Comprehensive structure and functional adaptations of the yeast nuclear pore complex.

Nuclear pore complexes (NPCs) mediate the nucleocytoplasmic transport of macromolecules. Here we provide a structure of the isolated yeast NPC in which the inner ring is resolved by cryo-EM at sub-nanometer resolution to show how flexible connectors tie together different structural and functional layers. These connectors may be targets for phosphorylation and regulated disassembly in cells with an open mitosis. Moreover, some nucleoporin pairs and transport factors have similar interaction motifs, which suggests an evolutionary and mechanistic link between assembly and transport. We provide evidence for three major NPC variants that may foreshadow functional specializations at the nuclear periphery. Cryo-electron tomography extended these studies, providing a model of the in situ NPC with a radially expanded inner ring. Our comprehensive model reveals features of the nuclear basket and central transporter, suggests a role for the lumenal Pom152 ring in restricting dilation, and highlights structural plasticity that may be required for transport.

Connexins: Key Players in the Control of Vascular Plasticity and Function.

Of the 21 members of the connexin family, 4 (Cx37, Cx40, Cx43, and Cx45) are expressed in the endothelium and/or smooth muscle of intact blood vessels to a variable and dynamically regulated degree. Full-length connexins oligomerize and form channel structures connecting the cytosol of adjacent cells (gap junctions) or the cytosol with the extracellular space (hemichannels). The different connexins vary mainly with regard to length and sequence of their cytosolic COOH-terminal tails. These COOH-terminal parts, which in the case of Cx43 are also translated as independent short isoforms, are involved in various cellular signaling cascades and regulate cell functions. This review focuses on channel-dependent and -independent effects of connexins in vascular cells. Channels play an essential role in coordinating and synchronizing endothelial and smooth muscle activity and in their interplay, in the control of vasomotor actions of blood vessels including endothelial cell reactivity to agonist stimulation, nitric oxide-dependent dilation, and endothelial-derived hyperpolarizing factor-type responses. Further channel-dependent and -independent roles of connexins in blood vessel function range from basic processes of vascular remodeling and angiogenesis to vascular permeability and interactions with leukocytes with the vessel wall. Together, these connexin functions constitute an often underestimated basis for the enormous plasticity of vascular morphology and function enabling the required dynamic adaptation of the vascular system to varying tissue demands.

High time-resolved studies of stick-slip show similar dilatancy to fast and slow earthquakes.

Fast and slow earthquakes are two modes of energy release by the slip in tectonic fault rupture. Although fast and slow slips were observed in the laboratory stick-slip experiments, due to the sampling rate limitation, the details of the fault thickness variation were poorly understood. Especially, why a single fault would show different modes of slip remains elusive. Herein, we report on ring shear experiments with an ultrahigh sampling rate (10 MHz) that illuminate the different physical processes between fast and slow slip events. We show that the duration of slips ranged from dozens to hundreds of milliseconds. Fast slip events are characterized by continuous large-amplitude AE (acoustic emission) and somewhat intricate variation of the sample thickness: A short compaction pulse during the rapid release of stress is followed by dilation and vibrations of the sample thickness. As the slip ends, the thickness of the sample first recovers by slow compaction and then dilates again before nucleation of the following slip event. In contrast, during slow slip events, the shear stress reduction is accompanied by intermittent bursts of low-amplitude AE and sample dilation. We observed the detailed thickness variation during slips and found that dilation occurs during both fast and slow slips, which is consistent with natural observations of coseismic dilatation. This study may be used to reveal the mechanism of fault slips during fast and slow earthquakes, which explain the potential effect of fast and slow slips on stress redistribution and structural rearrangement in faults.

Cross-Modal Interactions Between Auditory Attention and Oculomotor Control.

Microsaccades are small, involuntary eye movements that occur during fixation. Their role is debated with recent hypotheses proposing a contribution to automatic scene sampling. Microsaccadic inhibition (MSI) refers to the abrupt suppression of microsaccades, typically evoked within 0.1 s after new stimulus onset. The functional significance and neural underpinnings of MSI are subjects of ongoing research. It has been suggested that MSI is a component of the brain's attentional re-orienting network which facilitates the allocation of attention to new environmental occurrences by reducing disruptions or shifts in gaze that could interfere with processing. The extent to which MSI is reflexive or influenced by top-down mechanisms remains debated. We developed a task that examines the impact of auditory top-down attention on MSI, allowing us to disentangle ocular dynamics from visual sensory processing. Participants (N = 24 and 27; both sexes) listened to two simultaneous streams of tones and were instructed to attend to one stream while detecting specific task "targets." We quantified MSI in response to occasional task-irrelevant events presented in both the attended and unattended streams (frequency steps in Experiment 1, omissions in Experiment 2). The results show that initial stages of MSI are not affected by auditory attention. However, later stages (∼0.25 s postevent onset), affecting the extent and duration of the inhibition, are enhanced for sounds in the attended stream compared to the unattended stream. These findings provide converging evidence for the reflexive nature of early MSI stages and robustly demonstrate the involvement of auditory attention in modulating the later stages.

Effects of Adult Age and Functioning of the Locus Coeruleus Norepinephrinergic System on Reward-Based Learning.

Age-related impairments in value representations and updating during decision-making and reward-based learning are often related to age-related attenuation in the catecholamine system such as dopamine (DA) and norepinephrine (NE). However, it is unclear to what extent age-related declines in NE functioning in humans affect reward-based decision-making. We conducted a probabilistic decision-making task and applied a Q-learning model to investigate participants' anticipatory values and value sensitivities. Task-related pupil dilations and locus coeruleus (LC) magnetic resonance imaging (MRI) contrast, which served as a potential window of the LC-NE functions, were assessed in younger and older adults. Results showed that in both choice and feedback phases, younger adults' (N = 42, 22 males) pupil dilations negatively correlated with anticipatory values, indicating uncertainty about outcome probabilities. Uncertainty-evoked pupil dilations in older adults (N = 41, 27 males) were smaller, indicating age-related impairments in value estimation and updating. In both age groups, participants who showed a larger uncertainty-evoked pupil dilation exhibited a higher value sensitivity as reflected in the ß parameter of the reinforcement Q-learning model. Furthermore, older adults (N = 34, 29 males) showed a lower LC-MRI contrast than younger adults (N = 25, 15 males). The LC-MRI contrast positively correlated with value sensitivity only in older but not in younger adults. These findings suggest that task-related pupillary responses can reflect age-related deficits in value estimation and updating during reward-based decision-making. Our evidence with the LC-MRI contrast further showed the age-related decline of the LC structure in modulating value representations during reward-based learning.SIGNIFICANCE STATEMENT Age-related impairments in value representation and updating during reward-based learning are associated with declines in the catecholamine modulation with age. However, it is unclear how age-related declines in the LC-NE system may affect reward-based learning. Here, we show that compared with younger adults, older adults exhibited reduced uncertainty-induced pupil dilations, suggesting age-related deficits in value estimation and updating. Older adults showed a lower structural MRI of the LC contrast than younger adults, indicating age-related degeneration of the LC structure. The association between the LC-MRI contrast and value sensitivity was only observed in older adults. Our findings may demonstrate a pioneering model to unravel the role of the LC-NE system in reward-based learning in aging.

Neural α Oscillations and Pupil Size Differentially Index Cognitive Demand under Competing Audiovisual Task Conditions.

Cognitive demand is thought to modulate two often used, but rarely combined, measures: pupil size and neural α (8-12 Hz) oscillatory power. However, it is unclear whether these two measures capture cognitive demand in a similar way under complex audiovisual-task conditions. Here we recorded pupil size and neural α power (using electroencephalography), while human participants of both sexes concurrently performed a visual multiple object-tracking task and an auditory gap detection task. Difficulties of the two tasks were manipulated independent of each other. Participants' performance decreased in accuracy and speed with increasing cognitive demand. Pupil size increased with increasing difficulty for both the auditory and the visual task. In contrast, α power showed diverging neural dynamics: parietal α power decreased with increasing difficulty in the visual task, but not with increasing difficulty in the auditory task. Furthermore, independent of task difficulty, within-participant trial-by-trial fluctuations in pupil size were negatively correlated with α power. Difficulty-induced changes in pupil size and α power, however, did not correlate, which is consistent with their different cognitive-demand sensitivities. Overall, the current study demonstrates that the dynamics of the neurophysiological indices of cognitive demand and associated effort are multifaceted and potentially modality-dependent under complex audiovisual-task conditions.SIGNIFICANCE STATEMENT Pupil size and oscillatory α power are associated with cognitive demand and effort, but their relative sensitivity under complex audiovisual-task conditions is unclear, as is the extent to which they share underlying mechanisms. Using an audiovisual dual-task paradigm, we show that pupil size increases with increasing cognitive demands for both audition and vision. In contrast, changes in oscillatory α power depend on the respective task demands: parietal α power decreases with visual demand but not with auditory task demand. Hence, pupil size and α power show different sensitivity to cognitive demands, perhaps suggesting partly different underlying neural mechanisms.

Real-World Efficacy of Dupilumab in Severe, Treatment-Refractory, and Fibrostenotic Patients With Eosinophilic Esophagitis.

BACKGROUND & AIMS: Dupilumab is approved for treatment of eosinophilic esophagitis (EoE), but real-world data are lacking. We aimed to determine the real-world efficacy of dupilumab in patients with severe, treatment-refractory, and fibrostenotic EoE. METHODS: We conducted a retrospective cohort study of EoE patients prescribed dupilumab and who were treatment-refractory to standard modalities. Patient demographics, clinical characteristics, EoE history, and procedural data (including the histologically worst, predupilumab, and postdupilumab endoscopies) were extracted from medical records. Symptomatic, endoscopic, and histologic responses were assessed for the worst and predupilumab endoscopies compared with the postdupilumab endoscopy. RESULTS: We identified 46 patients with refractory fibrostenotic EoE who were treated with dupilumab. Patients showed endoscopic, histologic, and symptomatic improvement on dupilumab compared with both the worst and the predupilumab esophagogastroduodenoscopies. The peak eosinophil counts decreased markedly, and postdupilumab histologic response rates were 80% and 57% for fewer than 15 eosinophils per high-power field and 6 or fewer eosinophils per high-power field, respectively, and the Endoscopic Reference Score decreased from 5.01 to 1.89 (P < .001 for all). Although the proportion of strictures was stable, there was a significant increase in the predilation esophageal diameter (from 13.9 to 16.0 mm; P < .001). Global symptom improvement was reported in 91% (P < .001). CONCLUSIONS: In this population of severe, refractory, and fibrostenotic EoE patients, most achieved histologic, endoscopic, and symptom improvement with a median of 6 months of dupilumab, and esophageal stricture diameter improved. Dupilumab has real-world efficacy for a severe EoE population, most of whom would not have qualified for prior clinical trials.

The Efficacy of Peroral Endoscopic Myotomy vs Pneumatic Dilation as Treatment for Patients With Achalasia Suffering From Persistent or Recurrent Symptoms After Laparoscopic Heller Myotomy: A Randomized Clinical Trial.

BACKGROUND & AIMS: For patients with achalasia experiencing persistent or recurrent symptoms after laparoscopic Heller myotomy (LHM), pneumatic dilation (PD) is the most frequently used treatment. Per-oral endoscopic myotomy (POEM) is increasingly being investigated as rescue therapy. This study aimed to determine the efficacy of POEM vs PD for patients with persistent or recurrent symptoms after LHM. METHODS: This randomized multicenter controlled trial included patients after LHM with an Eckardt score >3 and substantial stasis (≥2 cm) on timed barium esophagogram and randomized to POEM or PD. The primary outcome was treatment success, defined as an Eckardt score of ≤3 and without unscheduled re-treatment. Secondary outcomes included the presence of reflux esophagitis, high-resolution manometry, and timed barium esophagogram findings. Follow-up duration was 1 year after initial treatment. RESULTS: Ninety patients were included. POEM had a higher success rate (28 of 45 patients [62.2%]) than PD (12 of 45 patients [26.7%]; absolute difference, 35.6%; 95% CI, 16.4%-54.7%; P = .001; odds ratio, 0.22; 95% CI, 0.09-0.54; relative risk for success, 2.33; 95% CI, 1.37-3.99). Reflux esophagitis was not significantly different between POEM (12 of 35 [34.3%]) and PD (6 of 40 [15%]). Basal lower esophageal sphincter pressure and integrated relaxation pressure (IRP-4) were significantly lower in the POEM group (P = .034; P = .002). Barium column height after 2 and 5 minutes was significantly less in patients treated with POEM (P = .005; P = .015). CONCLUSIONS: Among patients with achalasia experiencing persistent or recurrent symptoms after LHM, POEM resulted in a significantly higher success rate than PD, with a numerically higher incidence of grade A-B reflux esophagitis. NETHERLANDS TRIAL REGISTRY: NL4361 (NTR4501), https://trialsearch.who.int/Trial2.aspx?TrialID = NTR4501.

Heart failure with preserved ejection fraction in pigs causes shifts in post-transcriptional checkpoints.

Background: Left ventricular pressure overload (LVPO) can lead to heart failure with a preserved ejection fraction (HFpEF) and LV chamber stiffness (LV Kc) is a hallmark. This project tested the hypothesis that the development of HFpEF due to an LVPO stimulus, will alter post-transcriptional regulation, specifically microRNAs (miRs). Methods: LVPO was induced in pigs (n=9) by sequential ascending aortic cuff and age and weight matched pigs (n=6) served as controls. LV function was measured by echocardiography and LV Kc by speckle tracking. LV myocardial miRs were quantified using an 84 miR array. Treadmill testing and natriuretic peptide-A (NPPA) mRNA levels in controls and LVPO were performed (n=10, n=9, respectively). LV samples from LVPO and controls (n=6, respectively) were subjected to RNA sequencing. Results: LV mass and Kc increased by over 40% with LVPO (p<0.05). A total of 30 miRs shifted with LVPO of which 11 miRs correlated to LV Kc (p<0.05) which mapped to functional domains relevant to Kc such as fibrosis and calcium handling. LVPO resulted in reduced exercise tolerance (oxygen saturation, respiratory effort) and NPPA mRNA levels increased by 4-fold (p<0.05). RNA analysis identified several genes which mapped to specific miRs that were altered with LVPO. Conclusion: A specific set of miRs are changed in a large animal model consistent with the HFpEF phenotype, were related to LV stiffness properties and several miRs mapped to molecular pathways which may hold relevance in terms of prognosis and therapeutic targets.

Neuraminidase-induced externalization of phosphatidylserine activates ADAM17 and impairs insulin signaling in endothelial cells.

Endothelial insulin resistance represents a causal factor in the pathogenesis of type 2 diabetes (T2D) and vascular disease, thus the need to identify molecular mechanisms underlying defects in endothelial insulin signaling. We previously have shown that a disintegrin and metalloproteinase-17 (ADAM17) is increased while insulin receptor α-subunit (IRα) is decreased in the vasculature of patients with T2D, leading to impaired insulin-induced vasodilation. We have also demonstrated that ADAM17 sheddase activity targets IRα; however, the mechanisms driving endothelial ADAM17 activity in T2D are largely unknown. Herein, we report that externalization of phosphatidylserine (PS) to the outer leaflet of the plasma membrane causes ADAM17-mediated shedding of IRα and blunting of insulin signaling in endothelial cells. Furthermore, we demonstrate that endothelial PS externalization is mediated by the phospholipid scramblase anoctamin-6 (ANO6) and that this process can be stimulated by neuraminidase, a soluble enzyme that cleaves sialic acid residues. Of note, we demonstrate that men and women with T2D display increased levels of neuraminidase activity in plasma, relative to age-matched healthy individuals, and this occurs in conjunction with increased ADAM17 activity and impaired leg blood flow responses to endogenous insulin. Collectively, this work reveals the neuraminidase-ANO6-ADAM17 axis as a novel potential target for restoring endothelial insulin sensitivity in T2D.NEW & NOTEWORTHY This work provides the first evidence that neuraminidase, an enzyme increased in the circulation of men and women with type 2 diabetes (T2D), promotes anoctamin-6 (ANO6)-dependent externalization of phosphatidylserine in endothelial cells, which in turn leads to activation of a disintegrin and metalloproteinase-17 (ADAM17) and consequent shedding of the insulin receptor-α from the cell surface. Hence, this work supports that consideration should be given to the neuraminidase-ANO6-ADAM17 axis as a novel potential target for restoring endothelial insulin sensitivity in T2D.

Antecubital venous endothelial ETB receptor protein expression is preserved with aging in men.

Changes in endothelial function precede the development of cardiovascular disease (CVD). We have previously shown that age-related declines in endothelial function in women are due in part to a reduction in endothelial cell endothelin-B receptor (ETBR) protein expression. However, it is not known if ETBR protein expression changes with aging in men. The purpose of this study was to test the hypothesis that ETBR protein expression is attenuated in older men (OM) compared with younger men (YM). Primary endothelial cells were harvested from the antecubital vein of 14 OM (60 ± 6 yr; 26 ± 3 kg/m2) and 17 YM (24 ± 5 yr; 24 ± 2 kg/m2). Cells were stained with 4',6-diamidino-2-phenylindole, vascular endothelial cadherin, and ETBR. Images were quantified using immunocytochemistry. Endothelial function was assessed using brachial artery flow-mediated dilation (FMD). Systolic BP was similar (OM, 123 ± 11 vs. YM, 122 ± 10 mmHg) whereas diastolic BP was higher in OM (OM, 77 ± 7 vs. YM, 70 ± 6 mmHg; P < 0.01). Total testosterone was lower in OM (OM, 6.28 ± 4.21 vs. YM, 9.10 ± 2.68 ng/mL; P = 0.03). As expected, FMD was lower in OM (OM, 3.85 ± 1.51 vs. YM, 6.40 ± 2.68%; P < 0.01). However, ETBR protein expression was similar between OM and YM (OM, 0.39 ± 0.17 vs. YM, 0.42 ± 0.17 AU; P = 0.66). These data suggest that ETBR protein expression is not altered with age in men. These findings contrast with our previous data in women and further support sex differences in the endothelin system.NEW & NOTEWORTHY Our laboratory has previously shown that age-related declines in endothelial function are associated with a reduction in endothelial cell ETBR protein expression in women. However, it is unclear if endothelial cell ETBR protein expression is reduced with aging in men. This study demonstrates that endothelial cell ETBR protein expression is preserved with aging in men, and provides additional evidence for sex differences in the endothelin system.

Vascular adaptation to exercise: a systematic review and audit of female representation.

Biological sex is a salient factor in exercise-induced vascular adaptation. Although a male bias is apparent in the literature, the methodological quality of available studies in females is not yet known. This systematic review with narrative synthesis aimed to assess available evidence of exercise interventions on endothelial function, measured using flow-mediated dilation, in otherwise healthy individuals and athletes. A standardized audit framework was applied to quantify the representation of female participants. Using a tiered grading system, studies that met best-practice recommendations for conducting physiological research in females were identified. A total of 210 studies in 5,997 participants were included, with 18% classified as athletes. The primary exercise mode and duration were aerobic (49%) and acute (61%), respectively. Despite 53% of studies (n = 111) including at least one female, female participants accounted for only 39% of the total study population but 49% of the athlete population. Majority (49%) of studies in females were conducted in premenopausal participants. No studies in naturally menstruating, hormonal contraceptive-users or in participants experiencing menstrual irregularities met all best-practice recommendations. Very few studies (∼5%) achieved best-practice methodological guidelines for studying females and those that did were limited to menopause and pregnant cohorts. In addition to the underrepresentation of female participants in exercise-induced vascular adaptation research, there remains insufficient high-quality evidence with acceptable methodological control of ovarian hormones. To improve the overall methodological quality of evidence, adequate detail regarding menstrual status should be prioritized when including females in vascular and exercise research contexts.

Remote and local effects of ischemic preconditioning on vascular function: a case for cumulative benefit.

Brief, repeated cycles of limb ischemia and reperfusion [ischemic preconditioning (IPC)] can protect against vascular insult. Few papers have considered the effect of IPC on resting vascular function, and no single study has simultaneously considered the local (trained arm) and remote (untrained arm) effects of a single session of IPC and following repeated sessions. We determined macrovascular [allometrically scaled flow-mediated dilation (FMD)] and microvascular [cutaneous vascular conductance (CVC)] function in healthy adults before, immediately post, 20 min post, and 24 h post a single session of IPC (4 × 5 min of single arm ischemia). These outcomes also were remeasured 24 h after six IPC sessions, performed over 2 wk. FMD and CVC increased in both arms 20 min post [FMD mean difference (MD) 1.1%, P < 0.001; CVC MD 0.08 arbitrary units (AU), P = 0.004] but not 24 h post (FMD MD -0.2%, P = 0.459; CVC MD -0.02 AU, P = 0.526] a single session of IPC, with no differences between trained and untrained arms. Although FMD did not increase 24 h after one IPC session, it was elevated in both arms 24 h after the sixth session (MD 1.2%, P = 0.009). CVC was not altered in either arm 24 h after the last IPC session. These data indicate that the local and remote effects of IPC on vascular health may be equivalent and that the benefits to FMD may be greater with sustained training compared with a single IPC exposure.

5,6-diHETE lactone (EPA-L) mediates hypertensive microvascular dilation by activating the endothelial GPR-PLC-IP3 signaling pathway.

Endothelial microvascular dysfunction affects multi-organ pathologic processes that contribute to increased vascular tone and is at the base of impaired metabolic and cardiovascular diseases. The vascular dilation impaired by nitric oxide (NO) deficiency in such dysfunctional endothelium is often balanced by endothelial-derived hyperpolarizing factors (EDHFs), which play a critical role in managing vascular tone. Our latest research has uncovered a new group of lactone oxylipins produced in the polyunsaturated fatty acids (PUFAs) CYP450 epoxygenase pathway, significantly affecting vascular dilation. The lactone oxylipin, derived from arachidonic acid (5,6-diHET lactone, AA-L), has been previously shown to facilitate vasodilation dependent on the endothelium in isolated human microvessels. The administration of the lactone oxylipin derived from eicosapentaenoic acid (5,6-diHETE lactone, EPA-L) to hypertensive rats demonstrated a significant decrease in blood pressure and improvement in the relaxation of microvessels. However, the molecular signaling processes that underlie these observations were not fully understood. The current study delineates the molecular pathways through which EPA-L promotes endothelium-dependent vascular dilation. In microvessels from hypertensive individuals, it was found that EPA-L mediates endothelium-dependent vasodilation while the signaling pathway was not dependent on NO. In vitro studies on human endothelial cells showed that the hyperpolarization mediated by EPA-L relies on G-protein-coupled receptor (GPR)-phospholipase C (PLC)-IP3 signaling that further activates calcium-dependent potassium flux. The pathway was confirmed using a range of inhibitors and cells overexpressing GPR40, where a specific antagonist reduced the calcium levels and outward currents induced by EPA-L. The downstream AKT and endothelial NO synthase (eNOS) phosphorylations were non-significant. These findings show that the GPR-PLC-IP3 pathway is a key mediator in the EPA-L-triggered vasodilation of arterioles. Therefore, EPA-L is identified as a significant lactone-based PUFA metabolite that contributes to endothelial and vascular health.

Advanced glycated end-products inhibit dilation through constitutive endothelial RAGE and Nox1/4 in rat isolated skeletal muscle arteries.

OBJECTIVE: This study investigated the actions of advanced glycated end-products (AGE), their receptors (RAGE), and NAD(P)H oxidase (Nox) subtypes 1, 2, and 4 on mechanisms of endothelium-dependent dilation of the rat cremaster muscle artery (CMA). METHODS: Immunofluorescence studies were used to examine expression of RAGE in rat arteries. ROS accumulation was measured using luminescence and fluorescence assays. Functional studies were performed using pressure myography. RESULTS: High levels of RAGE expression were shown in the endothelial cells of the CMA, compared with low endothelial expression in middle cerebral and mesenteric arteries and the aorta. Exogenous AGE (in vitro glycated bovine serum albumin) stimulated H2O2 accumulation in CMA, which was prevented by the RAGE antagonist FPS-ZM1, the NAD(P)H oxidase (Nox) inhibitor apocynin and inhibited by the Nox1/4 inhibitor setanaxib, but not the Nox2 inhibitor GSK2795039. In functional studies, AGE inhibited vasodilation of CMA stimulated by acetylcholine, sodium nitroprusside, and the BKCa activator NS1619, but not adenosine-induced dilation. FPS-ZM1, apocynin, and setanaxib prevented the inhibitory effects of AGE on responses to acetylcholine and NS-1619. CONCLUSION: These observations suggest RAGE are constitutively expressed in the endothelium of the rat CMA and may be activated by AGE to stimulate Nox1/4 and ROS formation with resulting inhibition of NO and BKCa-mediated endothelium-dependent dilation.

Long-Term Outcomes of Recurrent Bulbar Urethral Stricture Treatment With the Optilume Drug-Coated Balloon: Five-Year Results From the ROBUST I Study.

PURPOSE: We report the 5-year study closeout results for the ROBUST I trial evaluating the safety and efficacy of the Optilume drug-coated balloon (DCB) for men with short, recurrent bulbar urethral strictures. MATERIALS AND METHODS: Adult men with recurrent bulbar urethral strictures ≤ 2 cm long and lumen < 12F were included in the study and treated with the Optilume DCB. Outcome measures included symptom questionnaires, maximum urinary flow rate, postvoid residual, and freedom from repeat intervention. Functional success was defined as improvement in International Prostate Symptom Score ≥ 50% without re-treatment. RESULTS: Fifty-three men were enrolled and treated, and 31 subjects completed all follow-up. Functional success was achieved in 58% (25/43) patients at 5 years. Average International Prostate Symptom Score improved from a mean of 25.2 at baseline to 7.2 at 5 years (P < .001). Freedom from repeat intervention was maintained through 5 years at 71.7% estimated by Kaplan-Meier. Maximum urinary flow rate improved from 5.0 mL/s at baseline to 19.9 (P < .01), and average postvoid residual was reduced from 141.4 mL to 59.5 mL (P < .01) at 5 years of follow-up. Erectile function remained unaffected. There were no serious treatment-related adverse events. CONCLUSIONS: In this challenging cohort of men with failed prior endoscopic treatment, the Optilume DCB shows sustained improvement in subjective and objective voiding parameters at 5 years. Optilume is a safe and effective treatment option for appropriately selected men with recurrent bulbar urethral stricture who wish to avoid urethroplasty. Results are in line with the ROBUST III randomized controlled trial that will continue follow-up through 5 years. CLINICAL TRIAL NO.: : NCT03014726.

Obesity does not alter vascular function and handgrip exercise hemodynamics in middle-aged patients with hypertension.

Lifestyle modification including exercise training is often the first line of defense in the treatment of obesity and hypertension (HTN), however, little is known regarding how these potentially compounding disease states impact vasodilatory and hemodynamic responses at baseline and exercise. Therefore, this study sought to compare the impact of obesity on vascular function and hemodynamics at baseline and during handgrip (HG) exercise among individuals with HTN. Non-obese (13M/7F, 56 ± 16 yr, 25 ± 4 kg/m2) and obese (17M/4F, 50 ± 7 yr, 35 ± 4 kg/m2) middle-aged individuals with HTN forwent antihypertensive medication use for ≥2 wk before assessment of vascular function by brachial artery flow-mediated dilation (FMD) and exercise hemodynamics during progressive HG exercise at 15-30-45% maximal voluntary contraction (MVC). FMD was not different between Non-Obese (4.1 ± 1.7%) and Obese (5.2 ± 1.9%, P = 0.11). Systolic blood pressure (SBP) was elevated by ∼15% during the supine baseline and during HG exercise in the obese group. The blood flow response to HG exercise at 30% and 45% MVC was ∼20% greater (P < 0.05) in the obese group but not different after normalizing for the higher, albeit, nonsignificant differences in workloads (MVC: obese: 24 ± 5 kg, non-obese: 21 ± 5 kg, P = 0.11). Vascular conductance and the brachial artery shear-induced vasodilatory response during HG were not different between groups (P > 0.05). Taken together, despite elevated SBP during HG exercise, obesity does not lead to additional impairments in vascular function and peripheral exercising hemodynamics in patients with HTN. Obesity may not be a contraindication when prescribing exercise for the treatment of HTN among middle-aged adults, however, the elevated SBP should be appropriately monitored.NEW & NOTEWORTHY This study examined vascular function and handgrip exercise hemodynamics in obese and nonobese individuals with hypertension. Obesity, when combined with hypertension, was neither associated with additional vascular function impairments at baseline nor peripheral hemodynamics and vasodilation during exercise compared with nonobese hypertension. Interestingly, systolic blood pressure and pulse pressure were greater in the obese group during supine baseline and exercise. These findings should not be ignored and may be particularly important for rehabilitation strategies.

Reversal of Pharmacologically Induced Mydriasis with Phentolamine Ophthalmic Solution.

PURPOSE: Evaluate safety and efficacy of 0.75% phentolamine ophthalmic solution (POS), an alpha-1 antagonist, in reversal of pharmacologically induced mydriasis. DESIGN: Two Phase 3, multicenter, placebo-controlled, randomized, double-masked clinical trials in healthy subjects. SUBJECTS: 553 healthy 12 to 80 year old subjects were randomized 1:1 (MIRA-2) and 2:1 (MIRA-3) to receive either POS or placebo eye drops OU. METHODS: Subjects received POS or placebo administered 1 hour after mydriasis, induced by instillation of either 2.5% phenylephrine, 1% tropicamide, or Paremyd (1% hydroxyamphetamine / 0.25% tropicamide). MAIN OUTCOME MEASURES: Primary endpoint was percent of subjects returning to ≤0.2 mm greater than baseline pupil diameter in study eye at 90 minutes after POS administration. Safety measures included treatment-emergent adverse events (TEAEs) and tolerability measures, including conjunctival hyperemia. RESULTS: In MIRA-2, 185 subjects were randomized to treatment with placebo (94) or POS (91). In MIRA-3, 368 subjects were randomized to treatment with placebo (124) or POS (244). A statistically significant greater percentage of subjects treated with POS had study eyes that showed reversal of mydriasis at 90 minutes (primary endpoint) compared with the placebo treatment (48.9% vs 6.6% for MIRA-2; p<0.0001 and 58% VS 6% for MIRA-3; p<0.0001) and as early as 60 minutes (24.5% vs 5.5% for MIRA-2; p<0.0003 and 42% VS 2% for MIRA-3; p<0.0001). Between 28 to 34% of placebo-treated subjects had not returned to baseline PD at 24 hours following pharmacological dilation compared to 8 to 11% treated with POS (p<0.0001). CONCLUSION: POS treatment had a rapid onset in reducing PD within 60- to 90-minutes, with a statistically significant time savings of 3 to 4 hours to return to baseline PD compared to placebo. One or 2 drops of POS rapidly reversed mydriasis in all subjects regardless of mydriatic agent or iris color. More subjects receiving POS reported a perceived benefit in the resolution of visual symptoms caused by pharmacologically induced mydriasis compared to placebo, with statistically significant differences noted as early as 1 hour. The safety profile was favorable, with the most common adverse effects being mild transient conjunctival hyperemia (11.2%), instillation site discomfort (10.9%), and dysgeusia (3.6%).

Association between endothelial function and skin advanced glycation end-products (AGEs) accumulation in a sample of predominantly young and healthy adults.

BACKGROUND: In populations with chronic disease, skin autofluorescence (SAF), a measure of long-term fluorescent advanced glycation end-products (AGEs) accumulation in body tissues, has been associated with vascular endothelial function, measured using flow-mediated dilation (FMD). The primary aim of this study was to quantify the relationship between endothelial function and tissue accumulation of AGEs in adults from the general population to determine whether SAF could be used as a marker to predict early impairment of the endothelium. METHODS: A cross-sectional study was conducted with 125 participants (median age: 28.5 y, IQR: 24.4-36.0; 54% women). Endothelial function was measured by fasting FMD. Skin AGEs were measured as SAF using an AGE Reader. Participant anthropometry, blood pressure, and blood biomarkers were also measured. Associations were evaluated using multivariable regression analysis and were adjusted for significant covariates. RESULTS: FMD was inversely correlated with SAF (ρ = -0.50, P < 0.001) and chronological age (ρ = -0.51, P < 0.001). In the multivariable analysis, SAF, chronological age, and male sex were independently associated with reduced FMD (B [95% CI]; -2.60 [-4.40, -0.80]; -0.10 [-0.16, -0.03]; 1.40 [0.14, 2.67], respectively), with the multivariable model adjusted R2 = 0.31, P < 0.001. CONCLUSIONS: Higher skin AGE levels, as measured by SAF, were associated with lower FMD values, in a predominantly young, healthy population. Additionally, older age and male participants exhibited significantly lower FMD values, corresponding with compromised endothelial function. These results suggest that SAF, a simple and inexpensive marker, could be used to predict endothelial impairment before the emergence of any structural artery pathophysiology or classic cardiovascular disease risk markers. TRIAL REGISTRATION: The study was prospectively registered with the Australian New Zealand Clinical Trials Registry (ACTRN12621000821897) and concurrently entered into the WHO International Clinical Trials Registry Platform under the same ID number.

Scoping Review: Integration of the Major Mechanisms Underlying the Regulation of Arteriolar Tone.

BACKGROUND: Cardiovascular diseases remain the leading cause of morbidity and mortality worldwide. Arteriolar tone regulation plays a critical role in maintaining appropriate organ blood flow and perfusion distribution, which is vital for both vascular and overall health. SUMMARY: This scoping review aimed to explore the interplay between five major regulators of arteriolar tone: metabolism (adenosine), adrenergic control (norepinephrine), myogenic activation (intravascular pressure), perivascular oxygen tension, and intraluminal flow rates. Specifically, the aim was to address how arteriolar reactivity changes in the presence of other vasoactive stimuli and by what mechanisms. The review focused on animal studies that investigated the impact of combining two or more of these stimuli on arteriolar diameter. Overall, 848 articles were identified through MEDLINE and EMBASE database searches, and 38 studies were included in the final review. KEY MESSAGES: The results indicate that arteriolar reactivity is influenced by multiple factors, including competitive processes, structural limitations, and indirect interactions among stimuli. Additionally, the review identified a lack of research involving female animal models and limited insight into the interaction of molecular signaling pathways, which represent gaps in the literature.