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Translational Vision Science &... Jun 2024To assess the impact of ocular confounding factors on aqueous humor (AH) proteomic and metabolomic analyses for retinal disease characterization.
PURPOSE
To assess the impact of ocular confounding factors on aqueous humor (AH) proteomic and metabolomic analyses for retinal disease characterization.
METHODS
This study recruited 138 subjects (eyes): 102 with neovascular age-related macular degeneration (nAMD), 18 with diabetic macular edema (DME), and 18 with cataract (control group). AH samples underwent analysis using Olink Target 96 proteomics and Metabolon's metabolomics platform Data analysis included correlation, differential abundance, and gene-set analysis.
RESULTS
In total, 756 proteins and 408 metabolites were quantified in AH. Total AH protein concentration was notably higher in nAMD (3.2-fold) and DME (4.1-fold) compared to controls. Pseudophakic eyes showed higher total AH protein concentrations than phakic eyes (e.g., 1.6-fold in nAMD) and a specific protein signature indicative of matrix remodeling. Unexpectedly, pupil-dilating drugs containing phenylephrine/tropicamide increased several AH proteins, notably interleukin-6 (5.4-fold in nAMD). Correcting for these factors revealed functionally relevant protein correlation clusters and disease-relevant, differentially abundant proteins across the groups. Metabolomics analysis, for which the relevance of confounder adjustment was less apparent, suggested insufficiently controlled diabetes and chronic hyperglycemia in the DME group.
CONCLUSIONS
AH protein concentration, pseudophakia, and pupil dilation with phenylephrine/tropicamide are important confounding factors for AH protein analyses. When these factors are considered, AH analyses can more clearly reveal disease-relevant factors.
TRANSLATIONAL RELEVANCE
Considering AH protein concentration, lens status, and phenylephrine/tropicamide administration as confounders is crucial for accurate interpretation of AH protein data.
Topics: Humans; Aqueous Humor; Female; Proteomics; Male; Aged; Metabolomics; Eye Proteins; Middle Aged; Cataract; Diabetic Retinopathy; Macular Edema; Wet Macular Degeneration; Aged, 80 and over
PubMed: 38913008
DOI: 10.1167/tvst.13.6.17 -
Journal of Clinical Monitoring and... Jun 2024General Anaesthesia (GA) is accompanied by a marked decrease in sympathetic outflow and thus loss of vasomotor control of cardiac preload. The use of vasoconstriction...
General Anaesthesia (GA) is accompanied by a marked decrease in sympathetic outflow and thus loss of vasomotor control of cardiac preload. The use of vasoconstriction during GA has mainly focused on maintaining blood pressure. Phenylephrine (PE) is a pure α1-agonist without inotropic effects widely used to correct intraoperative hypotension. The potential of PE for augmenting cardiac stroke volume (SV) and -output (CO) by venous recruitment is controversial and no human studies have explored the effects of PE in preload dependent circulation using indicator dilution technique. We hypothesized that PE-infusion in patients with cardiac stroke volume limited by reduced preload would restore preload and thus augment SV and CO. 20 patients undergoing GA for gastrointestinal surgery were monitored with arterial catheter and LiDCO unity monitor. Upon stable haemodynamics after induction patients were placed in head-up tilt (HUT). All patients became preload responsive as verified by a stroke volume variation (SVV) of > 12%. PE-infusion was then started at 15-20mikrg/min and adjusted until preload was restored (SVV < 12%). Li-dilution cardiac output (CO) was initially measured after induction (baseline), again with HUT in the preload responsive phase, and finally when preload was restored with infusion of PE.At baseline SVV was 10 ± 3% (mean ± st.dev.), CI was 2,6 ± 0,4 L/min*m, and SVI 43 ± 7mL/m. With HUT SVV was 19 ± 4%, CI was 2,2 ± 0,4 L/min*m, SVI 35 ± 7mL/m. During PE-infusion SVV was reduced to 6 ± 3%, CI increased to 2,6 ± 0,5 L/min*m, and SVI increased to 49 ± 11mL/m. All differences p < 0,001. In conclusion: Infusion of phenylephrine during preload dependency increased venous return abolishing preload dependency as evaluated by SVV and increased cardiac stroke volume and -output as measured by indicator-dilution technique. (ClinicalTrials.gov NCT05193097).
PubMed: 38907106
DOI: 10.1007/s10877-024-01186-7 -
The Medical Letter on Drugs and... Jun 2024
Topics: Humans; Mydriasis; Phentolamine; Ophthalmic Solutions; Mydriatics; Administration, Ophthalmic
PubMed: 38905525
DOI: 10.58347/tml.2024.1705c -
Microvascular Research Jun 2024Patients with Takotsubo syndrome displayed endothelial dysfunction, but underlying mechanisms have not been fully clarified. This study aimed to explore molecular...
Patients with Takotsubo syndrome displayed endothelial dysfunction, but underlying mechanisms have not been fully clarified. This study aimed to explore molecular signalling responsible for catecholamine excess induced endothelial dysfunction. Human cardiac microvascular endothelial cells were challenged by epinephrine to mimic catecholamine excess. Patch clamp, FACS, ELISA, PCR, and immunostaining were employed for the study. Epinephrine (Epi) enhanced small conductance calcium-activated potassium channel current (I) through activating α1 adrenoceptor. Phenylephrine enhanced edothelin-1 (ET-1) and reactive oxygen species (ROS) production, and the effects involved contribution of I. HO enhanced I and ET-1 production. Enhancing I caused a hyperpolarization, which increases ROS and ET-1 production. BAPTA partially reduced phenylephrine-induced enhancement of ET-1 and ROS, suggesting that α1 receptor activation can enhance ROS/ET-1 generation in both calcium-dependent and calcium-independent ways. The study demonstrates that high concentration catecholamine can activate SK1-3 channels through α1 receptor-ROS signalling and increase ET-1 production, facilitating vasoconstriction.
PubMed: 38901735
DOI: 10.1016/j.mvr.2024.104699 -
Aesthetic Surgery Journal. Open Forum 2024The posterior Müller muscle-conjunctival resection (MMCR) procedure is a straightforward procedure for the correction of eyelid ptosis with a relatively short operating...
BACKGROUND
The posterior Müller muscle-conjunctival resection (MMCR) procedure is a straightforward procedure for the correction of eyelid ptosis with a relatively short operating time and fast recovery. Traditionally, its use was limited to patients with mild involutional ptosis and good levator function and a positive phenylephrine test result.
OBJECTIVES
To evaluate the efficacy of the MMCR procedure as a primary step to treat eyelid ptosis with varying etiology and severity, including patients with more severe ptosis and moderate levator function, and to produce a treatment algorithm.
METHODS
A retrospective analysis of the results of 34 patients, comprising 56 operated eyelids, treated with the MMCR procedure for eyelid ptotis between 2016 and 2018, was performed. Preoperative and postoperative pictures were analyzed for determining the margin-to-reflex distance (MRD1), symmetry, and complications.
RESULTS
We found a mean preoperative MRD1 of 1.3 mm (SD 1.1) and postoperative MRD1 of 3.2 mm (SD 1.0). The mean postoperative MRD1 for unilateral and bilateral cases was 3.4 (SD 0.8) and 3.2 (SD 1.1), respectively. Only 2 patients (5.9%) had an asymmetrical postoperative result (>1.0 mm MRD1 difference), and both were unilateral cases. Complications were scarce: only 1 patient (2.9%) developed dry eyes and 2 patients experienced temporary discomfort from the conjunctival sutures.
CONCLUSIONS
The MMCR procedure appears to be an excellent procedure as a primary step to correct eyelid ptosis with varying etiologies and severity, due to its low risk of asymmetry, short learning curve, and high success rate. A flow chart as treatment algorithm is provided for clinical decision making.
PubMed: 38887214
DOI: 10.1093/asjof/ojad111 -
Journal of Clinical Anesthesia Jun 2024Spinal anesthesia often causes hypotension, with consequent risk to the fetus. The use of vasopressor agents has been highly recommended for the prevention of spinal...
Norepinephrine or phenylephrine for the prevention of post-spinal hypotension after caesarean section: A double-blinded, randomized, controlled study of fetal heart rate and fetal cardiac output.
STUDY OBJECTIVE
Spinal anesthesia often causes hypotension, with consequent risk to the fetus. The use of vasopressor agents has been highly recommended for the prevention of spinal anesthesia-induced hypotension during caesarean delivery. Many studies have shown that norepinephrine can provide more stable maternal hemodynamics than phenylephrine. We therefore tested the hypothesis that norepinephrine preserves fetal circulation better than phenylephrine when used to treat maternal hypotension consequent to spinal anesthesia.
DESIGN
Prospective, randomized, double-blinded study.
SETTING
Operating room.
PATIENTS
We recruited 223 parturients with uncomplicated singleton pregnancies who were scheduled for elective caesarean section under combined spinal-epidural anesthesia.
INTERVENTIONS
The patients received prophylactic intravenous infusion of either 0.08 μg/kg/min norepinephrine or 0.5 μg/kg/min phenylephrine for prevention of spinal anesthesia-induced hypotension.
MEASUREMENTS
Changes in fetal heart rate and fetal cardiac output before and after spinal anesthesia were measured using noninvasive Doppler ultrasound.
MAIN RESULTS
90 subjects who received norepinephrine infusion and 93 subjects who received phenylephrine infusion were ultimately analyzed in the present study. The effects of norepinephrine and phenylephrine on the change of fetal heart rate and fetal cardiac output at 3 and 6 min after spinal block were similar. Although there was a statistically significant decrease in fetal cardiac output at 6 min after subarachnoid block initiation in both the norepinephrine group (mean difference 0.02 L/min; 95% CI, 0-0.04 L/min; P = 0.03) and the phenylephrine group (mean difference 0.02 L/min; 95% CI, 0-0.04 L/min; P = 0.02), it remained within the normal range.
CONCLUSIONS
Prophylactic infusion of comparable doses of phenylephrine or norepinephrine has similar effects on fetal heart rate and cardiac output changes after spinal anesthesia. Neither phenylephrine nor norepinephrine has meaningful detrimental effects on fetal circulation or neonatal outcomes.
PubMed: 38880002
DOI: 10.1016/j.jclinane.2024.111533 -
Atherosclerosis May 2024Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce the risk of cardiovascular events independently of glycemic control. However, the...
BACKGROUND AND AIMS
Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce the risk of cardiovascular events independently of glycemic control. However, the possibility that SGLT2 inhibitors improve vascular restenosis is unknown. The aim of this study was to examine whether dapagliflozin could prevent neointima thickening following balloon injury and, if so, to determine the underlying mechanisms.
METHODS
Saline, dapagliflozin (1.5 mg/kg/day), or losartan (30 mg/kg/day) was administered orally for five weeks to male Wistar rats. Balloon injury of the left carotid artery was performed a week after starting the treatment and rats were sacrificed 4 weeks later. The extent of neointima was assessed by histomorphometric and immunofluorescence staining analyses. Vascular reactivity was assessed on injured and non-injured carotid artery rings, changes of target factors by immunofluorescence, RT-qPCR, and histochemistry.
RESULTS
Dapagliflozin and losartan treatments reduced neointima thickening by 32 % and 27 %, respectively. Blunted contractile responses to phenylephrine and relaxations to acetylcholine and down-regulation of eNOS were observed in the injured arteries. RT-qPCR investigations indicated an increased in gene expression of inflammatory (IL-1beta, VCAM-1), oxidative (p47phox, p22phox) and fibrotic (TGF-beta1) markers in the injured carotid. While these changes were not affected by dapagliflozin, increased levels of AT1R and NTPDase1 (CD39) and decreased levels of ENPP1 were observed in the restenotic carotid artery of the dapagliflozin group.
CONCLUSIONS
Dapagliflozin effectively reduced neointimal thickening. The present data suggest that dapagliflozin prevents restenosis through interfering with angiotensin and/or extracellular nucleotides signaling. SGLT2 represents potential new target for limiting vascular restenosis.
PubMed: 38879387
DOI: 10.1016/j.atherosclerosis.2024.117595 -
Pharmacological Research Jul 2024Pressure overload-induced pathological cardiac hypertrophy eventually leads to heart failure (HF). Unfortunately, lack of effective targeted therapies for HF remains a...
Pressure overload-induced pathological cardiac hypertrophy eventually leads to heart failure (HF). Unfortunately, lack of effective targeted therapies for HF remains a challenge in clinical management. Mixed-lineage leukemia 4 (MLL4) is a member of the SET family of histone methyltransferase enzymes, which possesses histone H3 lysine 4 (H3K4)-specific methyltransferase activity. However, whether and how MLL4 regulates cardiac function is not reported in adult HF. Here we report that MLL4 is required for endoplasmic reticulum (ER) stress homeostasis of cardiomyocytes and protective against pressure overload-induced cardiac hypertrophy and HF. We observed that MLL4 is increased in the heart tissue of HF mouse model and HF patients. The cardiomyocyte-specific deletion of Mll4 (Mll4-cKO) in mice leads to aggravated ER stress and cardiac dysfunction following pressure overloading. MLL4 knockdown neonatal rat cardiomyocytes (NRCMs) also display accelerated decompensated ER stress and hypertrophy induced by phenylephrine (PE). The combined analysis of Cleavage Under Targets and Tagmentation sequencing (CUT&Tag-seq) and RNA sequencing (RNA-seq) data reveals that, silencing of Mll4 alters the chromatin landscape for H3K4me1 modification and gene expression patterns in NRCMs. Interestingly, the deficiency of MLL4 results in a marked reduction of H3K4me1 and H3K27ac occupations on Thrombospondin-4 (Thbs4) gene loci, as well as Thbs4 gene expression. Mechanistically, MLL4 acts as a transcriptional activator of Thbs4 through mono-methylation of H3K4 and further regulates THBS4-dependent ER stress response, ultimately plays a role in HF. Our study indicates that pharmacologically targeting MLL4 and ER stress might be a valid therapeutic approach to protect against cardiac hypertrophy and HF.
Topics: Animals; Heart Failure; Histone-Lysine N-Methyltransferase; Myocytes, Cardiac; Endoplasmic Reticulum Stress; Male; Mice, Inbred C57BL; Humans; Mice, Knockout; Rats; Mice; Cells, Cultured; Cardiomegaly; Rats, Sprague-Dawley; Thrombospondins
PubMed: 38876442
DOI: 10.1016/j.phrs.2024.107263 -
Journal of AAPOS : the Official... Jun 2024Hyphema is rarely seen in neonates. Although most cases are secondary to instrument-assisted delivery, neonatal hyphema can occur spontaneously or result from an...
Hyphema is rarely seen in neonates. Although most cases are secondary to instrument-assisted delivery, neonatal hyphema can occur spontaneously or result from an underlying coagulopathy. We report the case of an infant who was born with unilateral hyphema and was subsequently found to have gestational alloimmune liver disease-a condition where maternal antibodies attack the infant's liver, leading to a hypocoagulable state. Our patient was treated with topical prednisolone and cyclopentolate/phenylephrine, with subsequent resolution of the hyphema.
PubMed: 38876158
DOI: 10.1016/j.jaapos.2024.103957 -
Pharmacological Reports : PR Jun 2024Apart from antagonizing ß-adrenoceptors, carvedilol antagonizes vascular α-adrenoceptors and activates G protein-independent signaling. Even though it is a commonly...
BACKGROUND
Apart from antagonizing ß-adrenoceptors, carvedilol antagonizes vascular α-adrenoceptors and activates G protein-independent signaling. Even though it is a commonly used antihypertensive and α-adrenoceptors are essential for the treatment of voiding symptoms in benign prostatic hyperplasia, its actions in the human prostate are still unknown. Here, we examined carvedilol effects on contractions of human prostate tissues, and on stromal cell growth.
METHODS
Contractions of prostate tissues from radical prostatectomy were induced by electric field stimulation (EFS) or α-agonists. Growth-related functions were examined in cultured stromal cells.
RESULTS
Concentration-response curves for phenylephrine, methoxamine and noradrenaline were right shifted by carvedilol (0.1-10 µM), around half a magnitude with 100 nM, half to one magnitude with 1 µM, and two magnitudes with 10 µM. Right shifts were reflected by increased EC values for agonists, with unchanged E values. EFS-induced contractions were reduced by 21-54% with 0.01-1 µM carvedilol, and by 94% by 10 µM. Colony numbers of stromal cells were increased by 500 nM, but reduced by 1-10 µM carvedilol, while all concentrations reduced colony size. Decreases in viability were time-dependent with 0.1-0.3 µM, but complete with 10 µM. Proliferation was slightly increased by 0.1-0.5 µM, but reduced with 1-10 µM.
CONCLUSIONS
Carvedilol antagonizes α-adrenoceptors in the human prostate, starting with concentrations in ranges of known plasma levels. In vitro, effect sizes resemble those of α-blockers used for the treatment of voiding symptoms, which requires concentrations beyond plasma levels. Bidirectional and dynamic effects on the growth of stromal cells may be attributed to "biased agonism".
PubMed: 38858312
DOI: 10.1007/s43440-024-00605-5