of adverse outcomes. Hyoscine butylbromide is a spasmolytic drug with few side effects shown to shorten labor when used in a general population of laboring women. However, research on its effect on preventing prolonged labor is lacking. We aimed to assess the effect of hyoscine butylbromide on the duration of labor in nulliparous women showing early signs of slow labor.
METHODS AND FINDINGS
In this double-blind randomized placebo-controlled trial, we included 249 nulliparous women at term with 1 fetus in cephalic presentation and spontaneous start of labor, showing early signs of prolonged labor by crossing the alert line of the World Health Organization (WHO) partograph. The trial was conducted at Oslo University Hospital in Norway from May 2019 to December 2021. One hundred and twenty-five participants were randomized to receive 1 ml hyoscine butylbromide (Buscopan) (20 mg/ml), while 124 received 1 ml sodium chloride intravenously. Randomization was computer-generated, with allocation concealment by opaque sequentially numbered sealed envelopes. The primary outcome was duration of labor from administration of the investigational medicinal product (IMP) to vaginal delivery, which was analyzed by Weibull regression to estimate the cause-specific hazard ratio (HR) of vaginal delivery between the 2 treatment groups, with associated 95% confidence interval (CI). A wide range of secondary maternal and perinatal outcomes were also evaluated. Time-to-event outcomes were analyzed by Weibull regression, whereas continuous and dichotomous outcomes were analyzed by median regression and logistic regression, respectively. All main analyses were based on the modified intention-to-treat (ITT) set of eligible women with signed informed consent receiving either of the 2 treatments. The follow-up period lasted during the postpartum hospital stay. All personnel, participants, and researchers were blinded to the treatment allocation. Median (mean) labor duration from IMP administration to vaginal delivery was 401 (440.8) min in the hyoscine butylbromide group versus 432.5 (453.6) min in the placebo group. We found no statistically significant association between IMP and duration of labor from IMP administration to vaginal delivery: cause-specific HR of 1.00 (95% CI [0.77, 1.29]; p = 0.993). Among 255 randomized women having received 1 dose of IMP, 169 women (66.3%) reported a mild adverse event: 75.2% in the hyoscine butylbromide group and 57.1% in the placebo group (Pearson's chi-square test: p = 0.002). More than half of eligible women were not included in the study because they did not wish to participate or were not included upon admission. The participants might have represented a selected group of women reducing the external validity of the study.
CONCLUSIONS
One intravenous dose of 20 mg hyoscine butylbromide was not found to be superior to placebo in preventing slow labor progress in a population of first-time mothers at risk of prolonged labor. Further research is warranted to answer whether increased and/or repeated doses of hyoscine butylbromide might have an effect on duration of labor.
TRIAL REGISTRATION
ClinicalTrials.gov (NCT03961165) EudraCT (2018-002338-19).
Topics: Female; Humans; Pregnancy; Butylscopolammonium Bromide; Double-Blind Method; Hydrocarbons, Brominated; Labor, Obstetric; Parasympatholytics; Scopolamine
PubMed: 38547322
DOI: 10.1371/journal.pmed.1004352 -
International Journal of Molecular... Mar 2024Anaphylactic shock (AS) is the most severe form of acute systemic hypersensitivity reaction. Although epinephrine can restore patients' hemodynamics, it might also be...
Anaphylactic shock (AS) is the most severe form of acute systemic hypersensitivity reaction. Although epinephrine can restore patients' hemodynamics, it might also be harmful, supporting the need for adjuvant treatment. We therefore investigated whether NButGT, enhancing O-GlcNAcylation and showing beneficial effects in acute heart failure might improve AS therapy. Ovalbumin-sensitized rats were randomly allocated to six groups: control (CON), shock (AS), shock treated with NButGT alone before (AS+pre-Nbut) or after (AS+post-Nbut) AS onset, shock treated with epinephrine alone (AS+EPI) and shock group treated with combination of epinephrine and NButGT (AS+EPI+preNBut). Induction of shock was performed with an intravenous (IV) ovalbumin. Cardiac protein and cycling enzymes O-GlcNAcylation levels, mean arterial pressure (MAP), heart rate, cardiac output (CO), left ventricle shortening fraction (LVSF), mitochondrial respiration, and lactatemia were evaluated using Western blotting experiments, invasive arterial monitoring, echocardiography, mitochondrial oximetry and arterial blood samples. AS decreased MAP (-77%, < 0.001), CO (-90%, < 0.001) and LVSF (-30%, < 0.05). Epinephrine improved these parameters and, in particular, rats did not die in 15 min. But, cardiac mitochondrial respiration remained impaired (complexes I + II -29%, < 0.05 and II -40%, < 0.001) with hyperlactatemia. NButGT pretreatment (AS+pre-Nbut) efficiently increased cardiac O-GlcNAcylation level as compared to the AS+post-Nbut group. Compared to epinephrine alone, the adjunction of NButGT significantly improved CO, LVSF and mitochondrial respiration. MAP was not significantly increased but lactatemia decreased more markedly. Pretreatment with NButGT increases O-GlcNAcylation of cardiac proteins and has an additive effect on epinephrine, improving cardiac output and mitochondrial respiration and decreasing blood lactate levels. This new therapy might be useful when the risk of AS cannot be avoided.
Topics: Humans; Rats; Animals; Anaphylaxis; Ovalbumin; Epinephrine; Cardiac Output; Hemodynamics; Respiration; Bridged Bicyclo Compounds, Heterocyclic
PubMed: 38542290
DOI: 10.3390/ijms25063316 -
BMC Ophthalmology Mar 2024Photoscreeners have been shown to provide excellent measurements of the refractive error. However, whether they could be used for assessing cycloplegic refraction has...
INTRODUCTION
Photoscreeners have been shown to provide excellent measurements of the refractive error. However, whether they could be used for assessing cycloplegic refraction has not been examied. This study aimed to evaluate the agreement between cycloplegic and non-cycloplegic measurements obtained using a photoscreener and stationary autorefractor, respectively.
METHODS
This study included all patients undergoing routine ophthalmic examination at the Hygeia Clinic (Poland) from June to July 2022. Each patient underwent non-cycloplegic and cycloplegic refraction assessments using the 2WIN photoscreener (Adaptica SRL, Padova, Italy) and an ARK-1 stationary autorefractor ARK-1 (Nidek Co Ltd., Tokyo, Japan), respectively. Each pair of assessments was conducted in random order, and all values were determined at a vertical distance of 12 mm. The agreement between cycloplegic and non-cycloplegic measurements was assessed using paired t-tests, Bland-Altman and ABCD ellipsoids.
RESULTS
This analysis included 82 patients, of which 52 were female. Their mean age was 34.39 ± 13.13 years. The non-cycloplegic spherical equivalent (SE) did not differ significantly between the 2WIN (- 1.22 ± 2.45) and ARK-1 (- 1.19 ± 2.96) devices (p = 0.580). However, the cycloplegic SE values demonstrated more negative values with the 2WIN device (- 1.13 ± 2.19) than with the ARK-1 device (- 0.75 ± 3.03; p = 0.007). The non-cycloplegic and cycloplegic measurements were strongly correlated between the devices (r = 0.9473 and 0.9411, respectively). However, the correlation between their cycloplegic shifts in SE was low (r = 0.2645). Ellipsoid refraction aligned better non-cycloplegic (ARK-1 = 1.00; 2WIN = 1.74) than with cycloplegic refraction (ARK-1 = 1.43; 2WIN = 1.90).
CONCLUSION
While the cycloplegic measurements obtained with the 2WIN photoscreener were strongly correlated with those obtained with the ARK-1 stationary autorefractor for most of the analyzed parameters, they should not be considered interchangeable.
Topics: Humans; Female; Young Adult; Adult; Middle Aged; Male; Mydriatics; Vision Tests; Refraction, Ocular; Refractive Errors; Japan
PubMed: 38528448
DOI: 10.1186/s12886-024-03375-z -
Resuscitation May 2024Endotracheal (ET) epinephrine administration is an option during neonatal resuscitation, if the preferred intravenous (IV) route is unavailable.
INTRODUCTION
Endotracheal (ET) epinephrine administration is an option during neonatal resuscitation, if the preferred intravenous (IV) route is unavailable.
OBJECTIVES
We assessed whether endotracheal epinephrine achieved return of spontaneous circulation (ROSC), and maintained physiological stability after ROSC, at standard and higher dose, in severely asphyxiated newborn lambs.
METHODS
Near-term fetal lambs were asphyxiated until asystole. Resuscitation was commenced with ventilation and chest compressions. Lambs were randomly allocated to: IV Saline placebo (5 ml/kg), IV Epinephrine (20 micrograms/kg), Standard-dose ET Epinephrine (100 micrograms/kg), and High-dose ET Epinephrine (1 mg/kg). After three allocated treatment doses, rescue IV Epinephrine was administered if ROSC had not occurred. Lambs achieving ROSC were monitored for 60 minutes. Brain histology was assessed for microbleeds.
RESULTS
ROSC in response to allocated treatment (without rescue IV Epinephrine) occurred in 1/6 Saline, 9/9 IV Epinephrine, 0/9 Standard-dose ET Epinephrine, and 7/9 High-dose ET Epinephrine lambs respectively. Blood pressure during CPR increased after treatment with IV Epinephrine and High-dose ET Epinephrine, but not Saline or Standard-dose ET Epinephrine. After ROSC, both ET Epinephrine groups had lower pH, higher lactate, and higher blood pressure than the IV Epinephrine group. Cortex microbleeds were more frequent in High-dose ET Epinephrine lambs (8/8 lambs examined, versus 3/8 in IV Epinephrine lambs).
CONCLUSIONS
The currently recommended dose of ET Epinephrine was ineffective in achieving ROSC. Without convincing clinical or preclinical evidence of efficacy, use of ET Epinephrine at this dose may not be appropriate. High-dose ET Epinephrine requires further evaluation before clinical translation.
Topics: Animals; Epinephrine; Sheep; Animals, Newborn; Cardiopulmonary Resuscitation; Heart Arrest; Vasoconstrictor Agents; Dose-Response Relationship, Drug; Intubation, Intratracheal; Disease Models, Animal; Return of Spontaneous Circulation; Random Allocation
PubMed: 38522732
DOI: 10.1016/j.resuscitation.2024.110191 -
European Review For Medical and... Mar 2024Methyl-2-(4-chloro- phenyl)-5-benzoxazoleacetate (MCBA), a synthetic benzoxazole derivative with established antipsoriatic efficacy, was investigated for potential...
OBJECTIVE
Methyl-2-(4-chloro- phenyl)-5-benzoxazoleacetate (MCBA), a synthetic benzoxazole derivative with established antipsoriatic efficacy, was investigated for potential antinociceptive effects. This study employs various nociceptive assays in mice to elucidate MCBA's antinociceptive mechanisms.
MATERIALS AND METHODS
MCBA's antinociceptive potential was tested against various nociception models induced by formalin, glutamate, capsaicin, a transient receptor potential vanilloid 1 (TRPV1) receptor agonist, and phorbol 12-myristate 13-acetate, a protein kinase C (PKC) activator. It was then assessed using the hot plate test and examined within the acetic acid-induced writhing test. During the acetic acid-induced writhing test, MCBA was pre-challenged against selective receptor antagonists such as naloxone, caffeine, atropine, yohimbine, ondansetron, and haloperidol. It was also pre-challenged with ATP-sensitive potassium channel inhibitor (glibenclamide) to further elucidate its antinociceptive mechanism.
RESULTS
The results showed that oral administration of MCBA led to a dose-dependent and significant inhibition (p < 0.05) of nociceptive effects across all evaluated models at doses of 60, 120, and 240 mg/kg. Moreover, the efficacy of MCBA's antinociceptive potential was significantly counteracted (p < 0.0001) by specific antagonists: (i) directed at adenosinergic, alpha-2 adrenergic, and cholinergic receptors using caffeine, yohimbine, and atropine, respectively; and (ii) targeting ATP-sensitive potassium channels, employing glibenclamide. Antagonists aimed at opioidergic and serotoninergic receptors (naloxone and ondansetron, respectively) had poor utility in inhibiting antinociceptive activity. Conversely, the dopaminergic receptor antagonist haloperidol potentiated locomotor abnormalities associated with MCBA treatment.
CONCLUSIONS
MCBA-induced antinociception involves modulation of glutamatergic-, TRVP1 receptors- and PKC-signaling pathways. It impacts adenosinergic, alpha-2 adrenergic, and cholinergic receptors and opens ATP-sensitive potassium channels.
Topics: Animals; Mice; Caffeine; Glyburide; Haloperidol; Nociception; Ondansetron; Adrenergic Agents; Atropine; KATP Channels; Naloxone; Receptors, Cholinergic; Yohimbine; Analgesics; Acetates
PubMed: 38497888
DOI: 10.26355/eurrev_202403_35620 -
International Journal of Obstetric... May 2024Hypotension is common during spinal anesthesia for cesarean delivery. Preventive strategies include fluid loading and phenylephrine. We hypothesized that if prophylactic... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Hypotension is common during spinal anesthesia for cesarean delivery. Preventive strategies include fluid loading and phenylephrine. We hypothesized that if prophylactic phenylephrine infusion is used, omission of fluid loading would be non-inferior to fluid co-loading in maintaining cardiac output. We assumed that if there was a difference, the increase in cardiac output would be greater in the no-loading than in the co-loading group.
METHODS
Term pregnant women scheduled for elective cesarean delivery were randomized to receive 1 L crystalloid co-loading or maintenance fluids only. Phenylephrine was titrated to maintain blood pressure. Changes in cardiac output following spinal anesthesia were the primary outcome. The study was powered as a non-inferiority trial, allowing the no-loading arm to have a 50% greater change in cardiac output. Heart rate, dose of phenylephrine, occurrence of nausea and vomiting, Apgar scores and neonatal acid base status were secondary outcomes.
RESULTS
Data from 63 women were analyzed. In contrast to our hypothesis, there was 33% less increase in cardiac output with no loading (ratio 0.67, 95% CI 0.15 to 1.36), and 60% greater reduction of cardiac output with no loading (ratio 1.6, 95% CI 1.0 to 2.7). Total dose of phenylephrine was higher in the no-loading group. There may be a less favorable neonatal acid base status without volume loading.
CONCLUSION
Omission of crystalloid co-loading leads to a decrease in cardiac output which has a potentially unfavorable impact on neonatal acid base status. We conclude that crystalloid co-loading may be useful in the presence of phenylephrine infusion.
Topics: Humans; Female; Cesarean Section; Pregnancy; Crystalloid Solutions; Double-Blind Method; Hypotension; Adult; Anesthesia, Spinal; Phenylephrine; Anesthesia, Obstetrical; Elective Surgical Procedures; Cardiac Output; Vasoconstrictor Agents
PubMed: 38485584
DOI: 10.1016/j.ijoa.2023.103968 -
Medical Archives (Sarajevo, Bosnia and... 2024Anaphylaxis is known as an acute, severe hypersensitivity reaction that rapidly initiates after exposure to a triggering agent. It is a life-threatening condition, and...
BACKGROUND
Anaphylaxis is known as an acute, severe hypersensitivity reaction that rapidly initiates after exposure to a triggering agent. It is a life-threatening condition, and early recognition and swift intervention are crucial to saving patients' lives. Objective: The objective of this study is to assess the ability of certified non-critical care physicians to recognize, manage, and dispose cases of anaphylaxis.
METHODS
A survey consisting of 19 questions was developed by expert emergency consultants to evaluate physicians' knowledge regarding the recognition, management, and disposition of anaphylactic episodes. Responses were collected through in-person surveys conducted with physicians from various specialties and varying clinical experience levels at a tertiary care center in the Eastern Province of Saudi Arabia.
RESULTS
In this cross-sectional study, a total of 173 physicians completed the survey, with 81.5% being consultants and 18.5% specialists. Only 5.2% correctly identified all three proposed anaphylaxis clinical scenarios, 16.8% identified two scenarios correctly, and 51.4% identified only one scenario. While 42.8% recognized the first-line management of anaphylaxis, only 24.3% and 24.9% knew the correct epinephrine dose and route, respectively. Regarding the disposition of patients experiencing an anaphylactic episode, 61.9% of responders opted to dispose the case to the emergency department.
CONCLUSION
Our study reveals a knowledge gap among non-critical care physicians practicing in a tertiary care center concerning the identification and management of anaphylaxis. Raising awareness of this life-threatening condition is imperative to address this serious issue.
Topics: Humans; Anaphylaxis; Cross-Sectional Studies; Epinephrine; Surveys and Questionnaires; Physicians
PubMed: 38481593
DOI: 10.5455/medarh.2024.78.44-50 -
Drug Design, Development and Therapy 2024Norepinephrine has fewer negative effects on heart rate (HR) and cardiac output (CO) for treating postspinal hypotension (PSH) compared with phenylephrine during... (Randomized Controlled Trial)
Randomized Controlled Trial Clinical Trial
Randomized Double-Blinded Comparison of Intermittent Boluses Phenylephrine and Norepinephrine for the Treatment of Postspinal Hypotension in Patients with Severe Pre-Eclampsia During Cesarean Section.
BACKGROUND
Norepinephrine has fewer negative effects on heart rate (HR) and cardiac output (CO) for treating postspinal hypotension (PSH) compared with phenylephrine during cesarean section. However, it remains unclear whether fetuses from patients with severe pre-eclampsia could benefit from the superiority of CO. The objective of this study was to compare the safety and efficacy of intermittent intravenous boluses of phenylephrine and norepinephrine used in equipotent doses for treating postspinal hypotension in patients with severe pre-eclampsia during cesarean section.
METHODS
A total of 80 patients with severe pre-eclampsia who developed PSH predelivery during cesarean section were included. Eligible patients were randomized at a 1:1 ratio to receive either phenylephrine or norepinephrine for treating PSH. The primary outcome was umbilical arterial pH. Secondary outcomes included other umbilical cord blood gas values, Apgar scores at 1 and 5 min, changes in hemodynamic parameters including CO, mean arterial pressure (MAP), HR, stroke volume (SV), and systemic vascular resistance (SVR), the number of vasopressor boluses required, and the incidence of bradycardia, hypertension, nausea, vomiting, and dizziness.
RESULTS
No significant difference was observed in umbilical arterial pH between the phenylephrine and norepinephrine groups (7.303±0.38 vs 7.303±0.44, respectively; P=0.978). Compared with the phenylephrine group, the overall CO (P=0.009) and HR (P=0.015) were greater in the norepinephrine group. The median [IQR] total number of vasopressor boluses required was comparable between the two groups (2 [1 to 3] and 2 [1 to 3], respectively; P=0.942). No significant difference was found in Apgar scores or the incidence of maternal complications between groups.
CONCLUSION
A 60 µg bolus of phenylephrine and a 4.5 µg bolus of norepinephrine showed similar neonatal outcomes assessed by umbilical arterial pH and were equally effective when treating PSH during cesarean section in patients with severe pre-eclampsia. Norepinephrine provided a higher maternal CO and a lower incidence of bradycardia.
Topics: Female; Humans; Infant, Newborn; Pregnancy; Anesthesia, Spinal; Bradycardia; Cesarean Section; Double-Blind Method; Hypotension; Norepinephrine; Phenylephrine; Pre-Eclampsia; Vasoconstrictor Agents
PubMed: 38476203
DOI: 10.2147/DDDT.S446657 -
International Journal of Molecular... Mar 2024Adrenaline has recently been found to trigger phosphatidylserine (PS) exposure on blood platelets, resulting in amplification of the coagulation process, but the...
Adrenaline has recently been found to trigger phosphatidylserine (PS) exposure on blood platelets, resulting in amplification of the coagulation process, but the mechanism is only fragmentarily established. Using a panel of platelet receptors' antagonists and modulators of signaling pathways, we evaluated the importance of these in adrenaline-evoked PS exposure by flow cytometry. Calcium and sodium ion influx into platelet cytosol, after adrenaline treatment, was examined by fluorimetric measurements. We found a strong reduction in PS exposure after blocking of sodium and calcium ion influx via Na/H exchanger (NHE) and Na/Ca exchanger (NCX), respectively. ADP receptor antagonists produced a moderate inhibitory effect. Substantial limitation of PS exposure was observed in the presence of GPIIb/IIIa antagonist, phosphoinositide-3 kinase (PI3-K) inhibitors, or prostaglandin E, a cyclic adenosine monophosphate (cAMP)-elevating agent. We demonstrated that adrenaline may develop a procoagulant response in human platelets with the substantial role of ion exchangers (NHE and NCX), secreted ADP, GPIIb/IIIa-dependent outside-in signaling, and PI3-K. Inhibition of the above mechanisms and increasing cytosolic cAMP seem to be the most efficient procedures to control adrenaline-evoked PS exposure in human platelets.
Topics: Humans; Blood Platelets; Platelet Activation; Calcium; Epinephrine; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Sodium; Thrombin
PubMed: 38474244
DOI: 10.3390/ijms25052997