Dilator Responses Research Articles

DOES ENDOTHELIAL FUNCTION DIFFER AMONG SEXES IN PATIENTS WITH DIABETES OR KIDNEY DISEASE?

Objective: Endothelial dysfunction is a known driver of disease progression in both type 2 diabetes mellitus (T2DM) and kidney disease. Brachial artery flow-mediated dilation (FMD), representing endothelium-dependent nitric oxide-mediated dilation in response to increased shear stress, is considered gold standard to quantify macrovascular dysfunction non-invasively. As evidence is mounting that men are more likely to suffer from macrovascular dysfunction than women, we hypothesized that this would be reflected in patient populations with T2DM and/or kidney disease. Design and method: Preliminary baseline data was collected from 2 ongoing randomized controlled trials in patients with T2DM and in kidney transplant recipients (KTRs) 3 months post-transplantation. FMD was assessed with the semi-automated UNEX EF device under standardized conditions. Biochemical analyses were done using routine techniques. Images were manually analyzed by a single researcher (MR) using PCAnalysis software (version 1.0.14). Results: Twenty-five subjects, 13 with T2DM and 12 KTRs were included. As expected, patients with T2DM had a higher BMI, higher HbA1c but higher eGFR compared to KTRs (Table 1). Compared to KTRs, patients with T2DM presented with a significantly worse FMD (FMD= 4.50% [IQR=5.77]) vs 10.88% [6.48]). Overall, no significant difference in FMD between men and women was found (p=0.11), but higher values could be observed in females (FMD= 9.08% [IQR=6.97] vs 4.50% [7.88]). As depicted in Figure 2, this tendency was also observed in the 2 subgroups: KTRs (M: FMD = 9.07% [IQR=9.62] | F: 11.92% [5.16]) and T2DM (M: FMD = 3.90% [IQR=5.00%] | F: 7.09% [6.83]). Conclusions: Although no significant differences in vascular function between sexes were detected, our preliminary data showed a tendency for higher FMD-values in women; both in T2DM and KTRs. This supports the statement that male subjects seem to suffer more from macrovascular dysfunction. Further research is needed to elucidate the underlying pathways via which sex impacts the disease process in T2DM and kidney disease and to evaluate how personalized preventive lifestyle measures might differentially impact on outcome.

Elevated plasma aldosterone impairs functional hyperemia and cognitive function

Aldosterone, a steroid hormone, plays an important role in blood pressure homeostasis and the maintenance of plasma electrolyte levels by activating the mineralocorticoid receptor (MR) in renal distal tubule and collecting duct epithelial cells. Recent studies revealed that MRs are also expressed in other tissues, including cardiac myocytes, vascular smooth muscle cells, and vascular endothelial cells (EC), and that elevated plasma aldosterone, termed hyperaldosteronemia (HA), has deleterious effects on the cardiovascular system. HA is present in 10-30% of hypertensive patients and unrecognized and asymptomatic HA is estimated to occur in > 10% of individuals with normal blood pressure. Despite the high prevalence of HA, little is known about its impact on cerebral blood flow (CBF) regulation and brain health. This study focused on the physiological processes that support the on-demand delivery of blood to regions of heightened neuronal activity (functional hyperemia). Specifically, we examined the impact of HA on the recently discovered novel mechanism, termed capillary-to-arteriole signaling, through which capillaries and their strong inward rectifier K+ (Kir 2.1) channels play a significant role in functional hyperemia. Importantly, early deficits in functional hyperemia are a hallmark of small vessel diseases of the brain, which are significant contributors to cognitive impairment and dementia. Employing HA model mice, we examined the impact of HA on functional hyperemia, capillary-to-arteriole signaling, Kir2.1 channel activity in freshly isolated capillary ECs (cECs), and cognitive function. Functional hyperemia, measured as whisker stimulation-induced CBF increases using laser Doppler flowmetry, was impaired in HA animals compared to vehicle-treated animals. Retrograde capillary-to-arteriole signaling, evaluated as upstream arteriolar dilation in response to capillary stimulation with 10 mM K+ in Capillary-Parenchymal Arteriole (CaPA), preparations was significantly attenuated in HA mice. Furthermore, cEC Kir2.1 channel currents, recorded using the conventional whole-cell configuration of the patch-clamp technique, were significantly smaller in HA mice compared to vehicle-treated mice. Further, HA model animals obtained lower scores in the Novel Object Recognition test, indicating that cognitive function in the form of memory retention may be impacted by elevated plasma aldosterone. These data suggest that HA impairs functional hyperemia and cognitive function, and that HA may be a novel risk factor for vascular cognitive impairment. This work was supported by The National Institute of Health (P20-GM-135007 to MK and R01-HL-142888 to GCW). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Store-operated calcium entry is necessary for sustained K+-induced capillary-to-arteriole dilation in the brain

Neurovascular coupling (NVC) is a physiological process that directs blood flow to the most active regions of the brain. The extensive network of capillaries in the brain acts as a sensory web that detects local neuronal activity and orchestrates the dilation of upstream arterioles to meet the brain’s metabolic demands. Activation of inwardly rectifying K+ (KIR) channels on brain capillary endothelial cells (cECs) by modest concentrations of extracellular K+ initiates retrograde propagating hyperpolarizing signals that induce vasodilation and increase blood flow. Brain capillaries exhibit diverse and dynamic patterns of Ca2+ signaling in vivo, but little is known about their origins or physiological function. Store-operated Ca2+ entry (SOCE) is fundamental to Ca2+homeostasis in non-excitable cells, but the contribution of SOCE to capillary-to-arteriole dilation has not been explored. Here, we report that brain cECs express the endoplasmic reticulum-resident Ca2+ sensing protein stromal interaction molecule 1 ( Stim1) and the Ca2+-selective Orai1 and Orai3 channels. Ca2+ imaging experiments using brain cECs from transgenic mice expressing GCaMP8 in the endothelium or loaded with Fluo-4 showed that these cells exhibited robust SOCE that was blocked by the Orai1 inhibitor Synta66. Using EC-specific knockout (ecKO) mice, we found that Stim1 and Orai1 but not Orai3 are required for SOCE. Ex vivo brain microvascular preparations consisting of cannulated and pressured parenchymal arterioles with intact capillary beds were used to examine the role of SOCE in capillary-to-arteriole dilation. Arteriole dilation in response to a train of K+ pulses applied to capillaries exhibited dramatic run-down when preparations were treated with Snyta66 or when tissues from Stim1-ecKO mice were used. Preparations from Orai3-ecKO mice did not demonstrate run-down. Moreover, inhibition of Ca2+-activated K+ (SK and IK) channels also induced run-down, suggesting that SOCE activates SK and IK channels to boost KIR-induced hyperpolarizing signals to dilate upstream arterioles during multiple stimulations. We conclude that brain cECs exhibit SOCE that requires Stim1 and Orai1. Our data further show that brain cEC SOCE is necessary for capillary-to-arteriole dilation during repeated stimulations, suggesting an essential role for SOCE in NVC. R35HL155008, R33NS115132, and P20GM130459 (to SE). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The Role of NO and H2O2 in Ach-Induced Dilation of Human Arterioles in the Absence and Presence of Coronary Artery Disease

The endothelium regulates vascular tone through the release of various vasodilatory factors such as NO, PGI2, and endothelium-derived hyperpolarizing (EDH) signaling that is more important in resistance arteries and arterioles. Using freshly isolated human arterioles, previous studies indicate that hydrogen peroxide (H2O2), an EDH factor, mediates flow-mediated dilation in patients with coronary artery disease (CAD), whereas NO plays a more prominent role in patients without CAD. However, the mechanisms of receptor agonists (e.g., acetylcholine)-induced dilation remains to be clarified in human arterioles. The objective of this study was to compare the role of NO and H2O2 in acetylcholine (Ach-induced dilation in human adipose arterioles (HAA) from non-CAD and CAD patients. HAA (100-200 μm) dissected from discarded surgical samples of non-CAD and CAD patients, were cannulated onto glass micropipettes and pressurized at 60 mmHg for measurement of diameter changes by using videomicroscopy. Microvessels were incubated with L-NAME (100 μM), an inhibitor of NO synthase, Indomethacin (Indo, 10 μM), an inhibitor of PGI2 synthesis and peg-CAT (500 U/ml), a scavenger of H2O2. To study the dose-dependent response to Ach (log 10-9 – 10-5 M), HAA were preconstricted with endothelin-1 (0.1-0.5 nM). In non-CAD tissues Ach induced potent concentration-dependent dilation (maximal dilation at 10−5 M: 95.6±1.8%). After preincubation with L-NAME, this dilation was partially reduced (maximal dilation at 10−5 M: 77.4±3.1%, P<0.05 vs. control), while the combination of L-NAME and Indo reduced it to the same extent as L-NAME by itself (maximal dilation at 10−5 M: 73.1±7.4%, P<0.05 vs. control). To further determine the role of H2O2 in dilatory response to Ach, we treated HAA with peg-CAT. Incubation of peg-CAT significantly reduced the dilation (maximal dilation at 10−5 M: 74.6±8.1% and 51.3±8.7% in the absence and presence of L-NAME and Indo, P<0.05 vs. control). In HAA obtained from CAD patients, the dilation response to Ach was similar to non-CAD (maximal dilation at 10−5 M: 93.9± 1.8%) and the combination of L-NAME and Indo reduced this dilation to a lesser extent (maximal dilation at 10−5 M: 83.1±3%, P=0.055), compared to non-CAD patients (maximal dilation at 10−5 M: 73.1±7.4%, P<0.05 vs. control). The preincubation with peg-CAT attenuated the dilation only at log -7 M (maximal dilation at 10−7 M: 33.8±9.5%, P<0.05 vs. 54.6±7.5% in control). The large portion of the dilation remaining after the combination of L-NAME and Indo was almost completely abolished in the presence of high K+ concentration (maximal dilation at 10−5 M: 12.9±5.1% P<0.05 vs. control). Together, these results provide new evidence that in non-CAD arterioles both NO and H2O2 play an important role in Ach-induced dilation whereas PGI2 is likely not involved. In CAD arterioles, NO, PGI2 and H2O2 have much less contribution to Ach-induced dilation, while a H2O2-independent EDH signaling plays the major role in the dilatory response. Further studies are required to determine the specific mechanism or factor involved in Ach-induced EDH-dependent dilation in HAA. This work was supported by the National Heart, Lung, and Blood Institute [R01HL096647]. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Local Activation of Angiotensin II Type 2 Receptors Improves Microvascular Endothelial Function in Healthy Women With a History Preeclampsia

Women who had preeclampsia (hxPE) have a >4-fold risk for developing cardiovascular disease (CVD) compared to women who had an uncomplicated pregnancy (hxHC). These women demonstrate attenuated vascular endothelium- and nitric oxide (NO)-dependent dilation, secondary to exaggerated angiotensin (ang) II-mediated constriction, following pregnancy but before the onset of CVD. Despite the known dysregulation of ang II-mediated responses postpartum, the role of vasodilatory ang II type 2 receptors (AT2R) in this dysfunction is unknown. We hypothesized that, compared to hxHC, hxPE would have reduced AT2R-mediated dilation and reduced AT2R expression in primary biopsied endothelial cells. We further hypothesized that endothelium- and NO-dependent dilation would be attenuated in hxPE, and that local AT2R activation would improve these responses in hxPE. Nine hxPE (34±7 years, 25±14 months postpartum) and 9 hxHC (35±3 years, 32±12 months postpartum) had 4 intradermal microdialysis fibers placed in the ventral forearm. Sites 1-2 received graded infusions of compound 21 (C21, AT2R agonist; 10−14-10−3mol/L) alone or with L-NAME (NO-synthase inhibitor; 15mM). Sites 3-4 received lactated Ringer’s (control) or 10−11M C21 and underwent a standard local heating (LH) protocol (42°C; 0.1°C·s−1) to assess endothelium-dependent dilation. After full expression of the LH response, 15mM L-NAME was perfused to assess NO-dependent dilation. Red cell flux was measured over each site with laser-Doppler flowmetry. Cutaneous vascular conductance was calculated (CVC=flux/mean arterial pressure) and normalized to maximum (%CVCmax; 28mM SNP+43°C). AT2R protein expression in biopsied venous endothelial cells (n=4/group) was quantified using immunofluorescence. AT2R-mediated dilation (31±8 vs. hxHC: 95±25%CVCmax, p=0.01) and the NO-dependent portion of this response (21±9 vs. hxHC: 64±23%, p=0.04) was reduced in hxPE. AT2R expression in biopsied endothelial cells was attenuated in hxPE (0.59±0.10 vs. hxHC: 0.79±0.07 arbitrary units; p=0.008). hxPE had attenuated endothelium- (79±7 vs. hxHC: 94±9%CVCmax, p<0.001) and NO-dependent dilation (55±11 vs. hxHC: 71±13%; p=0.01) responses to LH. Local AT2R activation augmented endothelium- (92±11%CVCmax vs. control; p=0.02) and NO-dependent (78±12% vs. control; p<0.001) dilation in hxPE but had no effect in hxHC (all p>0.05). These data suggest that reductions in AT2R-mediated dilation and expression contribute to attenuated endothelial function after preeclampsia. Furthermore, AT2R activation may improve endothelial function through NO-dependent mechanisms in women who have had preeclampsia before the onset of CVD. Internal Funds. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Sodium Loading Does Not Induce Oxidative Stress-Mediated Reductions in Vascular Function in Young Adults

Short-term, high sodium diets decrease dilation responses in conduit arteries and the microvasculature when compared to low sodium diets (e.g., 7000 vs. 500 mg/day). Supraphysiological antioxidant treatment mitigates these effects supporting a role for oxidative stress in sodium-induced vascular impairments. It is unclear whether these effects are present when high sodium conditions are compared to the sodium level of a typical American diet (~3400 mg/day). Therefore, we tested the hypotheses that sodium added to the habitual diet of young adults would reduce flow mediated dilation (FMD) and post-ischemic reactive hyperemia (RH) and that an acute infusion of the antioxidant ascorbic acid (AA) would attenuate the vascular consequences of excess sodium. Methods: Young adults (6M / 8F; age: 26 ± 4 y; BMI: 23.6 ± 2.5 kg/m2) were studied following 10 days of sodium loading (SL) via table salt-filled capsules (3900 mg sodium/day) and 10 days of placebo capsules in addition to their normal diet, in random order. Total sodium intake was estimated via 24-hour urinary sodium content on day 10. On day 11, brachial artery diameter and blood velocity were continuously measured via duplex ultrasound at baseline and after 5 min of forearm ischemia. FMD, the post-ischemic change in brachial artery diameter relative to baseline diameter, provided an index of conduit artery endothelial function. The total RH in the 2 min following ischemia was measured for an index of microvascular function. Within each condition, testing was performed before (pre-AA) and after (post-AA) a 20 min intravenous infusion of 0.06 g of AA/kg lean body mass. Results: Urinary sodium content was increased by SL compared to the placebo (285 ± 94 vs. 160 ± 75 mmol/24 h, p<0.001) indicating approximate sodium intakes of 6600 and 3700 mg/day, respectively. Mean arterial pressure did not differ across conditions pre-AA (SL: 77 ± 7; placebo: 75 ± 5 mmHg, P=0.40) or post-AA (SL: 79 ± 8; placebo: 76 ± 5 mmHg, P=0.17). Brachial artery FMD was not different across time or condition (SL pre-AA: 8.7 ± 3.6, post-AA: 8.8 ± 4.2% vs. placebo pre-AA: 8.8 ± 3.2, post-AA: 8.1 ± 3.5%, time x condition interaction P=0.48). RH was similar following SL and placebo (condition effect: P=0.38) but was reduced in both conditions post AA (SL: Δ-45 ± 44 ml, P=0.01; placebo: Δ-72 ± 59ml, p<0.001). Conclusion: Contrary to our hypothesis, 10 days of sodium loading did not decrease FMD or post- ischemic RH in young adults compared to their habitual diet. Likewise, acute antioxidant treatment did not augment FMD in either condition and paradoxically decreased total RH independent of sodium intake. These data suggest that a short-term increase in dietary sodium intake in healthy young adults does not elicit oxidative stress-induced reductions in vascular function. NIH 5R01HL104106 and 5P20GM113125; AHA 20POST35080171. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

A new hydrocolloid to rival gum Arabic: Characterisation of a traditional food gum from Australian Acacia cambagei.

This study investigated a new gum sourced from Acacia cambagei, Gidyea gum, by comparative characterisation with gum Arabic. The polysaccharide compositional analysis of Gidyea gum via Fourier transfer infrared and nuclear magnetic resonance spectroscopies was conducted, showing common structural features to gum Arabic, with minor differences in polymer branching. Microstructural imaging using transmission electron microscopy revealed the typical globular arabinogalactan glycoprotein structures of ∼10 nm diameter for both samples. Size exclusion chromatography also confirmed a similar molecular weight with 28 × 103 g mol−1 and 25 × 103 g mol−1 for Gidyea gum and gum Arabic, respectively. Gum rheological analysis determined a significantly lower apparent viscosity in the Gidyea gum. Modelling of the temporal evolution of dynamic surface and interfacial tensions revealed that Gidyea gum had a significantly lower rate of diffusion to the interfaces but similar adsorption and rearrangement rates. The dilatational viscoelastic response of Gidyea gum at the oil-water interface was consistent with gum Arabic, indicating similarities in functional performance. Indeed, Gidyea gum could stabilise orange oil-water emulsions for 15 days, exhibiting a comparable performance to those stabilised with gum Arabic. This study revealed that Gidyea gum is a functional emulsifier with the potential to be a gum Arabic alternative within the food and pharmaceutical industries.

Interface frictional anisotropy of dilative sand.

Understanding direction-dependent friction anisotropy is necessary to optimize interface shear resistance across soil-structure. Previous studies estimated interface frictional anisotropy quantitatively using contractive sands. However, no studies have explored how sand with a high dilative tendency around the structural surface affects the interface shear response. In this study, a series of interface direct shear tests are conducted with selected French standard sand and snakeskin-inspired surfaces under three vertical stresses (50, 100, and 200kPa) and two shearing directions (cranial → caudal or caudal → cranial). First, the sand-sand test observes a higher dilative response, and a significant difference between the peak and residual friction angles (ϕpeak - ϕres = 8°) is obtained at even a lower initial relative density Dr = 40%. In addition, the interface test results show that (1) shearing against the scales (cranial shearing) mobilizes a larger shear resistance and produces a dilative response than shearing along the scales (caudal shearing), (2) a higher scale height or shorter scale length exhibits a higher dilative tendency and produces a higher interface friction angle, and (3) the interface anisotropy response is more pronounced during cranial shearing in all cases. Further analysis reveals that the interface friction angle and dilation angle are decreased with the scale geometry ratio (L/H). For L/H values between 16.67 and 60, the interface dilation angle varies between 9° and 4° for cranial first shearing and 3.9°-2.6° for caudal first shearing. However, the difference in dilation angle within the same shearing direction is less than 1°.

The pupil dilation response as an indicator of visual cue uncertainty and auditory outcome surprise.

In everyday perception, we combine incoming sensory information with prior expectations. Expectations can be induced by cues that indicate the probability of following sensory events. The information provided by cues may differ and hence lead to different levels of uncertainty about which event will follow. In this experiment, we employed pupillometry to investigate whether the pupil dilation response to visual cues varies depending on the level of cue-associated uncertainty about a following auditory outcome. Also, we tested whether the pupil dilation response reflects the amount of surprise about the subsequently presented auditory stimulus. In each trial, participants were presented with a visual cue (face image) which was followed by an auditory outcome (spoken vowel). After the face cue, participants had to indicate by keypress which of three auditory vowels they expected to hear next. We manipulated the cue-associated uncertainty by varying the probabilistic cue-outcome contingencies: One face was most likely followed by one specific vowel (low cue uncertainty), another face was equally likely followed by either of two vowels (intermediate cue uncertainty) and the third face was followed by all three vowels (high cue uncertainty). Our results suggest that pupil dilation in response to task-relevant cues depends on the associated uncertainty, but only for large differences in the cue-associated uncertainty. Additionally, in response to the auditory outcomes, the pupil dilation scaled negatively with the cue-dependent probabilities, likely signalling the amount of surprise.

An examination of measures of young children's interest in natural object categories

Developmental research utilizes various different methodologies and measures to study the cognitive development of young children; however, the reliability and validity of such measures have been a critical issue in all areas of research practices. To address this problem, particularly in the area of research on infants' interests, we examined the convergent validity of previously reported measures of children's interests in natural object categories, as indexed by (1) parents' estimation of their child's interest in the categories, (2) extrinsic (overt choices in a task), (3) intrinsic (looking time toward objects), and (4) physiological (pupil dilation) responses to objects of different categories. Additionally, we also examined the discriminant validity of all the aforementioned measures against the well-established and validated measure of parents' estimations of children's vocabulary knowledge. Children completed two tasks: (a) an eye-tracking task, where they were presented with images from a range of defined categories, which collected indices of looking time and pupillary activity; (b) a sticker-choice task, where they were asked to choose between two sticker-images from two different categories belonging to the range of categories assessed in the previous task. Parents completed two questionnaires to estimate (i) their child's interests and (ii) vocabulary knowledge in the categories presented. We first analyzed the discriminant validity between the two parent measures, and found a significant positive association between them. Our successive analyses showed no strong or significant associations between any of our measures, apart from a significant positive association between children's looking time and parents' estimations of children's vocabulary knowledge. From our findings, we conclude that measures of infants' interests thus far may not have sufficient reliability to adequately capture any potential relationship between these measures, or index different components of interest in young children. We suggest next steps for further validation studies in infant research.

Pupil Data Upon Stimulation by Auditory Stimuli

Evaluating hearing in newborns and uncooperative patients can pose a considerable challenge. One potential solution might be to employ the Pupil Dilation Response (PDR) as an objective physiological metric. In this dataset descriptor paper, we present a collection of data showing changes in pupil dimension and shape upon presentation of auditory stimuli. In particular, we collected pupil data from 16 subjects, with no known hearing loss, upon different lighting conditions, measured in response to a series of 60–100 audible tones, all of the same frequency and amplitude, which may serve to further investigate any relationship between hearing capabilities and PDRs.

Are depressive symptoms linked to a reduced pupillary response to novel positive information?-An eye tracking proof-of-concept study.

Depressive symptoms have been linked to difficulties in revising established negative beliefs in response to novel positive information. Recent predictive processing accounts have suggested that this bias in belief updating may be related to a blunted processing of positive prediction errors at the neural level. In this proof-of-concept study, pupil dilation in response to unexpected positive emotional information was examined as a psychophysiological marker of an attenuated processing of positive prediction errors associated with depressive symptoms. Participants (N = 34) completed a modified version of the emotional Bias Against Disconfirmatory Evidence (BADE) task in which scenarios initially suggest negative interpretations that are later either confirmed or disconfirmed by additional information. Pupil dilation in response to the confirmatory and disconfirmatory information was recorded. Behavioral results showed that depressive symptoms were related to difficulties in revising negative interpretations despite disconfirmatory positive information. The eye tracking results pointed to a reduced pupil response to unexpected positive information among people with elevated depressive symptoms. Altogether, the present study demonstrates that the adapted emotional BADE task can be appropriate for examining psychophysiological aspects such as changes in pupil size along with behavioral responses. Furthermore, the results suggest that depression may be characterized by deviations in both behavioral (i.e., reduced updating of negative beliefs) and psychophysiological (i.e., decreased pupil dilation) responses to unexpected positive information. Future work should focus on a larger sample including clinically depressed patients to further explore these findings.

In vivo mitochondria-targeted protection against uterine artery vascular dysfunction and remodelling in rodent hypoxic pregnancy.

Gestational hypoxia adversely affects uterine artery function, increasing complications. However, an effective therapy remains unidentified. Here, we show in rodent uterine arteries that hypoxic pregnancy promotes hypertrophic remodelling, increases constrictor reactivity via protein kinase C signalling, and triggers compensatory dilatation via nitric oxide-dependent mechanisms and stimulation of large conductance Ca2+ -activated K+ -channels. Maternal in vivo oral treatment with the mitochondria-targeted antioxidant MitoQ in hypoxic pregnancy normalises uterine artery reactivity and prevents vascular remodelling. From days 6-20 of gestation (term ∼22 days), female Wistar rats were randomly assigned to normoxic or hypoxic (13-14% O2 ) pregnancy±daily maternal MitoQ treatment (500 µm in drinking water). At 20 days of gestation, maternal, placental and fetal tissue was frozen to determine MitoQ uptake. The uterine arteries were harvested and, in one segment, constrictor and dilator reactivity was determined by wire myography. Another segment was fixed for unbiased stereological analysis of vessel morphology. Maternal administration of MitoQ in both normoxic and hypoxic pregnancy crossed the placenta and was present in all tissues analysed. Hypoxia increased uterine artery constrictor responses to norepinephrine, angiotensin II and the protein kinase C activator, phorbol 12,13-dibutyrate. Hypoxia enhanced dilator reactivity to sodium nitroprusside, the large conductance Ca2+ -activated K+ -channel activator NS1619 and ACh via increased nitric oxide-dependent mechanisms. Uterine arteries from hypoxic pregnancy showed increased wall thickness and MitoQ treatment in hypoxic pregnancy prevented all effects on uterine artery reactivity and remodelling. The data support mitochondria-targeted therapy against adverse changes in uterine artery structure and function in high-risk pregnancy. KEY POINTS: Dysfunction and remodelling of the uterine artery are strongly implicated in many pregnancy complications, including advanced maternal age, maternal hypertension of pregnancy, maternal obesity, gestational diabetes and pregnancy at high altitude. Such complications not only have immediate adverse effects on the growth of the fetus, but also they can also increase the risk of cardiovascular disease in the mother and offspring. Despite this, there is a significant unmet clinical need for therapeutics that treat uterine artery vascular dysfunction in adverse pregnancy. Here, we show in a rodent model of gestational hypoxia that in vivo oral treatment of the mitochondria-targeted antioxidant MitoQ protects against uterine artery vascular dysfunction and remodelling, supporting the use of mitochondria-targeted therapy against adverse changes in uterine artery structure and function in high-risk pregnancy.

Do reflection prompts promote children's conflict monitoring and revision of misconceptions?

We tested whether reflection prompts enhance conflict monitoring and facilitate the revision of misconceptions. German children (N = 97, Mage = 7.20, 56% female) were assigned to a prediction or a prediction with reflection condition that included reflection prompts. Children in the prediction with reflection condition (1) showed greater error-related response times and pupil dilation responses, indicating better conflict monitoring, and(2) performed closer to an optimal Bayesian learner, indicating better monitoring-based control. However, by the end of the study, all children had similar levels of misconception revision. Thus, reflection prompts can enhance learning from anomalous evidence by improving conflict monitoring, but they may need to be repeated often to sustain their beneficial effects.

Internal erosion of a gap-graded soil and influences on the critical state

Water retaining structures are critical elements of civil infrastructure. Internal erosion of soils forming the containment structures may occur progressively and lead to expensive maintenance costs or failures. The strength, stress–strain behavior and critical state of soils which have eroded, as well as the characteristics of the erosion, may be affected by hydraulic gradient, confining stress and relative density of the soil at the start of the erosion. Here, erosion and triaxial tests have been conducted on gap-graded soil samples. The tests and results are novel as the samples were prepared to be homogenous post-erosion and prior to triaxial testing by adopting a new sample formation procedure. The post-erosion homogeneity was evaluated in terms of particle size distribution and void ratio along a sample’s length. The erosion-induced mechanical property changes can then be linked to a measure of initial state, more reliably than when erosion causes samples to be heterogeneous. The results show that erosion causes the critical state line in the compression plane to move upwards. The movement is lesser than the increase in void ratio caused by erosion. The state parameter is therefore reduced, consistent with the soil’s reduced peak strength and its less dilative response. Regarding the erosion characteristics, the flow rate decreases with the increase in initial relative density or effective stress, but increases with the increase in the hydraulic gradient being applied. The cumulative eroded soil mass increases with the increase in hydraulic gradient and decreases with the increase in initial density and effective confining stress.

Changes in Listening Effort Through Pupil Response After Atresioplasty in Children With Congenital Aural Atresia.

This study aimed to determine whether the improvement of hearing by surgical treatment alleviates cognitive demands through pupil response in patients with unilateral congenital aural atresia (CAA). A prospective study was performed on patients with unilateral CAA who were scheduled to undergo primary atresioplasty between November 2017 and May 2020. Pure-tone audiometry, auditory digit span test, Korean Speech Perception in Noise test, pupil measurement during speech tests, and questionnaires (Sound-Spatial-Qualities of Hearing Scale; subjective listening effort rating) were performed before and 6 months after surgery. Of 30 consecutive patients who initially enrolled, only 18 patients (12 males and 6 females) were included in the analysis. When the improvement of the air-bone gap and interaural difference of air conduction within 30 dB was defined as a successful hearing outcome, successful hearing improvement was achieved in 50% of the 18 patients. In pupil measurement, the success group had a significantly smaller mean pupil dilation response than the nonsuccess group at 0 and -3 dB signal to noise ratio (SNR) (all p < 0.01). In addition, significant differences were identified between the two groups for peak dilation and peak latency at all noise levels (all p < 0.01). When analyzing the change in pupil response before and after surgery, the difference in relative mean pupil dilation in the success group was significantly greater than that in the nonsuccess group at -3 dB SNR ( p = 0.02). In addition, the success group showed a significantly greater change in peak latency than the nonsuccess group at the -3 dB SNR ( p < 0.01). The difference in peak dilation tended to be greater in the success group than in the nonsuccess group, but the difference was not statistically significant. Patients with unilateral CAA who achieved surgically improved hearing had a smaller pupil dilation response than those who did not. These results suggest that successful hearing outcomes after surgery in patients with unilateral CAA may reduce the cognitive effort required to understand speech under difficult listening conditions.

Assessing perceptual chromatic equiluminance using a reflexive pupillary response

Equiluminant stimuli help assess the integrity of colour perception and the relationship of colour to other visual features. As a result of individual variation, it is necessary to calibrate experimental visual stimuli to suit each individual’s unique equiluminant ratio. Most traditional methods rely on training observers to report their subjective equiluminance point. Such paradigms cannot easily be implemented on pre-verbal or non-verbal observers. Here, we present a novel Pupil Frequency-Tagging Method (PFTM) for detecting a participant’s unique equiluminance point without verbal instruction and with minimal training. PFTM analyses reflexive pupil oscillations induced by slow (< 2 Hz) temporal alternations between coloured stimuli. Two equiluminant stimuli will induce a similar pupil dilation response regardless of colour; therefore, an observer’s equiluminant point can be identified as the luminance ratio between two colours for which the oscillatory amplitude of the pupil at the tagged frequency is minimal. We compared pupillometry-based equiluminance ratios to those obtained with two established techniques in humans: minimum flicker and minimum motion. In addition, we estimated the equiluminance point in non-human primates, demonstrating that this new technique can be successfully employed in non-verbal subjects.

Effect of fibre orientation on the mechanical response of reinforced sand, detected with x-ray tomography

The mechanical behaviour of fibre-reinforced sands (FRS) has been thoroughly explored with a laboratory study, firstly investigating the influence of relevant parameters such as grading index, soil density, amount, diameter, and length of fibres then focusing on their orientation with respect to the principal stress directions. This aspect has been deeply investigated performing parallel tests on samples of pure sand and on samples with randomly and uniformly oriented fibres compacted at a similarly high relative density (Dr≈1). Direct and triaxial shear tests have been performed, the former enforcing deformation on a predetermined shear plane. The results show that reinforcement with oriented fibres provides a higher strength and ductility to the sand. The grain scale investigation of the materials’ response to direct shearing has been carried out performing X-ray tomography post-mortem (i.e., after the test). The evolution of porosity in several samples prepared with the same procedure and sheared under the same conditions has been studied freezing the material fabric with nanosilica grout injected at different displacement levels. On the contrary, X-ray tomography performed along with miniature triaxial tests (operando method) enabled the analysis of the spatial distribution of deviatoric strain too. In both cases, maps show the relevant role of fibres orientation with reference to the shear band. If adequately activated, fibres tension modifies the strain field in the samples, preventing the fragile rupture along a shear plane and transferring the stresses to the outer soil portions, in this way providing a more dilatant and ductile overall response of the reinforced material.

Jaboticaba berry (Myrciaria jaboticaba) supplementation protects against micro- and macrovascular dysfunction induced by eccentric exercise: a randomized clinical trial.

Physical activities that are unaccustomed and involve eccentric muscle contractions have been demonstrated to temporarily impair macrovascular and microvascular functions, which may be caused by exercise-induced oxidative stress. Jaboticaba (Myrciaria jaboticaba) is a famous Brazilian berry that has been described to exhibit high antioxidant activity. However, no human study has investigated the protective effects of jaboticaba consumption against the vascular damage induced by eccentric exercise. Therefore, the present study aimed to assess whether supplementation with jaboticaba berry juice could positively affect macro- and microvascular functions within 48 hours after eccentric exercise. This randomized, double-blind, placebo-controlled, parallel trial enrolled 24 healthy participants consuming 250 mL per day of jaboticaba berry juice (containing ∼1,300 mg of total polyphenols) or placebo for 6 days. At the baseline, pre-exercise, and 24 h and 48 h postexercise stages, blood samples were taken for analysis of reduced glutathione (GSH) levels. Also, brachial artery flow-mediated dilation (FMD), blood flow, and tissue oxygen saturation (StO2) responses to 5-minute cuff occlusion were assessed using Doppler ultrasound and near-infrared spectroscopy, respectively. Our findings revealed significant decreases in blood GSH (P < 0.001, ES = 0.76), FMD (P = 0.005, ES = 0.48), reperfusion slope of StO2 (P = 0.018, ES = 0.42) at 24 h and blood flow (P = 0.012, ES = 0.42) at 48 h following eccentric exercise in the control group as compared to the jaboticaba berry juice group. Our results demonstrated that jaboticaba berry juice prevented the exercise-induced increase in reactive oxygen species production and protected macro- and microvascular functions against the damage caused by eccentric exercise, suggesting that jaboticaba berry consumption could protect the vascular function under conditions of imbalance in redox homeostasis.

Retinal microcirculation alterations in rheumatoid arthritis patients compared to healty volunteers and their correlation to the disease activity and duration of disease

Aims/Purpose: Patients with rheumatoid arthritis (RA) have a high risk of developing cardiovascular diseases due to endothelial dysfunction, which is a risk factor for cardiovascular events. The retinal Vessel Analyzer (RVA, IMEDOS Systems) can capture retinal vessels non‐invasively in real‐time and analyse their dynamic responses to stimuli.Methods: In order to assess the structural and functional changes in the retinal microvasculature, a non‐invasive Retinal Vessels Analyzer (RVA) was used to study 44 patients with RA (mean age 57.4 ± 13.2 years) and compare them to a control group of 44 age‐matched healthy individuals. The RVA was used to measure various parameters, including the Central Retinal Artery Equivalent (CRAE), Central Retinal Vein Equivalent (CRVE), and Arterio‐Venous Ratio (AVR), as well as the response of the retinal vessels to flickering light. After a 50 s baseline, rectangular shape, monochromatic flickering light (530–600 nm) of 12.5 Hz for 20 s was applied three times. The dilation of retinal vessels after flicker light stimulation was analysed.Results: The results of the study showed that patients with RA had significantly higher CRVE and lower AVR compared to the control group (p = 0.04 and p = 0.01, respectively), indicating structural changes in the retinal microvasculature. The patients with RA also had a significantly stronger arterial dilation response to flickering light compared to the control group (n = 43), indicating functional changes in the retinal microvasculature. In patients with moderate to high disease activity according to the Disease Activity Score (DAS‐28 &gt; 3.2) (n = 9), there was a negative significant correlation between the maximum arterial diameter (aMAX) and interleukin‐6 (IL‐6).Conclusions: These findings suggest that RVA can be a useful tool for detecting structural and functional changes in the retinal microvasculature of patients with RA and that the disease activity and inflammation in RA may be related to these changes. However, the study notes that a larger cohort with a wider range of disease activity is needed to fully understand the effect of chronic inflammatory diseases on endothelial function.