Acute increases in sympathetic nervous system activity (SNA) often elicit peripheral vasoconstriction and increases in blood pressure (BP). Given sympathetic support of BP is modulated by ovarian sex ...hormones (e.g., estradiol), we sought to examine the effect of menstrual cycle and oral hormonal contraceptive pill (OC) phase on the hemodynamic response to acute increases in SNA. We hypothesized sympathoexcitation via cold pressor test (CPT) would elicit greater peripheral vasoconstriction and increases BP in females with natural menstrual cycles (NC) compared with females taking OC. We further hypothesized that SNA-mediated vasoconstriction would be attenuated during the high estradiol (HE) phase versus the low estradiol (LE) phase of the menstrual/pill cycle. Female NC (
= 11, 25 ± 1 yr) and OC (
= 10, 24 ± 1 yr) participants were studied during the LE (early follicular, placebo pill) and HE (late follicular, active pill) phase of the menstrual/pill cycle. BP (finger photoplethysmography), heart rate (HR, ECG), and forearm blood flow (FBF, venous occlusion plethysmography) were measured during a 5-min baseline and a 2-min CPT. CPT elicited an increase in BP in both groups (time,
< 0.01). During CPT, OC participants exhibited greater and sustained increases in HR compared with NC participants (group × time,
< 0.01). Higher HRs were met with increases in FBF in OC participants during the CPT, which was not observed in NC participants (group × time,
< 0.01). OC participants exhibit greater increases in HR, and paradoxical vasodilation during acute sympathetic activation compared with NC participants. Group differences are unaffected by menstrual/pill phase.
Acute increases in sympathetic nervous system activity often elicit peripheral vasoconstriction and increases in blood pressure (BP). Given sympathetic support of BP is modulated by ovarian sex hormones (e.g., estradiol), we sought to examine the effect of menstrual cycle and oral hormonal contraceptive pill (OC) phase on the hemodynamic response to acute increases in sympathetic nervous system activity via the cold pressor test. We show OC participants exhibit paradoxical vasodilation during acute sympathetic activation compared with participants with natural menstrual cycles; notably, group differences were unaffected by menstrual/pill phase.
New Findings
What is the central question of this study?
We sought to establish between‐day reproducibility in estimates of middle cerebral artery blood velocity (MCAv) and cerebrovascular reactivity ...(CVR) in young, healthy male and female adults in tightly controlled experimental conditions.
What is the main finding and its importance?
Measures of MCAv assessed during morning, afternoon and evening hours are reproducible between days. There is diurnal variation in CVR, with values being highest during the evening compared with the morning. Greater diurnal variation in CVR is associated with more efficient sleep and greater nocturnal blood pressure dipping. These data enhance our understanding of modulators of MCAv and CVR.
Transcranial Doppler (TCD) is used to assess cerebral blood velocity (CBV) and cerebrovascular reactivity (CVR). Assessments of TCD reproducibility are limited, and few include multiple within‐day measurements. We sought to establish reproducibility of CBV and CVR in healthy adults during three time periods (morning, afternoon and evening). We hypothesized that CBV and CVR measured at the same time of day are reproducible between days. We also hypothesized that CBV and CVR exhibit diurnal variation, with measurements being higher in the evening compared with morning/afternoon hours. Twelve adults six male and six female, 27 years (95% CI, 22–31 years) completed three measurements (morning, afternoon and evening) on two separate days in controlled conditions (e.g., meals, activity and sleep). Middle cerebral artery blood velocity (MCAv, TCD) was measured continuously at rest and during two CVR tests (end‐expiratory apnoea and carbogen inhalation). Intraclass correlation coefficients for resting MCAv showed moderate to good reproducibility, which did not differ between morning, afternoon and evening (0.87, 0.56 and 0.67, respectively; P > 0.05). Intraclass correlation coefficients for peak MCAv during apnoea (0.80, 0.46 and 0.65, respectively; P > 0.05) and minute 2 of carbogen inhalation (0.81, 0.74 and 0.73, respectively; P > 0.05) were also not different from morning compared with afternoon/evening. Time of day had no effect on resting MCAv (F = 0.69, P = 0.51, ƞp2 = 0.06) or the peak response to apnoea (F = 1.00, P = 0.39, ƞp2 = 0.08); however, peak MCAv during carbogen breathing exhibited diurnal variation, with highest values in the evening (F = 3.41, P = 0.05, ƞp2 = 0.24). Measures of CBV and CVR assessed via TCD during morning, afternoon and evening hours are reproducible between days. There is diurnal variation in the MCAv response to carbogen exposure, with CVR being highest during evening compared with morning hours.
The nucleolus is a common target of viruses and viral proteins, but for many viruses the functional outcomes and significance of this targeting remains unresolved. Recently, the first intranucleolar ...function of a protein of a cytoplasmically‐replicating negative‐sense RNA virus (NSV) was identified, with the finding that the matrix (M) protein of Hendra virus (HeV) (genus Henipavirus, family Paramyxoviridae) interacts with Treacle protein within nucleolar subcompartments and mimics a cellular mechanism of the nucleolar DNA‐damage response (DDR) to suppress ribosomal RNA (rRNA) synthesis. Whether other viruses utilise this mechanism has not been examined. We report that sub‐nucleolar Treacle targeting and modulation is conserved between M proteins of multiple Henipaviruses, including Nipah virus and other potentially zoonotic viruses. Furthermore, this function is also evident for P3 protein of rabies virus, the prototype virus of a different RNA virus family (Rhabdoviridae), with Treacle depletion in cells also found to impact virus production. These data indicate that unrelated proteins of viruses from different families have independently developed nucleolar/Treacle targeting function, but that modulation of Treacle has distinct effects on infection. Thus, subversion of Treacle may be an important process in infection by diverse NSVs, and so could provide novel targets for antiviral approaches with broad specificity.
Synopsis statement: The nucleolus is a common target of RNA viruses, but the roles and significance of this remain unresolved. Previously we found the Hendra virus (a Henipavirus) M protein targets a subnucleolar compartment and interacts with Treacle, impairing ribosome biogenesis. Here we show that targeting of Treacle is conserved among multiple Henipavirus M proteins and also the unrelated P3 protein of rabies virus (a Lyssavirus). These data suggest viral targeting of Treacle/sub‐nucleolar regions may be an important process of diverse viruses.
The zoonotic potential of paramyxoviruses is particularly demonstrated by their broad host range like the highly pathogenic Hendra and Nipah viruses originating from bats. But while so far all ...bat-borne paramyxoviruses have been identified in fruit bats across Africa, Australia, South America, and Asia, we describe the detection and characterization of the first paramyxoviruses in free-ranging European bats. Moreover, we examined the possible impact of paramyxovirus infection on individual animals by comparing histo-pathological findings and virological results. Organs from deceased insectivorous bats of various species were sampled in Germany and tested for paramyxovirus RNA in parallel to a histo-pathological examination. Nucleic acids of three novel paramyxoviruses were detected, two viruses in phylogenetic relationship to the recently proposed genus Jeilongvirus and one closely related to the genus Rubulavirus. Two infected animals revealed subclinical pathological changes within their kidneys, suggestive of a similar pathogenesis as the one described in fruit bats experimentally infected with Hendra virus.Our findings indicate the presence of bat-born paramyxoviruses in geographic areas free of fruit bat species and therefore emphasize a possible virus-host co-evolution in European bats. Since these novel viruses are related to the very distinct genera Rubulavirus and Jeilongvirus, a similarly broad genetic diversity among paramyxoviruses in other Microchiroptera compared to Megachiroptera can be assumed. Given that the infected bats were either found in close proximity to heavily populated human habitation or areas of intensive agricultural use, a potential risk of the emergence of zoonotic paramyxoviruses in Europe needs to be considered.
The present study evaluated cardiovagal baroreflex sensitivity (BRS) across the menstrual/pill cycle in naturally menstruating women (NAT women) and women using oral hormonal contraceptives (OCP ...women). In 21 NAT women (23 ± 4 years old) and 22 OCP women (23 ± 3 years old), cardiovagal BRS and circulating concentrations of estradiol and progesterone were evaluated during the lower hormone (early follicular/placebo pill) and higher hormone (late follicular to early luteal/active pill) phases. During the lower hormone phase, cardiovagal BRS up, down and mean gain were lower in NAT women (15.6 ± 8.3, 15.2 ± 6.1 and 15.1 ± 7.1 ms/mmHg) compared with OCP women (24.7 ± 9.4, 22.9 ± 8.0 and 23.0 ± 8.0 ms/mmHg) (P = 0.003, P = 0.002 and P = 0.003, respectively), and higher oestrogen (R2 = 0.15, P = 0.024), but not progesterone (R2 = 0.06, P = 0.18), concentrations were predictive of lower BRS mean gain. During the higher hormone phase, higher progesterone concentrations were predictive of lower BRS mean gain (R2 = 0.12, P = 0.024). A multivariate regression model revealed group (NAT or OCP) to be a significant predictor of cardiovagal BRS mean gain in the lower hormone phase when hormone concentrations were adjusted for (R2 = 0.36, P = 0.0044). The multivariate regression model was not significant during the higher hormone phase (P > 0.05). In summary, cardiovagal BRS is lower in NAT compared with OCP women during the lower hormone phase of the menstrual/pill cycle and might be associated with higher oestrogen concentrations. In contrast, during the higher hormone phase of the menstrual/OCP cycle, higher progesterone concentrations were predictive of lower cardiovagal BRS.
New Findings
What is the central question of this study?
Does cardiovagal baroreflex sensitivity (BRS) differ between naturally menstruating women (NAT women) and women using oral contraceptives (OCP women)?
What is the main finding and its importance?
The main findings are as follows: (1) NAT women exhibit lower cardiovagal BRS than OCP women during the lower hormone phase of the menstrual or pill cycle; and (2) circulating oestrogen concentrations are significant predictors of cardiovagal BRS during the lower hormone phase, with higher oestrogen concentrations predicting lower BRS. The present data advance our understanding of the effect of endogenous ovarian hormones and OCP use on cardiovascular control mechanisms.
The paper addresses the application of foresight to research and innovation policy and strategy. It seeks to show an evolution away from a traditional focus on broad-based technological priority ...setting to a much more focussed and adapted set of applications. The inherent limitations of prioritisation processes are discussed. The more limited aim of articulating specific fields is noted. Recent trends in research and innovation policy have opened new opportunities for the application of foresight. Systemic and demand-side policies require a shared vision on the part of purchasers and suppliers. The role of foresight in such contexts needs both to be enhanced and better understood.
An increasing structural focus for foresight exercises is associated not only with broader R&I system reform but also with an engagement with new-wave innovation policies. The success of demand-side measures such as cluster policies and the use of procurement or regulation to stimulate innovation is dependent upon the formation of a common vision between the supply and demand sides, opening the possibility for the application of foresight approaches. We note the emergence of a combination of corrective, disruptive and creative roles.
Pediatric anxiety disorders involve greater capture of attention by threatening stimuli. However, it is not known if disturbances extend to nonthreatening stimuli, as part of a pervasive disturbance ...in attention-related brain systems. We hypothesized that pediatric anxiety involves greater capture of attention by salient, nonemotional stimuli, coupled with greater activity in the portion of the inferior frontal gyrus (IFG) specific to the ventral attention network (VAN).
A sample of children (n = 129, 75 girls, mean 10.6 years of age), approximately half of whom met criteria for a current anxiety disorder, completed a task measuring involuntary capture of attention by nonemotional (square boxes) and emotional (angry and neutral faces) stimuli. A subset (n = 61) completed a task variant during functional magnetic resonance imaging. A priori analyses examined activity in functional brain areas within the right IFG, supplemented by a whole-brain, exploratory analysis.
Higher clinician-rated anxiety was associated with greater capture of attention by nonemotional, salient stimuli (F1,125 = 4.94, p = .028) and greater activity in the portion of the IFG specific to the VAN (F1,57 = 10.311, p = .002). Whole-brain analyses confirmed that the effect of anxiety during capture of attention was most pronounced in the VAN portion of the IFG, along with additional areas of the VAN and the default mode network.
The pathophysiology of pediatric anxiety appears to involve greater capture of attention to salient stimuli, as well as greater activity in attention-related brain networks. These results provide novel behavioral and brain-based targets for treatment of pediatric anxiety disorders.
Introduction
The peripheral chemoreceptors have been implicated in the pathogenesis of type 2 diabetes. Our main objective was to examine peripheral chemosensitivity in individuals with type 2 ...diabetes, as well as the contribution of the peripheral chemoreceptors to basal cardiovascular control. We hypothesized individuals with type 2 diabetes exhibit exaggerated peripheral chemoreflex sensitivity to hypoxia compared to healthy, non‐diabetic controls. We further hypothesized the peripheral chemoreceptors contribute to cardiovascular dysfunction in type 2 diabetes.
Methods
Eight adults with diagnosed type 2 diabetes (3M/5F, 54±3 yrs, HbA1c 8.1±0.6%) and nineteen healthy controls (8M/11F, 50±3 yrs, HbA1c 5.3±0.1%) participated (IRB #2010295 and #2018486). Ventilatory and hemodynamic responses to acute hypoxia were assessed to determine peripheral chemosensitivity i.e., hypoxic ventilatory (HVR), heart rate (HHRR) and blood pressure (HBPR) response. Separately, heart rate, blood pressure and forearm blood flow (Doppler ultrasound) were measured while breathing normoxic or hyperoxic air (100% O2; Modified Dejours test) to acutely attenuate peripheral chemoreceptor activity. Forearm blood flow was normalized for mean arterial blood pressure for measures of vascular resistance.
Results
Peripheral chemosensitivity was augmented in adults with type 2 diabetes compared to control as assessed via the HVR (‐1.10±0.16 vs ‐0.50±0.10 L/min/%, p<0.01) and HBPR (‐0.92±0.17 vs ‐0.42±0.19 mmHg/%, p=0.06), with no differences in HHRR (‐0.68±0.22 vs ‐0.56±0.12 beats/min/%, p=0.64). Higher HVR and HBPR were associated with higher fasting insulin (R=‐0.58, p<0.01 and R=‐0.38, p=0.06) and HbA1c (R=‐0.60, p<0.01 and R=‐0.39, p=0.05). Attenuation of peripheral chemoreceptor activity with acute hyperoxia decreased heart rate (p<0.01) and blood pressure (p=0.02), with no effect on forearm vascular resistance (p=0.55); any effect of hyperoxia did not differ between adults with type 2 diabetes and controls (p>0.05).
Conclusion
Individuals with type 2 diabetes exhibit exaggerated peripheral chemoreflex sensitivity which is associated with disease severity (i.e., HbA1c). In contrast, the contribution of the peripheral chemoreceptors to basal cardiovascular function in type 2 diabetes does not differ from non‐diabetic controls. Results advance our understanding of the pathogenesis of type 2 diabetes and related complications.
Repetitive hypoxic apneas, similar to those observed in sleep apnea, result in resetting of the sympathetic baroreflex to higher blood pressures (BP). This baroreflex resetting is associated with ...hypertension in preclinical models of sleep apnea (intermittent hypoxia, IH); however, the majority of understanding comes from males. There are data to suggest that female rats exposed to IH do not develop high BP. Clinical data further support sex differences in the development of hypertension in sleep apnea, but mechanistic data are lacking. Here we examined sex-related differences in the effect of IH on sympathetic control of BP in humans. We hypothesized that after acute IH we would observe a rise in muscle sympathetic nerve activity (MSNA) and arterial BP in young men (
= 30) that would be absent in young women (
= 19). BP and MSNA were measured during normoxic rest before and after 30 min of IH. Baroreflex sensitivity (modified Oxford) was evaluated before and after IH. A rise in mean BP following IH was observed in men (+2.0 ± 0.7 mmHg,
= 0.03), whereas no change was observed in women (-2.7 ± 1.2 mmHg,
= 0.11). The elevation in MSNA following IH was not different between groups (4.7 ± 1.1 vs. 3.8 ± 1.2 bursts/min,
= 0.65). Sympathetic baroreflex sensitivity did not change after IH in either group (
> 0.05). Our results support sex-related differences in the effect of IH on neurovascular control of BP and show that any BP-raising effects of IH are absent in young women. These data enhance our understanding of sex-specific mechanisms that may contribute to BP changes in sleep apnea.
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