Effect of acute intranasal insulin administration on muscle sympathetic nerve activity in healthy young adults.

Systemic insulin increases muscle sympathetic nerve activity (MSNA) via both central actions within the brainstem and peripheral activation of the arterial baroreflex. Augmented MSNA during hyperinsulinemia likely restrains peripheral vasodilation and contributes to the maintenance of blood pressure (BP). However, in the absence of insulin action within the peripheral vasculature, whether central insulin stimulation increases MSNA and influences peripheral hemodynamics in humans remains unknown. Herein, we hypothesized intranasal insulin administration would increase MSNA and BP in healthy young adults. Participants were assigned to time control [TC, n = 13 (5 females/8 males), 28 ± 1 yr] or 160 IU of intranasal insulin administered over 5 min [n = 15 (5 females/10 males), 26 ± 2 yr]; five (1 female/4 males) participants completed both conditions. MSNA (fibular microneurography), BP (finger photoplethysmography), and leg blood flow (LBF, femoral Doppler ultrasound) were assessed at baseline, and 15 and 30 min following insulin administration. Leg vascular conductance [LVC = (LBF ÷ mean BP) × 100] was calculated. Venous insulin and glucose concentrations remained unchanged throughout (P > 0.05). Following intranasal insulin administration, MSNA (burst frequency; baseline = 100%; minute 15, 121 ± 8%; minute 30, 118 ± 6%; P = 0.009, n = 7) and mean BP (baseline = 100%; minute 15, 103 ± 1%; minute 30, 102 ± 1%; P = 0.003) increased, whereas LVC decreased (baseline = 100%; minute 15, 93 ± 3%; minute 30, 99 ± 3%; P = 0.03). In contrast, MSNA, mean BP, and LVC were unchanged in TC participants (P > 0.05). We provide the first evidence that intranasal insulin administration in healthy young adults acutely increases MSNA and BP and decreases LVC. These results enhance mechanistic understanding of the sympathetic and peripheral hemodynamic response to insulin.NEW & NOTEWORTHY Systemic insulin increases muscle sympathetic nerve activity (MSNA) via central actions within the brainstem and peripheral activation of the arterial baroreflex. In the absence of peripheral insulin action, whether central insulin stimulation increases MSNA and influences peripheral hemodynamics in humans was unknown. We provide the first evidence that intranasal insulin administration increases MSNA and blood pressure and reduces leg vascular conductance. These results enhance mechanistic understanding of the sympathetic and hemodynamic response to insulin.

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.

Gap analysis of diabetes-related foot disease management systems in Pacific Islands Countries and Territories.

BACKGROUND: Pacific Island Countries and Territories (PICTs) are known to have high prevalence of Diabetes Mellitus and high incidence of diabetes-related foot disease. Diabetes-related foot disease can lead to lower limb amputation and is associated with poor outcomes, with increased morbidity and mortality. The purpose of this study was to gain a better understanding of diabetes-related foot disease management in selected countries in PICTs and to identify potential barriers in management of diabetes-related foot disease management in the region. METHODS: A cross-sectional survey was sent to eleven hospitals across six selected PICTs. The survey instrument was designed to provide an overview of diabetes-related foot disease (number of admissions, and number of lower limb amputations over 12 months) and to identify clinical services available within each institution. Two open-ended questions (free text responses) were included in the instrument to explore initiatives that have helped to improve management and treatment of diabetes-related foot diseases, as well as obstacles that clinicians have encountered in management of diabetes-related foot disease. The survey was conducted over 6 weeks. RESULTS: Seven hospitals across four countries provided responses. Number of admissions and amputations related to diabetes-related foot disease were only reported as an estimate by clinicians. Diabetes-related foot disease was managed primarily by general medicine physician, general surgeon and/or orthopaedic surgeon in the hospitals surveyed, as there were no subspecialty services in the region. Only one hospital had access to outpatient podiatry. Common themes identified around barriers faced in management of diabetes-related foot disease by clinicians were broadly centred around resource availability, awareness and education, and professional development. CONCLUSION: Despite the high prevalence of diabetes-related foot disease within PICTs, there appears to be a lack of functional multi-disciplinary foot services (MDFs). To improve the outcomes for diabetes-related foot disease patients in the region, there is a need to establish functional MDFs and engage international stakeholders to provide ongoing supports in the form of education, mentoring, as well as physical resources.

A qualitative exploration of the experiences of Aboriginal and Torres Strait Islander people using a real-time video-based telehealth service for diabetes-related foot disease.

INTRODUCTION: Diabetes-related foot disease (DFD) is one of the most prevalent causes of global hospitalisation and morbidity, and it accounts for up to 75% of lower-extremity amputations globally. The 5-year mortality rate following any amputation ranges from 53% to 100%. Early identification of wounds and multidisciplinary management can reduce amputation rates by 39-56%. Rural and remote communities and Indigenous populations are disproportionately affected by DFD. This is reflected in amputation rates, which are much higher for Indigenous than for non-Indigenous Australians and for those in very remote areas than for those in major cities or inner regional areas. The large geographical spread of the population in Australia is a substantial barrier for those providing or accessing health services, particularly multidisciplinary and specialist services, which undoubtedly contributes to poorer DFD outcomes in rural and remote communities. METHODS: A real-time, video-based telehealth service for DFD management was established at the Royal Adelaide Hospital Vascular Services clinic to improve access to specialist services for rural and remote Aboriginal and Torres Strait Islander communities. An exploratory qualitative study that utilised one-on-one, semi-structured interviews was conducted with 11 participants who identified as Aboriginal and who had participated in the telehealth foot service. Interviews were transcribed, de-identified and analysed using thematic analysis, using an inductive approach. RESULTS: Four interrelated themes emerged. 'Practical benefits of staying home' describes the reduced burden of travel and advantages of having local healthcare providers and support people at consultations. 'Access to specialists and facilities' highlights how some participants felt that there was a lack of appropriate facilities in their area and appreciated the improved access telehealth provided. 'Feeling reassured that a specialist has seen their feet' reflects the positive impact on wellbeing that participants experienced when their feet were seen by specialist health staff. 'Facilitates communication' describes how participants felt included in consultations and how seeing a person on screen assisted conversation. CONCLUSION: The advantages of real-time, video-based telehealth go beyond reduced travel burden and improved access to specialist care. This model of care may facilitate relationship-building, patient wellbeing, and feelings of trust and safety for Aboriginal and Torres Strait Islander DFD patients.

Neuraminidase inhibition improves endothelial function in diabetic mice.

Neuraminidases cleave sialic acids from glycocalyx structures and plasma neuraminidase activity is elevated in type 2 diabetes (T2D). Therefore, we hypothesize circulating neuraminidase degrades the endothelial glycocalyx and diminishes flow-mediated dilation (FMD), whereas its inhibition restores shear mechanosensation and endothelial function in T2D settings. We found that compared with controls, subjects with T2D have higher plasma neuraminidase activity, reduced plasma nitrite concentrations, and diminished FMD. Ex vivo and in vivo neuraminidase exposure diminished FMD and reduced endothelial glycocalyx presence in mouse arteries. In cultured endothelial cells, neuraminidase reduced glycocalyx coverage. Inhalation of the neuraminidase inhibitor, zanamivir, reduced plasma neuraminidase activity, enhanced endothelial glycocalyx length, and improved FMD in diabetic mice. In humans, a single-arm trial (NCT04867707) of zanamivir inhalation did not reduce plasma neuraminidase activity, improved glycocalyx length, or enhanced FMD. Although zanamivir plasma concentrations in mice reached 225.8 ± 22.0 ng/mL, in humans were only 40.0 ± 7.2 ng/mL. These results highlight the potential of neuraminidase inhibition for ameliorating endothelial dysfunction in T2D and suggest the current Food and Drug Administration-approved inhaled dosage of zanamivir is insufficient to achieve desired outcomes in humans.NEW & NOTEWORTHY This work identifies neuraminidase as a key mediator of endothelial dysfunction in type 2 diabetes that may serve as a biomarker for impaired endothelial function and predictive of development and progression of cardiovascular pathologies associated with type 2 diabetes (T2D). Data show that intervention with the neuraminidase inhibitor zanamivir at effective plasma concentrations may represent a novel pharmacological strategy for restoring the glycocalyx and ameliorating endothelial dysfunction.

Impact of sex and diet-induced weight loss on vascular insulin sensitivity in type 2 diabetes.

Vascular insulin resistance, a major characteristic of obesity and type 2 diabetes (T2D), manifests with blunting of insulin-induced vasodilation. Although there is evidence that females are more whole body insulin sensitive than males in the healthy state, whether sex differences exist in vascular insulin sensitivity is unclear. Also uncertain is whether weight loss can reestablish vascular insulin sensitivity in T2D. The purpose of this investigation was to 1) establish if sex differences in vasodilatory responses to insulin exist in absence of disease, 2) determine whether female sex affords protection against the development of vascular insulin resistance with long-term overnutrition and obesity, and 3) examine if diet-induced weight loss can restore vascular insulin sensitivity in men and women with T2D. First, we show in healthy mice and humans that sex does not influence insulin-induced femoral artery dilation and insulin-stimulated leg blood flow, respectively. Second, we provide evidence that female mice are protected against impairments in insulin-induced dilation caused by overnutrition-induced obesity. Third, we show that men and women exhibit comparable levels of vascular insulin resistance when T2D develops but that diet-induced weight loss is effective at improving insulin-stimulated leg blood flow, particularly in women. Finally, we provide indirect evidence that these beneficial effects of weight loss may be mediated by a reduction in endothelin-1. In aggregate, the present data indicate that female sex confers protection against obesity-induced vascular insulin resistance and provide supportive evidence that, in women with T2D, vascular insulin resistance can be remediated with diet-induced weight loss.

Role of the arterial baroreflex in the sympathetic response to hyperinsulinemia in adult humans.

Muscle sympathetic nerve activity (MSNA) increases during hyperinsulinemia, primarily attributed to central nervous system effects. Whether peripheral vasodilation induced by insulin further contributes to increased MSNA via arterial baroreflex-mediated mechanisms requires further investigation. Accordingly, we examined baroreflex modulation of the MSNA response to hyperinsulinemia. We hypothesized that rescuing peripheral resistance with coinfusion of the vasoconstrictor phenylephrine would attenuate the MSNA response to hyperinsulinemia. We further hypothesized that the insulin-mediated increase in MSNA would be recapitulated with another vasodilator (sodium nitroprusside, SNP). In 33 young healthy adults (28 M/5F), MSNA (microneurography) and arterial blood pressure (BP, Finometer/brachial catheter) were measured, and total peripheral resistance (TPR, ModelFlow) and baroreflex sensitivity were calculated at rest and during intravenous infusion of insulin (n = 20) or SNP (n = 13). A subset of participants receiving insulin (n = 7) was coinfused with phenylephrine. Insulin infusion decreased TPR (P = 0.01) and increased MSNA (P < 0.01), with no effect on arterial baroreflex sensitivity or BP (P > 0.05). Coinfusion with phenylephrine returned TPR and MSNA to baseline, with no effect on arterial baroreflex sensitivity (P > 0.05). Similar to insulin, SNP decreased TPR (P < 0.02) and increased MSNA (P < 0.01), with no effect on arterial baroreflex sensitivity (P > 0.12). Acute hyperinsulinemia shifts the baroreflex stimulus-response curve to higher MSNA without changing sensitivity, likely due to insulin's peripheral vasodilatory effects. Results show that peripheral vasodilation induced by insulin contributes to increased MSNA during hyperinsulinemia.NEW & NOTEWORTHY We hypothesized that elevation in muscle sympathetic nervous system activity (MSNA) during hyperinsulinemia is mediated by its peripheral vasodilator effect on the arterial baroreflex. Using three separate protocols in humans, we observed increases in both MSNA and cardiac output during hyperinsulinemia, which we attributed to the baroreflex response to peripheral vasodilation induced by insulin. Results show that peripheral vasodilation induced by insulin contributes to increased MSNA during hyperinsulinemia.

Role of adropin in arterial stiffening associated with obesity and type 2 diabetes.

Adropin is a peptide largely secreted by the liver and known to regulate energy homeostasis; however, it also exerts cardiovascular effects. Herein, we tested the hypothesis that low circulating levels of adropin in obesity and type 2 diabetes (T2D) contribute to arterial stiffening. In support of this hypothesis, we report that obesity and T2D are associated with reduced levels of adropin (in liver and plasma) and increased arterial stiffness in mice and humans. Establishing causation, we show that mesenteric arteries from adropin knockout mice are also stiffer, relative to arteries from wild-type counterparts, thus recapitulating the stiffening phenotype observed in T2D db/db mice. Given the above, we performed a set of follow-up experiments, in which we found that 1) exposure of endothelial cells or isolated mesenteric arteries from db/db mice to adropin reduces filamentous actin (F-actin) stress fibers and stiffness, 2) adropin-induced reduction of F-actin and stiffness in endothelial cells and db/db mesenteric arteries is abrogated by inhibition of nitric oxide (NO) synthase, and 3) stimulation of smooth muscle cells or db/db mesenteric arteries with a NO mimetic reduces stiffness. Lastly, we demonstrated that in vivo treatment of db/db mice with adropin for 4 wk reduces stiffness in mesenteric arteries. Collectively, these findings indicate that adropin can regulate arterial stiffness, likely via endothelium-derived NO, and thus support the notion that "hypoadropinemia" should be considered as a putative target for the prevention and treatment of arterial stiffening in obesity and T2D.NEW & NOTEWORTHY Arterial stiffening, a characteristic feature of obesity and type 2 diabetes (T2D), contributes to the development and progression of cardiovascular diseases. Herein we establish that adropin is decreased in obese and T2D models and furthermore provide evidence that reduced adropin may directly contribute to arterial stiffening. Collectively, findings from this work support the notion that "hypoadropinemia" should be considered as a putative target for the prevention and treatment of arterial stiffening in obesity and T2D.

Chickadees discriminate contingency reversals presented consistently, but not frequently.

Chickadees are high-metabolism, non-migratory birds, and thus an especially interesting model for studying how animals follow patterns of food availability over time. Here, we studied whether black-capped chickadees (Poecile atricapillus) could learn to reverse their behavior and/or to anticipate changes in reinforcement when the reinforcer contingencies for each stimulus were not stably fixed in time. In Experiment 1, we examined the responses of chickadees on an auditory go/no-go task, with constant reversals in reinforcement contingencies every 120 trials across daily testing intervals. Chickadees did not produce above-chance discrimination; however, when trained with a procedure that only reversed after successful discrimination, chickadees were able to discriminate and reverse their behavior successfully. In Experiment 2, we examined the responses of chickadees when reversals were structured to occur at the same time once per day, and chickadees were again able to discriminate and reverse their behavior over time, though they showed no reliable evidence of reversal anticipation. The frequency of reversals throughout the day thus appears to be an important determinant for these animals' performance in reversal procedures.

Discrimination of acoustically similar conspecific and heterospecific vocalizations by black-capped chickadees (Poecile atricapillus).

Chickadees produce a multi-note chick-a-dee call in multiple socially relevant contexts. One component of this call is the D note, which is a low-frequency and acoustically complex note with a harmonic-like structure. In the current study, we tested black-capped chickadees on a between-category operant discrimination task using vocalizations with acoustic structures similar to black-capped chickadee D notes, but produced by various songbird species, in order to examine the role that phylogenetic distance plays in acoustic perception of vocal signals. We assessed the extent to which discrimination performance was influenced by the phylogenetic relatedness among the species producing the vocalizations and by the phylogenetic relatedness between the subjects' species (black-capped chickadees) and the vocalizers' species. We also conducted a bioacoustic analysis and discriminant function analysis in order to examine the acoustic similarities among the discrimination stimuli. A previous study has shown that neural activation in black-capped chickadee auditory and perceptual brain regions is similar following the presentation of these vocalization categories. However, we found that chickadees had difficulty discriminating between forward and reversed black-capped chickadee D notes, a result that directly corresponded to the bioacoustic analysis indicating that these stimulus categories were acoustically similar. In addition, our results suggest that the discrimination between vocalizations produced by two parid species (chestnut-backed chickadees and tufted titmice) is perceptually difficult for black-capped chickadees, a finding that is likely in part because these vocalizations contain acoustic similarities. Overall, our results provide evidence that black-capped chickadees' perceptual abilities are influenced by both phylogenetic relatedness and acoustic structure.

Pigeons perform poorly on a midsession reversal task without rigid temporal regularity.

Animals make surprising anticipatory and perseverative errors when faced with a midsession reversal of reinforcer contingencies on a choice task with highly predictable stimulus-time relationships. In the current study, we asked whether pigeons would anticipate changes in reinforcement when the reinforcer contingencies for each stimulus were not fixed in time. We compared the responses of pigeons on a simultaneous choice task when the initially correct stimulus was randomized or alternated across sessions. Pigeons showed more errors overall compared with the typical results of a standard midsession reversal procedure, and they did not show the typical anticipatory errors prior to the contingency reversal. Probe tests that manipulated the spacing between trials also suggested that timing of the session exerted little control of pigeons' behavior. The temporal structure of the experimental session thus appears to be an important determinant for animals' use of time in midsession reversal procedures.

A three-stimulus midsession reversal task in pigeons with visual and spatial discriminative stimuli.

In a two-stimulus visual discrimination task with a reversal in reward contingencies midway through each session, pigeons produce a surprising number of both anticipatory (i.e., before the reversal) and perseverative (i.e., after the reversal) errors. In the current work, we examined pigeons' (Columba livia) patterns of responding on a 90-trial, three-stimulus visual or spatial discrimination task with two changes in reward contingency (one after Trial 30 and one after Trial 60) during each session. On probe sessions where pecking the first-correct stimulus was rewarded for the first 60 rather than 30 trials, pigeons on a spatial discrimination pecked the first-correct stimulus until it was no longer rewarded, while visual discrimination birds ceased responding to the first-correct stimulus even while it was still being rewarded. On probe sessions where the onset of the first trial was delayed 7 min, pigeons' performance on the visual discrimination was disrupted by the interval delay, but performance in the spatial condition was more similar to baseline. Pigeons use different strategies (temporal control vs. local reinforcement) on midsession reversal tasks with visual versus spatial stimuli, suggesting that they are selectively permeable to changes in information (global vs. local reinforcement rates).

Pigeons rank-order responses to temporally sequential stimuli.

We explored pigeons' ability to learn a particular sequence of stimuli in which the durations of each stimulus varied among trials, where the first response at the end of the sequence was reinforced. In Experiment 1A, we found that pigeons failed to use the whole sequence of three stimuli to predict food reinforcement, and instead responded only to the third, "rewarded" stimulus. When rewarded (1-2-3) and nonrewarded (2-1-3) sequences were used in a go/no-go procedure in Experiment 1B, however, pigeons showed a tendency to rank-order responding, with higher response rates to the second than to the first stimulus, as well as lower response rates to the third stimulus on nonrewarded-sequence trials. In Experiment 2, pigeons showed rudimentary rank-ordering of five stimuli in sequence, with lower responding to the final stimulus on nonrewarded trials, even when the sequence presented differed from the rewarded sequence only in a reversal of the second and third stimuli. Pigeons were capable of using ordinal information in a temporal task, but only when that information was easily discriminable and led to explicit consequences (i.e., rewarded vs. nonrewarded sequences).

The experiences of health workers using telehealth services for diabetes-related foot complications: a qualitative exploration.

BACKGROUND: Diabetes-related foot disease (DFD) accounts for up to 75% of lower-extremity amputations globally. Rural and remote communities are disproportionately affected by DFD. Telehealth has been advocated as a strategy to improve equity of access to health care in rural and remote communities. Current literature suggests that successful implementation of telehealth requires access to adequate reliable equipment, staff training, and support. A real-time video-based telehealth foot service (TFS) for delivering DFD management has recently been established in a Vascular Surgery and Podiatry clinic within a large South Australian metropolitan hospital. The purpose of this study was to gain insights into the experiences of rural and remote health professionals utilising the TFS, as this could be invaluable in optimising the uptake of telehealth use in DFD. METHODS: This exploratory, descriptive qualitative study employed one-on-one, semi-structured interviews with health professionals who utilised the service. Thematic analysis using an essentialist inductive approach was employed. RESULTS: Participants included 14 rural and remote health professionals; 2 general practitioners, 2 nurses, 1 Aboriginal Health Practitioner, and 9 podiatrists. In addition, 2 metropolitan-based TFS staff were interviewed. Five key themes were identified. 'Patients have reduced travel burden' included that telehealth enabled Indigenous patients to stay on country. 'Patients had increased psychosocial support' covered the benefits of having health professionals who knew the patient present in consults. 'Improved access' incorporated how telehealth improved interprofessional relationship building and communication. 'Technological and equipment challenges' highlighted that poor network connectivity and poor access to equipment to conduct telehealth consults in rural areas were barriers. The last theme,'Lack of service communication to rural health professionals', highlighted the need for communication around service details. CONCLUSION: Telehealth is a valuable tool that can improve access to treatment for rural and remote Indigenous DFD patients. While this has the potential to improve DFD outcomes, empirical data is required to confirm outcomes. Considering the advantages of telehealth and rural staff shortages, there is an urgent need for investment in improved equipment and processes and an understanding of the training needs of the health care workforce to support the use of telehealth in DFD management.

Home-based exercise improves subclinical atherosclerosis marker in multiple sclerosis.

PURPOSE: Using a 12-week, randomized controlled trial coupled with social cognitive theory behavioral coaching, we aimed to assess the effect of a home-based aerobic training intervention versus an attention-control on aerobic fitness, subclinical atherosclerosis, and mobility in persons with MS. METHODS: Persons with MS with an expanded disability status scale score between 0 and 4 were randomized to a 12-week aerobic exercise (EX) (n = 26; 19 females; 49 yrs; 28.8 kg/m2) or attention-control (CON) condition (stretching; n = 22; 16 females; 44 yrs; 29.2 kg/m2). Aerobic capacity was assessed via a graded cycle ergometry test with indirect calorimetry. The co-primary measures of subclinical atherosclerosis assessed included carotid intima media thickness, a test of vasodilatory reactivity, and arterial stiffness. Mobility was assessed via a timed 25-foot walk test (T25FW) and a 6 min walk test. The EX group engaged in cycle ergometry 3d/wk with gradual increases in the intensity and duration of the exercise sessions. CON participated in standardized stretching designed to provide the same contact time as EX 3d/wk. Behavioral coaching took place via weekly phone/video chats to track adherence. RESULTS: Aerobic capacity, vasodilatory reactivity, and T25FW speed increased only in the EX group, 7%, 16%, and 13% (p<0.05), respectively; whereas the CON group did not change. CONCLUSION: The EX group had modest, yet significant, increases in aerobic capacity over the 12-week period, coupled with improvements in T25FW speed and vasodilatory reactivity. A home-based exercise intervention can improve outcomes of a subclinical marker of atherosclerosis, which provides a basis for examining these outcomes in persons prescreened for CVD-related comorbidities and/or mobility issues.

Young Women Are Protected Against Vascular Insulin Resistance Induced by Adoption of an Obesogenic Lifestyle.

Vascular insulin resistance is a feature of obesity and type 2 diabetes that contributes to the genesis of vascular disease and glycemic dysregulation. Data from preclinical models indicate that vascular insulin resistance is an early event in the disease course, preceding the development of insulin resistance in metabolically active tissues. Whether this is translatable to humans requires further investigation. To this end, we examined if vascular insulin resistance develops when young healthy individuals (n = 18 men, n = 18 women) transition to an obesogenic lifestyle that would ultimately cause whole-body insulin resistance. Specifically, we hypothesized that short-term (10 days) exposure to reduced ambulatory activity (from >10 000 to <5000 steps/day) and increased consumption of sugar-sweetened beverages (6 cans/day) would be sufficient to prompt vascular insulin resistance. Furthermore, given that incidence of insulin resistance and cardiovascular disease is lower in premenopausal women than in men, we postulated that young females would be protected against vascular insulin resistance. Consistent with this hypothesis, we report that after reduced ambulation and increased ingestion of carbonated beverages high in sugar, young healthy men, but not women, exhibited a blunted leg blood flow response to insulin and suppressed skeletal muscle microvascular perfusion. These findings were associated with a decrease in plasma adropin and nitrite concentrations. This is the first evidence in humans that vascular insulin resistance can be provoked by short-term adverse lifestyle changes. It is also the first documentation of a sexual dimorphism in the development of vascular insulin resistance in association with changes in adropin levels.

The shifting care and outcomes for patients with endangered limbs - Critical limb ischemia (SCOPE-CLI) registry overview of study design and rationale.

BACKGROUND: Critical limb ischemia (CLI), the most severe form of peripheral artery disease, is associated with pain, poor wound healing, high rates of amputation, and mortality (>20% at 1 year). Little is known about the processes of care, patients' preferences, or outcomes, as seen from patients' perspectives. The SCOPE-CLI study was co-designed with patients to holistically document patient characteristics, treatment preferences, patterns of care, and patient-centered outcomes for CLI. METHODS: This 11-center prospective observational registry will enroll and interview 816 patients from multispecialty, interdisciplinary vascular centers in the United States and Australia. Patients will be followed up at 1, 2, 6, and 12 months regarding their psychosocial factors and health status. Hospitalizations, interventions, and outcomes will be captured for 12 months with vital status extending to 5 years. Pilot data were collected between January and July of 2021 from 3 centers. RESULTS: A total of 70 patients have been enrolled. The mean age was 68.4 ± 11.3 years, 31.4% were female, and 20.0% were African American. CONCLUSIONS: SCOPE-CLI is uniquely co-designed with patients who have CLI to capture the care experiences, treatment preferences, and health status outcomes of this vulnerable population and will provide much needed information to understand and address gaps in the quality of CLI care and outcomes.ClinicalTrials.gov identifier (NCT Number): NCT04710563 https://clinicaltrials.gov/ct2/show/NCT04710563.

Do pigeons (Columba livia) study for a test?

In 4 experiments, the authors asked whether pigeons (Columba livia) would show metamemory by choosing to study a sample stimulus before taking a memory test. In Experiments 1a-1c, pigeons chose between cues that led either to exposure to a sample stimulus or directly to the comparison test stimuli without seeing the sample in a delayed matching-to-sample task. The same choice was used in Experiment 2 to see whether pigeons would take a reminder when memory of the sample was weak. In Experiments 3 and 4, pigeons' responses led to either a choice between red and green side keys with a sample present to guide the choice or a choice with no sample present. The findings of all of these experiments suggest the absence of metamemory in pigeons.

Anticipation of a midsession reversal in humans.

In a two-stimulus visual discrimination choice task with a reversal in reward contingencies midway through each session, pigeons produce a surprising number of anticipatory errors (i.e., responding to the second-correct stimulus before the reversal) based on failure to inhibit timing-based intrusion errors; limited prior research has suggested humans' performance is qualitatively different. Here we illustrate a partial replication of previous findings in humans, but suggest based on our results that humans process these tasks in a manner similar to pigeons. Humans made relatively few but consistent errors across both simultaneous- and successive-choice experiments. Anticipation errors were limited when the identity of the first-correct stimulus alternated between sessions, consistent with the behaviour of pigeons. Subsequent experiments found evidence for anticipation on a purely temporal simultaneous choice task, and fewer errors with symmetrical reinforcement and punishment of responses on a sequential choice task. Interval timing causes conflicts with decision-making processes on the midsession reversal task that are consistent, but differ in magnitude, across species.

Rats' memory for event duration in delayed matching-to-sample with nonspatial comparison response alternatives.

Previous research has suggested that using stationary and moving levers as nonspatial response alternatives can significantly enhance the speed of acquiring a temporal discrimination in rats. In Experiment 1, rats were trained to discriminate 2 and 8s of magazine light illumination by responding to either a stationary lever or a moving lever with a cue light illuminated above it. Rats learned to discriminate event durations at a high level of accuracy after 25 sessions of training. During subsequent delay tests, rats exhibited a strong choose-long bias, indicating that they were timing from the onset of the magazine light until the entry of levers into the chamber. This occurred regardless of whether intertrial intervals and delay intervals were dark or illuminated. On test trials in which the sample was omitted, rats responded as if the short sample had been presented. In Experiment 2, the rats received extensive training with dark and illuminated variable delay intervals (1-4 s). However, they continued to exhibit a tendency to time from the onset of the magazine light until entry of the levers into the chamber. Although the use of stationary/uncued and moving/cued levers as response alternatives enhanced the speed of acquisition of the event duration discrimination in rats, additional procedural modifications will be necessary to prevent rats from timing during the delay interval.