Phenylephrine alters phase synchronization between cerebral blood velocity and blood pressure in ME/CFS with orthostatic intolerance.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) with orthostatic intolerance (OI) is characterized by neurocognitive deficits perhaps related to upright hypocapnia and loss of cerebral autoregulation (CA). We performed N-back neurocognition testing and calculated the phase synchronization index (PhSI) between arterial pressure (AP) and cerebral blood velocity (CBV) as a time-dependent measurement of cerebral autoregulation in 11 control (mean age = 24.1 yr) and 15 patients with ME/CFS (mean age = 21.8 yr). All patients with ME/CFS had postural tachycardia syndrome (POTS). A 10-min 60° head-up tilt (HUT) significantly increased heart rate (109.4 ± 3.9 vs. 77.2 ± 1.6 beats/min, P < 0.05) and respiratory rate (20.9 ± 1.7 vs. 14.2 ± 1.2 breaths/min, P < 0.05) and decreased end-tidal CO2 (ETCO2; 33.9 ± 1.1 vs. 42.8 ± 1.2 Torr, P < 0.05) in ME/CFS versus control. In ME/CFS, HUT significantly decreased CBV compared with control (-22.5% vs. -8.7%, P < 0.005). To mitigate the orthostatic CBV reduction, we administered supplemental CO2, phenylephrine, and acetazolamide and performed N-back testing supine and during HUT. Only phenylephrine corrected the orthostatic decrease in neurocognition by reverting % correct n = 4 N-back during HUT in ME/CFS similar to control (ME/CFS = 38.5 ± 5.5 vs. ME/CFS + PE= 65.6 ± 5.7 vs. Control 56.9 ± 7.5). HUT in ME/CFS resulted in increased PhSI values indicating decreased CA. Although CO2 and acetazolamide had no effect on PhSI in ME/CFS, phenylephrine caused a significant reduction in PhSI (ME/CFS = 0.80 ± 0.03 vs. ME/CFS + PE= 0.69 ± 0.04, P < 0.05) and improved cerebral autoregulation. Thus, PE improved neurocognitive function in patients with ME/CFS, perhaps related to improved neurovascular coupling, cerebral autoregulation, and maintenance of CBV.NEW & NOTEWORTHY We evaluated cognitive function before and after CO2, acetazolamide, and phenylephrine, which mitigate orthostatic reductions in cerebral blood velocity. Neither CO2 nor acetazolamide affected N-back testing (% correct answers) during an orthostatic challenge. Only phenylephrine improved upright N-back performance in ME/CFS, as it both blocked hyperventilation and increased CO2 significantly compared with those untreated. And only phenylephrine resulted in improved PSI values in both ME/CFS and control while upright, suggesting improved cerebral autoregulation.

Restoration Algorithm-Based Ultrasound Image in Evaluating the Effect of Dexmedetomidine on Patients with Neurological Disorder Anesthetized by Sevoflurane.

The study focused on the application value of ultrasound images processed by restoration algorithm in evaluating the effect of dexmedetomidine in preventing neurological disorder in patients undergoing sevoflurane anesthesia. 90 patients undergoing tonsillectomy anesthesia were randomly divided into normal saline group, propofol group, and dexmedetomidine group. The ultrasound images were processed by restoration algorithm, and during the postoperative recovery period, ultrasound images were used to evaluate. The results showed that the original ultrasonic image was fuzzy and contained interference noise, and that the image optimized by restoration algorithm was clear, without excess noise, and the image quality was significantly improved. In the dexmedetomidine group, the extubation time was 10.6 ± 2.3 minutes, the recovery time was 8.4 ± 2.2 minutes, the average pain score during the recovery period was 2.6 ± 0.7, and the average agitation score was 7.2 ± 2.4. Of 30 patients, there were 13 cases with vertigo and 1 case with nausea and vomiting. The vascular ultrasound imaging showed that, in the dexmedetomidine group, the peak systolic velocities (PSV) of the bilateral vertebral arteries during the recovery period were 67.7 ± 14.3 and 67.9 ± 15.2 cm/s, respectively; the end-diastolic velocities (EDV) of the bilateral vertebral arteries were 27.8 ± 6.7 and 24.69 ± 5.9 cm/s, respectively; the PSV in bilateral internal carotid artery systolic peak velocities were 67.2 ± 13.9 and 67.8 ± 12.7 cm/s, respectively; the EDV in bilateral internal carotid arteries were 27.7 ± 5.3 and 26.9 ± 4.9 cm/s, respectively; bilateral vertebral artery resistance indexes (RIs) were 0.6 ± 0.02 and 0.71 ± 0.08, respectively; the bilateral internal carotid artery RIs were 0.57 ± 0.04 and 0.58 ± 0.06, respectively, all better than the normal saline group (12.1 ± 2.5 minutes, 10.1 ± 2.3 minutes, 3.9 ± 0.6, 10.6 ± 3.7, 15 cases, 11 cases, 81.5 ± 13.6, 80.7 ± 11.6 cm/s, 29.3 ± 6.8, 28.9 ± 6.7 cm/s, 74.3 ± 10.2, 73.9 ± 12.5 cm/s, 29.1 ± 4.3, 29 ± 4.5 cm/s, 0.84 ± 0.06, 0.83 ± 0.05, 0.8 ± 0.04, and 0.81 ± 0.05) and the propofol group (11.4 ± 2.1 minutes, 9.0 ± 2.1 minutes, 3.4 ± 0.8, 8.5 ± 2.3, 12 cases, 9 cases, 72.5 ± 12.9, 73.4 ± 11.8 cm/s, 28.6 ± 5.4, 26.5 ± 5.1 cm/s, 72.1 ± 11.4, 73.5 ± 10.6 cm/s, 28.8 ± 5.6, 27.3 ± 4.7 cm/s, 0.78 ± 0.07, 0.82 ± 0.06, 0.76 ± 0.03, and 0.78 ± 0.05), and the differences were statistically significant (P < 0.05). In conclusion, ultrasound images processed by restoration algorithm have high image quality and high resolution. The dexmedetomidine can prevent neurological disorder in patients with sevoflurane anesthesia and is suggested in postoperative rehabilitation.

Effect of empagliflozin on coronary microvascular function in patients with type 2 diabetes mellitus-A randomized, placebo-controlled cross-over study.

PURPOSE: Results from large scale cardiovascular outcome trials in patients with type 2 diabetes mellitus (DM2) have found that sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce cardiovascular death and hospitalization for heart failure, but the mechanisms behind the beneficial cardiovascular effects are not fully understood. We tested the hypothesis that the SGLT2i, empagliflozin, improves non-endothelial dependent coronary microvascular function, thereby leading to better cardiac function. METHODS: Patients with DM2 followed at the endocrinology outpatient clinic at Bispebjerg University Hospital were included in a double blinded, placebo-controlled cross-over study. Participants were allocated equally to each treatment sequence using simple randomization and treated with empagliflozin 25 mg and placebo for 12 weeks, interrupted by 2 weeks wash-out period. The primary outcome was coronary microvascular function, assessed as coronary flow velocity reserve (CFVR) and measured with transthoracic doppler echocardiography. Echocardiographic parameters of cardiac function were measured, and blood samples were analyzed for a broad panel of cardiovascular biomarkers. RESULTS: Thirteen patients were randomized to each sequence and 10 and 9 completed the study according to protocol, respectively, and were included in the analysis of outcome parameters. We found no improvement in CFVR (change in the empagliflozin period was -0.16 (SD 0.58)). There were no effects on cardiac systolic function or indicators of cardiac filling pressure. Well-known effects of empagliflozin were obtained, such as weight loss and reduction in Hba1c level. Creatinine level increased but remained within normal range. We observed a clear trend of reduction in cardiovascular biomarkers after empagliflozin treatment and increased levels after the placebo period. No serious adverse reactions were reported. CONCLUSIONS: Despite effect on weight-loss, Hba1c and biomarkers, treatment with empagliflozin for 12 weeks did not improve CFVR in patients with DM2.

Comparative Assessment of Retinal Blood Flow Velocity Changes Following Brimonidine and Brinzolamide Administration Using Retinal Function Imaging.

PURPOSE: Impaired ocular blood flow has been associated with the etiopathogenesis of glaucoma. Topical brimonidine lowers intraocular pressure, a major glaucoma risk factor. However, brimonidine's influence on retinal blood flow remains to be fully elucidated. Our aim was to compare the effect of topical brimonidine and brinzolamide administration on retinal blood flow velocity in second and third order vessels in healthy adults using the retinal function imager. METHODS: In 10 healthy probands between 23 and 32 years of age, one eye was randomly selected to receive 2 treatment rounds with 3 single doses of brimonidine 2 mg/mL and brinzolamide 10 mg/mL at 12-hour intervals each. The fellow eyes served as intra-individual controls. Immediately before the first drop and 2 hours after the last drop of each treatment round, all subjects were examined, including Goldmann tonometry, Pascal tonometry, assessment of retinal blood flow velocity using the retinal function imager, as well as blood pressure and pulse measurements. RESULTS: Intraocular pressure decreased significantly in treated eyes while remaining stable in control eyes, indicating reliable application of brimonidine and brinzolamide drops. In contrast, retinal blood flow velocities did not demonstrate any significant differences between groups after both treatment rounds. CONCLUSIONS: Neither brimonidine nor brinzolamide appear to alter retinal blood flow velocity in a clinically relevant manner. The slight velocity changes detected in our study are likely physiologic fluctuations. Our findings do not support the rationale of a detrimental effect of topical brimonidine on ocular blood flow and hence brimonidine may be further administered for lowering intraocular pressure with the appropriate caution. However, our study is strongly limited by the small sample size and, thus, further research with larger cohorts of healthy volunteers and patients with glaucoma is needed to confirm the results. TRANSLATIONAL RELEVANCE: The study provides information about the effect of the topically administered antiglaucoma medications brimonidine and brinzolamide on the ocular blood flow and its regulation. The findings indicate that beside the lowering of IOP there is no evidence for an additional effect on the development of glaucoma.

Metformin improves skeletal muscle microvascular insulin resistance in metabolic syndrome.

Microvascular insulin resistance is present in metabolic syndrome and may contribute to increased cardiovascular disease risk and the impaired metabolic response to insulin observed. Metformin improves metabolic insulin resistance in humans. Its effects on macro and microvascular insulin resistance have not been defined. Eleven subjects with nondiabetic metabolic syndrome were studied four times (before and after 12 wk of treatment with placebo or metformin) using a crossover design, with an 8-wk washout interval between treatments. On each occasion, we measured three indices of large artery function [pulse wave velocity (PWV), radial pulse wave separation analysis (PWSA), brachial artery endothelial function (flow-mediated dilation-FMD)] as well as muscle microvascular perfusion [contrast-enhanced ultrasound (CEU)] before and at 120 min into a 150 min, 1 mU/min/kg euglycemic insulin clamp. Metformin decreased body mass index (BMI), fat weight, and % body fat (P < 0.05, each), however, placebo had no effect. Metformin (not placebo) improved metabolic insulin sensitivity, (clamp glucose infusion rate, P < 0.01), PWV, and FMD after insulin were unaffected by metformin treatment. PWSA improved with insulin only after metformin P < 0.01). Insulin decreased muscle microvascular blood volume measured by contrast ultrasound both before and after placebo and before metformin (P < 0.02 for each) but not after metformin. Short-term metformin treatment improves both metabolic and muscle microvascular response to insulin. Metformin's effect on microvascular insulin responsiveness may contribute to its beneficial metabolic effects. Metformin did not improve aortic stiffness or brachial artery endothelial function, but enhanced radial pulse wave properties consistent with relaxation of smaller arterioles.NEW & NOTEWORTHY Metformin, a first-line treatment for type 2 diabetes, is often used in patients with insulin resistance and metabolic syndrome. Here, we provide the first evidence for metformin improving muscle microvascular insulin sensitivity in insulin-resistant humans. Simultaneously, metformin improved muscle glucose disposal, supporting a close relationship between insulin's microvascular and its metabolic actions in muscle. Whether enhanced microvascular insulin sensitivity contributes to metformin's ability to decrease microvascular complications in diabetes remains to be resolved.

Safety and efficacy of botulinum neurotoxin in the treatment of erectile dysfunction refractory to phosphodiesterase inhibitors: Results of a randomized controlled trial.

BACKGROUND: There has been recent interest in the use of botulinum neurotoxin (BoNT) in the field of Andrology, whereby it has been investigated in the treatment of penile retraction and premature ejaculation. OBJECTIVES: To evaluate the safety and efficacy of intracavernosal BoNT-A injection in the treatment of patients with erectile dysfunction (ED) refractory to oral phosphodiesterase inhibitors (PDE5Is). PATIENTS AND METHODS: A double-blind randomized placebo-controlled prospective comparative study conducted at one center and involved 70 patients with ED refractory to PDE5Is. At baseline, the following data were collected: erection hardness score (EHS), peak systolic velocity (PSV), end diastolic velocity (EDV), sexual health inventory for men (SHIM), and the sexual encounter profile 2&3 (SEP-2&3) questionnaires. Treatment group (n = 35) received a single ICI of 100 units of BoNT-A in 2 ml of saline and control group (n = 35) received a single ICI of 2 ml of saline. EHS, PSV, and EDV were assessed at 2 weeks post treatment. SHIM, SEP-2, SEP-3, and global assessment questionnaire (GAQ-Q1&Q2) were completed at 2-, 6-, and 12-weeks post treatment. RESULTS: Two weeks post treatment, the treatment group showed a statistically significant improvement in the mean EHS, PSV, EDV, and GAQ-Q1 positive responders (p < 0.001) compared to the control group. At 6- and 12-weeks post treatment, the treatment group showed a statistically significant improvement in the SHIM scores, SEP-2, and GAQ-Q1&Q2 positive responders compared to the control group. At 6 weeks, where there was a 5-point improvement in the mean SHIM score of the treatment group (10±5.9 from 5.4±1.7 at baseline) versus no improvement in the placebo group, 18 patients in the treatment group (53%) were able to have an erection hard enough for vaginal penetration versus only one patient in the control group. CONCLUSION: BoNT-A is safe and effective as a potential treatment for ED refractory to PDE5I therapy.

Influence of nimodipine combined with ulinastatin on neurological function and inflammatory reaction in patients with cerebral vasospasm after subarachnoid hemorrhage.

OBJECTIVE: This study aimed to discuss the influence of nimodipine+ulinastatin on the neurological function and inflammatory reaction in patients with cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH). METHODS: Overall, 90 patients with CVS after SAH who were admitted to our hospital were enrolled in this study and randomly divided into research and control groups (n = 45 for both groups). On the basis of conventional therapy, patients in the control group were injected with ulinastatin and those in the research group were injected with ulinastatin+nimodipine through an intravenous drip for 7 days with the others the same as those of the control group. RESULTS: Blood flow velocity in all cerebral arteries was lower in the research group than in the control group after treatment (P < 0.05). Calcitonin gene-related peptide and nitric oxide levels were higher in the research group than in the control group after treatment (P < 0.05). Endothelin levels were lower in the research group than in the control group (P < 0.05). The total effective rate was higher in the research group than in the control group (P < 0.05). Glasgow Coma Scale scores were higher in the research group than in the control group (P < 0.05). CONCLUSION: The drug combination of nimodipine and ulinastatin improved blood flow and neurological function in patients with CVS after SAH and enhanced the therapeutic efficacy; the underlying mechanism may be associated with the regulation of vascular endothelial dilatation function and the inhibition of relevant inflammatory factors' expression.

Telmisartan ameliorates cardiac fibrosis and diastolic function in cardiorenal heart failure with preserved ejection fraction.

Chronic kidney disease (CKD) is a major contributor to the development of heart failure with preserved ejection fraction (HFpEF), whereas the underlying mechanism of cardiorenal HFpEF is still elusive. The aim of this study was to investigate the role of cardiac fibrosis in a rat model of cardiorenal HFpEF and explore whether treatment with Telmisartan, an inhibitor of renin-angiotensin-aldosterone system (RAAS), can ameliorate cardiac fibrosis and preserve diastolic function in cardiorenal HFpEF. Male rats were subjected to 5/6 subtotal nephrectomy (SNX) or sham operation (Sham), and rats were allowed four weeks to recover and form a stable condition of CKD. Telmisartan or vehicle was then administered p.o. (8 mg/kg/d) for 12 weeks. Blood pressure, brain natriuretic peptide (BNP), echocardiography, and cardiac magnetic resonance imaging were acquired to evaluate cardiac structural and functional alterations. Histopathological staining, real-time polymerase chain reaction (PCR) and western blot were performed to evaluate cardiac remodeling. SNX rats showed an HFpEF phenotype with increased BNP, decreased early to late diastolic transmitral flow velocity (E/A) ratio, increased left ventricular (LV) hypertrophy and preserved ejection fraction (EF). Pathology revealed increased cardiac fibrosis in cardiorenal HFpEF rats compared with the Sham group, while chronic treatment with Telmisartan significantly decreased cardiac fibrosis, accompanied by reduced markers of fibrosis (collagen I and collagen III) and profibrotic cytokines (α-smooth muscle actin, transforming growth factor-ß1, and connective tissue growth factor). In addition, myocardial inflammation was decreased after Telmisartan treatment, which was in a linear correlation with cardiac fibrosis. Telmisartan also reversed LV hypertrophy and E/A ratio, indicating that Telmisartan can improve LV remodeling and diastolic function in cardiorenal HFpEF. In conclusion, cardiac fibrosis is central to the pathology of cardiorenal HFpEF, and RAAS modulation with Telmisartan is capable of alleviating cardiac fibrosis and preserving diastolic dysfunction in this rat model.

The effect of norepinephrine on common carotid artery blood flow in septic shock patients.

This study was designed to evaluate the hemodynamic effect of norepinephrine (NE) on the peak systolic velocity (PSV), diameter, and blood flow of the common carotid artery (CCA) using the point-of-care ultrasound (POCUS) in patients with septic shock. The study involved patients above 18 years old with septic shock. Arterial monitoring, carotid ultrasonography, and transthoracic echocardiography were performed before NE administration (T0). When the mean arterial pressure exceeded 65 mmHg after NE administration (T1), the measurement was repeated. Twenty-four patients (median age 67 [interquartile range: 54-77] years; 42% female) with septic shock were examined in this study. Before (T0) and after (T1) NE administration, the PSV (mean, standard deviation [SD]) changed from 85.3 (21.1) cm/s to 83.5 (23.5) cm/s (p = 0.417); this change was not significant. However, the diameter and blood flow of the CCA increased significantly from 0.6 (0.09) cm and 0.75 (0.27) L/min to 0.66 (0.09) cm and 0.85 (0.27) L/min, respectively (p < 0.001). The diameter of the left ventricular outflow tract (LVOT) remained unchanged, but the velocity time integral of the LVOT increased significantly from 21.7 (4.39) cm to 23.6 (5.14) cm. There was no significant correlation between changes in blood flow of the CCA and changes in cardiac output (coefficient -0.365, p = 0.079). In conclusion, NE increased the diameter and blood flow of the CCA significantly, without changing the PSV in patients with septic shock.

Acute Beetroot Juice Ingestion Does Not Alter Renal Hemodynamics during Normoxia and Mild Hypercapnia in Healthy Young Adults.

Arterial hypercapnia reduces renal perfusion. Beetroot juice (BRJ) increases nitric oxide bioavailability and may improve renal blood flow. We tested the hypothesis that acute consumption of BRJ attenuates both decreases in blood velocity and increases in vascular resistance in the renal and segmental arteries during acute hypercapnia. In fourteen healthy young adults, blood velocity and vascular resistance were measured with Doppler ultrasound in the renal and segmental arteries during five minutes of breathing a carbon dioxide gas mixture (CO2) before and three hours after consuming 500 mL of BRJ. There was no difference between pre- and post-BRJ consumption in the increase in the partial pressure of end-tidal CO2 during CO2 breathing (pre: +4 ± 1 mmHg; post: +4 ± 2 mmHg, p = 0.4281). Segmental artery blood velocity decreased during CO2 breathing in both pre- (by -1.8 ± 1.9 cm/s, p = 0.0193) and post-BRJ (by -2.1 ± 1.9 cm/s, p = 0.0079), but there were no differences between pre- and post-consumption (p = 0.7633). Segmental artery vascular resistance increased from room air baseline during CO2 at pre-BRJ consumption (by 0.4 ± 0.4 mmHg/cm/s, p = 0.0153) but not post-BRJ (p = 0.1336), with no differences between pre- and post-consumption (p = 0.7407). These findings indicate that BRJ consumption does not attenuate reductions in renal perfusion during acute mild hypercapnia in healthy young adults.

Effect of insulin treatment on pulsatility ratio and resistance index of the retinal artery in patients with type 2 diabetes.

This study aimed to evaluate whether long-term insulin treatment is associated with abnormalities in retinal circulation in type 2 diabetic patients. We evaluated 19 eyes of nondiabetic individuals and 68 eyes of type 2 diabetic patients. The eyes of diabetic patients were classified into two groups according to the presence or absence of long-term insulin therapy. We used a Doppler optical coherence tomography flowmeter to measure diameter, velocity, and blood flow in the major temporal retinal artery. The pulsatility ratio (PR) and resistance index (RI), indices of vascular rigidity, were calculated from the blood velocity profile. PR and RI were significantly elevated in type 2 diabetic patients compared with nondiabetic subjects (P < 0.05). In type 2 diabetes patients, PR and RI were significantly higher in patients receiving long-term insulin treatment than in those without (P < 0.01). There was a significant difference in velocity (P < 0.05), but not diameter and blood flow, between nondiabetic subjects and type 2 diabetes patients. No significant difference in diameter, velocity, or blood flow was observed between the groups with and without long-term insulin treatment. Long-term insulin treatment can affect PR and RI, which might be associated with vascular rigidity of the retinal artery in patients with type 2 diabetes.

Impairing flow-mediated endothelial remodeling reduces extravasation of tumor cells.

Tumor progression and metastatic dissemination are driven by cell-intrinsic and biomechanical cues that favor the growth of life-threatening secondary tumors. We recently identified pro-metastatic vascular regions with blood flow profiles that are permissive for the arrest of circulating tumor cells. We have further established that such flow profiles also control endothelial remodeling, which favors extravasation of arrested CTCs. Yet, how shear forces control endothelial remodeling is unknown. In the present work, we aimed at dissecting the cellular and molecular mechanisms driving blood flow-dependent endothelial remodeling. Transcriptomic analysis of endothelial cells revealed that blood flow enhanced VEGFR signaling, among others. Using a combination of in vitro microfluidics and intravital imaging in zebrafish embryos, we now demonstrate that the early flow-driven endothelial response can be prevented upon specific inhibition of VEGFR tyrosine kinase and subsequent signaling. Inhibitory targeting of VEGFRs reduced endothelial remodeling and subsequent metastatic extravasation. These results confirm the importance of VEGFR-dependent endothelial remodeling as a driving force of CTC extravasation and metastatic dissemination. Furthermore, the present work suggests that therapies targeting endothelial remodeling might be a relevant clinical strategy in order to impede metastatic progression.

What drives transcranial Doppler velocity improvement in paediatric sickle cell anaemia: analysis from the Sickle Cell Clinical Research and Intervention Program (SCCRIP) longitudinal cohort study.

Children with sickle cell anaemia (SCA) and conditional transcranial Doppler (TCD) flow velocities (conditional: 170-199 cm/s; normal: <170 cm/s) have an increased risk of stroke. The Sickle Cell Clinical Research and Intervention Program (SCCRIP), a lifetime observational study, assessed the influence of haematological markers on TCD velocities. In children (≤16 years) with SCA (HbSS/HbSß0 -thalassaemia) and conditional TCD velocities (n = 32), increases in haemoglobin and in fetal haemoglobin after hydroxyurea initiation were significantly associated with decreases in TCD velocities. The benefit of pharmacological intervention to increase haemoglobin and fetal haemoglobin and normalise TCD velocities was demonstrated in this real-world dataset.

Blood flow changes in the forearm arteries after ultrasound-guided costoclavicular brachial plexus blocks: a prospective observational study.

BACKGROUND: An increase in blood flow in the forearm arteries has been reported after brachial plexus block (BPB). However, few studies have quantitatively analysed the blood flow of the forearm arteries after BPB or have studied only partial haemodynamic parameters. The purpose of the present study was to comprehensively assess blood flow changes in the distal radial artery (RA) and ulnar artery (UA) after BPB performed via a new costoclavicular space (CCS) approach using colour Doppler ultrasound. METHODS: Thirty patients who underwent amputated finger replantation and received ultrasound-guided costoclavicular BPB were included in the study. The haemodynamic parameters of the RA and UA were recorded before the block and 10 min, 20 min, and 30 min after the block using colour Doppler ultrasound to determine the peak systolic velocity (PSV), end-diastolic velocity (EDV), mean velocity (Vmean), pulsatility index (PI), resistance index (RI) and area. The volumetric flow rate (VFR) was calculated using the formula Q = area×Vmean. The aforementioned parameters were compared not only before and after the BPB but also between the RA and UA. RESULTS: Compared with those of the respective baselines, there was a significant increase in the PSV, EDV, Vmean, area, and VFR and a significant decrease in the PI and RI of the RA and UA 10 min, 20 min, and 30 min post-block. The increase 30 min post-block in EDV (258.68 % in the RA, 279.63 % in the UA) was the most notable, followed by that in the Vmean (183.36 % in the RA, 235.24 % in the UA), and the PSV (139.11 % in the RA, 153.15 % in the UA) changed minimally. The Vmean and VFR of the RA were significantly greater than those of the UA before the BPB; however, there was no significant difference in the VFR between the RA and UA after the BPB. CONCLUSIONS: A costoclavicular BPB can increase blood flow in the forearm arteries. The RA had a higher volumetric flow rate than the UA before the BPB; however, the potential blood supply capacity of the UA was similar to that of the RA after a BPB. TRIAL REGISTRATION: This study was registered at the Chinese Clinical Trial Registry (http://www.chictr.org.cn/searchproj.aspx, clinical trial number: ChiCTR 1900023796, date of registration: June 12, 2019).

Dose Escalation and Safety of Capsaicin for Cerebral Perfusion Augmentation: A Pilot Study.

Background and Purpose: Sphenopalatine ganglion (SPG) electrical stimulation has been studied in the setting of acute ischemic stroke to enhance collateral flow. Capsaicin poses an alternative to chemically stimulate the sphenopalatine ganglion. Therefore, the objective of this study was to determine the safety and effect of increasing doses of capsaicin upon serial transcranial Doppler markers of cerebral blood flow. Methods: We performed serial transcranial Doppler testing in 30 healthy volunteers divided into 5 equal groups. Capsaicin doses ranged from 33 to 165 µMol. We recorded peak systolic and end-diastolic velocities in the middle cerebral artery, arterial pressure, and perceived pungency in 5-minute intervals up to 20 minutes. We then calculated the mean velocity, the pulsatility index, and the cerebral blood flow index. Results: The participants' median age was 21 years (range, 5 years); all reported consumption of capsaicin in their diets. After and during the study, none reported side effects. Perceived pungency peaked at 5 minutes, and by the 20-minute mark, none perceived any pungency. All the tested doses produced the same pattern, consisting of augmentation of the middle cerebral artery mean velocity with the pulsatility index's diminution. The effects peaked between the 5- and the 10-minute measurements and then returned to basal levels except for the 66-µMol doses, which produced a sustained effect. We found no correlation between perceived pungency and dose, but the middle cerebral artery mean velocity was strongly correlated with the dose administered. Conclusions: This study provides evidence supporting the safety and tolerability of oral capsaicin in a population of healthy volunteers. Capsaicin appears to produce effects similar to those of sphenopalatine ganglion electrical stimulation. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04545892.

Pilot assessment of omega-3 fatty acids and potassium thiocyanate in sickle cell anemia patients with conditional peak systolic cerebral artery blood velocity.

OBJECTIVE: The purpose of this pilot study was to explore the effect of omega-3 fatty acids and potassium thiocyanate on conditional peak systolic cerebral artery blood velocity in children with sickle cell anemia (SCA). METHODS: Transcranial doppler ultrasonography (TCD) was done on 232 SCA children, and 21 found with conditional peak systolic blood velocity (PSV) of 200-249 cm/s in internal carotid, middle or anterior cerebral arteries. These were randomized to receive omega-3 fatty acids and potassium thiocyanate with standard treatment of SCA (test group, N = 14), or standard treatment only (control group, N = 7). After 3 months of treatment, PSV was measured again. RESULTS: Right middle cerebral artery PSV was significantly reduced in the test relative to the control groups (p = 0.04). PSV returned to normal in 79% of the test versus 43% of the control group; and increased to abnormal in one member of the control group, but none of the test group. CONCLUSIONS: The pilot data suggest that in SCA, omega-3 fatty acids and potassium thiocyanate might reduce conditional blood velocity to normal, or prevent progression to abnormal values. A larger, randomized, clinical trial is required to further address the current gap in management of conditional TCD blood velocity.

Effect of immunosuppressive therapy on ocular blood flow in initial-onset acute uveitis associated with Vogt-Koyanagi-Harada disease.

PURPOSE: To investigate the effect of immunosuppressive therapy on blood flow and waveform parameters in the choroid and optic nerve head (ONH) in patients with initial-onset acute uveitis associated with Vogt-Koyanagi-Harada (VKH) disease. METHODS: In this prospective study, 18 patients (36 eyes) were studied. Laser speckle flowgraphy was performed at baseline and at 4 weeks, 8 weeks and 12 weeks after treatment. We analysed longitudinal changes in mean blur rate (MBR), blow-out time, blow-out score (BOS), acceleration time index (ATI), flow acceleration index (FAI), resistivity index (RI) and blood flow fluctuation. RESULTS: After immunosuppressive therapy, MBR, representing blood flow velocity, in the choroid and ONH significantly increased at each post-treatment time point compared to baseline values. Among the analysed pulse waveform parameters, BOS significantly increased, while RI and fluctuation significantly decreased. Increased BOS and decreased RI indicate decreased vascular resistance following treatment. There was a strong negative correlation between BOS and RI. Additionally, FAI increased in the choroid and ATI increased in ONH. CONCLUSIONS: Immunosuppressive therapy in the acute uveitic phase of VKH disease improved inflammation-related impairment in choroidal and ONH blood flow.

Effect of PCSK9 inhibitors on pulse wave velocity and monocyte-to-HDL-cholesterol ratio in familial hypercholesterolemia subjects: results from a single-lipid-unit real-life setting.

AIMS: Subjects with familial hypercholesterolemia (FH) are characterized by an increased amount of low-density lipoprotein cholesterol (LDL-C) that promotes a continuous inflammatory stimulus. Our aim was to evaluate the effect of PCSK9-i on inflammatory biomarkers, neutrophil-to-lymphocyte ratio, monocyte-to-high-density lipoprotein ratio (MHR), and on early atherosclerosis damage analyzed by pulse wave velocity (PWV) in a cohort of FH subjects. METHODS: In this prospective observational study, we evaluated 56 FH subjects on high-intensity statins plus ezetimibe and with an off-target LDL-C. All subjects were placed on PCSK9-i therapy and obtained biochemical analysis as well as PWV evaluation at baseline and after six months of PCSK9-i therapy. RESULTS: After six months of add-on PCSK9-i therapy, only 42.9% of FH subjects attained LDL-C targets. As expected, a significant reduction of LDL-C (- 49.61%, p < 0.001) was observed after PCSK9-i therapy. Neutrophil count (NC) and MHR were reduced by PCSK9-i (-13.82% and -10.47%, respectively, p value for both < 0.05) and PWV significantly decreased after PCSK9-i therapy (- 20.4%, p < 0.05). Finally, simple regression analyses showed that ∆ PWV was significantly associated with ∆ LDL-C (p < 0.01), ∆ NC and ∆ MHR (p value for both < 0.05). CONCLUSIONS: In conclusion, PCSK9-i therapy significantly improved lipid and inflammatory profiles and PWV values in FH subjects; our results support the positive effect of PCSK9-i in clinical practice.

Phase 1 study to access safety, tolerability, pharmacokinetics, and pharmacodynamics of kynurenine in healthy volunteers.

The kynurenine pathway (KP) is the main path for tryptophan metabolism, and it represents a multitude of potential sites for drug discovery in neuroscience, including pain, stroke, and epilepsy. L-kynurenine (LKYN), the first active metabolite in the pathway, emerges to be a prodrug targeting glutamate receptors. The safety, tolerability, pharmacokinetics, and pharmacodynamics of LKYN in humans have not been previously investigated. In an open-label, single ascending dose study, six participants received an intravenous infusion of 50, 100, and 150 µg/kg LKYN and new six participants received an intravenous infusion of 0.3, 0.5, 1, and 5 mg/kg LKYN. To compare the pharmacological effects between species, we investigated in vivo the vascular effects of LKYN in rats. In humans, LKYN was safe and well-tolerated at all dose levels examined. After infusion, LKYN plasma concentration increased significantly over time 3.23 ± 1.12 µg/mL (after 50 µg/kg), 4.04 ± 1.1 µg/mL (after 100 µg/kg), and 5.25 ± 1.01 µg/mL (after 150 µg/kg) (p ≤ 0.001). We observed no vascular changes after infusion compared with baseline. In rats, LKYN had no effect on HR and MAP and caused no dilation of dural and pial arteries. This first-in-human study of LKYN showed that LKYN was safe and well-tolerated after intravenous infusion up to 5 mg/kg over 20 minutes. The lack of change in LKYN metabolites in plasma suggests a relatively slow metabolism of LKYN and no or little feed-back effect of LKYN on its synthesis. The therapeutic potential of LKYN in stroke and epilepsy should be explored in future studies in humans.