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We present an enhancer AAV toolbox for accessing and perturbing striatal cell types and circuits. Best-in-class vectors were curated for accessing major striatal neuron populations including medium spiny neurons (MSNs), direct and indirect pathway MSNs, as well as Sst-Chodl, Pvalb-Pthlh, and cholinergic interneurons. Specificity was evaluated by multiple modes of molecular validation, three different routes of virus delivery, and with diverse transgene cargos. Importantly, we provide detailed information necessary to achieve reliable cell type specific labeling under different experimental contexts. We demonstrate direct pathway circuit-selective optogenetic perturbation of behavior and multiplex labeling of striatal interneuron types for targeted analysis of cellular features. Lastly, we show conserved in vivo activity for exemplary MSN enhancers in rat and macaque. This collection of striatal enhancer AAVs offers greater versatility compared to available transgenic lines and can readily be applied for cell type and circuit studies in diverse mammalian species beyond the mouse model., Competing Interests: Declaration of interests Authors JTT, BPL, EL, TLD, BTa, HZ, JKM are co-inventors on patent application PCT/US2021/45995 Artificial expression constructs for selectively modulating gene expression in striatal neurons. Authors JTT, BPL, TLD, BTa, TEB are co-inventors on provisional patent application US 63/582,759 Artificial expression constructs for modulating gene expression in the basal ganglia. HZ – is on the Scientific Advisory Board of MapLight Therapeutics, Palo Alto, CA

Identifying cell type-specific enhancers in the brain is critical to building genetic tools for investigating the mammalian brain. Computational methods for functional enhancer prediction have been proposed and validated in the fruit fly and not yet the mammalian brain. We organized the 'Brain Initiative Cell Census Network (BICCN) Challenge: Predicting Functional Cell Type-Specific Enhancers from Cross-Species Multi-Omics' to assess machine learning and feature-based methods designed to nominate enhancer DNA sequences to target cell types in the mouse cortex. Methods were evaluated based on in vivo validation data from hundreds of cortical cell type-specific enhancers that were previously packaged into individual AAV vectors and retro-orbitally injected into mice. We find that open chromatin was a key predictor of functional enhancers, and sequence models improved prediction of non-functional enhancers that can be deprioritized as opposed to pursued for in vivo testing. Sequence models also identified cell type-specific transcription factor codes that can guide designs of in silico enhancers. This community challenge establishes a benchmark for enhancer prioritization algorithms and reveals computational approaches and molecular information that are crucial for the identification of functional enhancers for mammalian cortical cell types. The results of this challenge bring us closer to understanding the complex gene regulatory landscape of the mammalian brain and help us design more efficient genetic tools and potential gene therapies for human neurological diseases., Competing Interests: Declaration of interests: None declared.

Objective: Postbariatric hypoglycemia affects >50% of individuals who have undergone Roux-en-Y gastric bypass surgery. Despite the often debilitating nature of this complication, existing treatment options are limited and often inefficient. Dasiglucagon is a stable glucagon analog available in a ready-to-use formulation and was recently shown to mitigate postbariatric hypoglycemia in experimental settings. Here, we aimed to evaluate the hypoglycemic hindering potential of dasiglucagon in an outpatient trial., Research Design and Methods: We conducted a randomized, double-blind, placebo-controlled, crossover, proof-of-concept study at the Center for Clinical Metabolic Research at Gentofte Hospital in Denmark. The study included 24 individuals who had undergone Roux-en-Y gastric bypass surgery (n = 23 women) with continuous glucose monitor-verified postbariatric hypoglycemia (≥15 min at <3.9 mmol/L three or more times per week) randomly assigned to two treatment periods of 4 weeks of self-administered subcutaneous dasiglucagon at 120 μg or placebo. The primary and key secondary outcomes were continuous glucose monitor-captured percentage of time in level 1 and 2 hypoglycemia (<3.9 and <3.0 mmol/L), respectively., Results: Compared with placebo, treatment with dasiglucagon significantly reduced time in level 1 hypoglycemia by 33% (-1.2 percentage points; 95% CI -2.0 to -0.5; P = 0.002) and time in level 2 hypoglycemia by 54% (-0.4 percentage points; 95% CI -0.6 to -0.2; P < 0.0001). Furthermore, dasiglucagon corrected hypoglycemia within 15 min in 401 of 412 self-administrations, compared with 104 of 357 placebo self-administrations (97.3% vs. 29.1% correction of hypoglycemia rate; P < 0.001). Dasiglucagon was generally well tolerated, with mostly mild to moderate adverse events of nausea., Conclusions: Compared with placebo, 4 weeks of self-administered dasiglucagon effectively reduced clinically relevant hypoglycemia in individuals who had undergone Roux-en-Y gastric bypass surgery., (© 2023 by the American Diabetes Association.)

In type 1 diabetes, average life expectancy is reduced by ˃10 years as compared with outside of diabetes. Residual cardiovascular risk defines high cardiovascular event rate despite modern, guideline-recommended standard of care of established risk factors like hypertension, dyslipidaemia, and glycaemic control, and it adds importantly to these lost years of life in type 1 diabetes due to atherosclerotic cardiovascular diseases like myocardial infarction and ischaemic stroke. With a growing understanding of inflammation as an important driver of atherosclerotic cardiovascular disease, residual inflammatory risk is a novel and common risk factor and a promising target for lowering residual cardiovascular risk in type 1 diabetes. Interestingly, the inexpensive anti-inflammatory agent colchicine reduced the risk of major adverse cardiovascular events by 25% in cardiovascular outcome trials in the secondary prevention of atherosclerotic cardiovascular disease. Here, we summarize the role of inflammation as a driver of atherosclerosis and review current evidence linking inflammation and atherosclerotic cardiovascular disease in type 1 diabetes. Also, we provide an overview of the evidence base for targeting residual inflammatory risk with colchicine for lowering residual cardiovascular risk in type 1 diabetes., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aim: To evaluate the efficacy of the short-acting glucagon-like peptide-1 receptor agonist, exenatide, added to insulin therapy in type 1 diabetes on bone mineral density and bone turnover markers., Materials and Methods: In a randomized, double-blinded, parallel-group trial, 108 individuals with type 1 diabetes aged 18 years or older on basal-bolus therapy with HbA1c 59-88 mmol/mol (7.5%-10.0%) and body mass index of more than 22.0 kg/m 2 were randomized (1:1) to preprandial subcutaneous injection of 10 μg exenatide (Byetta) before breakfast, lunch, and dinner over 26 weeks as add-on treatment to insulin therapy., Results: Exenatide elicited a body weight reduction of 4.4 kg compared with placebo, but no between-group differences in bone mineral density, as assessed by whole-body, hip, lumbar, and forearm dual-energy X-ray absorptiometry following 26 weeks of treatment, were observed. Fasting plasma levels of C-terminal telopeptides of type I collagen, a marker of bone resorption, and amino-terminal propeptide of type I procollagen, a marker of bone formation, were unchanged by exenatide compared with placebo after 26 weeks., Conclusions: Despite an exenatide-induced body weight reduction, no changes in bone metabolism were observed with exenatide added to insulin therapy in type 1 diabetes after 26 weeks., (© 2021 John Wiley & Sons Ltd.)

Aims: To investigate the effect of adding the short-acting glucagon-like peptide 1 receptor agonist (GLP-1RA) exenatide to insulin treatment on markers of cardiovascular risk in type 1 diabetes., Materials and Methods: In a randomized, double-blind, parallel-group trial, 108 individuals with type 1 diabetes aged ≥18 years on multiple daily injection therapy with a body mass index >22.0 kg/m 2 and glycated haemoglobin concentration of 59 to 88 mmol/mol (7.5%-10.0%) were randomized (1:1) to preprandial subcutaneous injection of 10 μg exenatide (Byetta®) or placebo three times daily over 26 weeks as add-on treatment to existing insulin therapy. Reported markers of cardiovascular risk were secondary endpoints and were analyzed in a baseline-adjusted linear mixed model in the intention-to-treat population. The primary results of this study, the MAG1C (Meal-time Administration of exenatide for Glycaemic control in type 1 diabetes Cases) trial, were previously reported., Results: Exenatide changed total fat mass by -2.6 kg (95% confidence interval [CI] -3.6; -1.6; P < 0.0001) and lean body mass by -1.1 kg (95% CI -1.9; -0.4; P = 0.01) compared with placebo, as assessed by dual-energy X-ray absorptiometry. Fat mass reductions were similar for central and peripheral fat mass. Exenatide did not change levels of interleukin-2 or -6; tumour necrosis factor-α; C-reactive protein; N-terminal prohormone of brain natriuretic peptide; or 8-oxo-7,8-dihydroguanosine (RNA oxidation marker) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (DNA oxidation marker)., Conclusions: Exenatide added to insulin therapy in type 1 diabetes for 26 weeks resulted in body weight loss primarily from fat mass reduction, but had no effect on biomarkers of cardiovascular disease risk., (© 2020 John Wiley & Sons Ltd.)

Background: In type 2 diabetes, long-acting GLP-1 receptor agonists lower fasting plasma glucose and improve glycaemic control via their insulinotropic and glucagonostatic effects. In type 1 diabetes, their efficacy as an add-on treatment to insulin therapy is modest. Short-acting GLP-1 receptor agonists also lower postprandial glucose excursions in type 2 diabetes by decelerating gastric emptying rate. We aimed to test the efficacy of a short-acting GLP-1 receptor agonist in type 1 diabetes., Methods: In the single-centre, parallel-group, randomised, double-blind, placebo-controlled MAG1C trial, patients with type 1 diabetes on multiple daily injection therapy aged 18 years and older with HbA 1c 59-88 mmol/mol (7·5-10·0%) and a BMI of more than 22·0 kg/m 2 were randomly assigned (1:1) through a computer-generated randomisation list to preprandial subcutaneous injection of 10 μg exenatide (Byetta) or placebo three times daily for 26 weeks as an add-on treatment to usual insulin therapy. Clinically assessed insulin titration was done by study staff. Participants and investigators were masked to treatment allocation. The primary endpoint was between-group difference in HbA 1c after 26 weeks. Data were analysed with a baseline-adjusted linear mixed model in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03017352, and is completed., Findings: Between Jan 4, 2017, and Jan 16, 2019, 108 participants were randomly assigned, 54 to exenatide and 54 to placebo; 23 participants discontinued treatment (17 in the exenatide group and six in the placebo group). From a baseline-adjusted mean of 66·4 mmol/mol (95% CI 64·9-67·8 [8·2%, 8·1-8·4]), HbA 1c changed by -3·2 mmol/mol (-5·0 to -1·4 [-0·3%, -0·5 to -0·1]) with exenatide and -2·1 mmol/mol (-3·7 to -0·6 [-0·2%, -0·3 to -0·1]) with placebo after 26 weeks (estimated treatment difference of -1·1 mmol/mol (-3·4 to 1·2 [-0·1%, -0·3 to 0·1]; p=0·36). Exenatide increased the number of self-reported gastrointestinal adverse events (primarily nausea [48 events among 37 patients with exenatide, nine with placebo among 9 patients]). Two serious adverse events occurred in the exenatide group, and six occurred in the placebo group (none were considered to be related to the study drug)., Interpretation: Short-acting exenatide does not seem to have a future as a standard add-on treatment to insulin therapy in type 1 diabetes., Funding: AstraZeneca., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: There are significant geographic inequalities in cancer survival with poorer survival rates in non-metropolitan areas compared to major cities. Physical activity (PA) can reduce cancer recurrence and prevent cardiovascular disease. However, few survivors participate in sufficient PA and the prevalence of inactivity is significantly higher in non-metropolitan survivors. The study investigated non-metropolitan survivors' recollections regarding PA advice received following cessation of active treatment, their knowledge of PA guidelines, and the factors that impact on PA behaviour change., Method: Sixteen individuals (14 women and 2 men) with breast (n = 8), endometrial (n = 4) or colorectal cancer (n = 4), with a mean age of 60 years (SD = 12) completed semi-structured interviews as part of a larger study to examine the acceptability and utility of wearable trackers to increase PA. Interviews explored survivors' recollections regarding the advice they received concerning PA following active treatment, knowledge of PA guidelines for cancer survivors and the influences on PA behaviour change. Interview transcripts were analysed using thematic analysis., Results: Four main themes emerged: (i) insufficient knowledge of guidelines, (ii) support from the treating oncology team, (iii) external accountability, and (iv) barriers to PA., Conclusions: Survivors' knowledge of PA guidelines was limited and they did not often recall their oncologists making specific recommendations concerning PA. Survivors' referred to the desire for accountability and monitoring in order to successfully change PA. Lack of motivation was the main barrier to PA participation. Other barriers included age, health status, and lack of facilities or exercise programs.

Introduction: Exenatide once weekly (QW) is a glucagon-like peptide 1 receptor agonist (GLP-1RA) that was approved in 2012 in Europe and the U.S.A. for the treatment of type 2 diabetes (T2D). Areas covered: This review provides an overview of the safety and efficacy of exenatide QW for the treatment of T2D and evaluates the benefit-risk ratio compared to other available long-acting GLP-1RAs. In addition, the authors provide an outline of the novel formulations and delivery methods of exenatide. Expert opinion: Exenatide QW is an efficacious and safe treatment for T2D. However, head-to-head trials have demonstrated exenatide QW to be inferior to liraglutide and semaglutide with respect to effects on fasting plasma glucose, glycated hemoglobin A1c, and bodyweight. In addition, exenatide QW appears inferior to liraglutide and semaglutide in terms of cardiovascular risk reduction. Currently, the overall risk-benefit profiles for the range of GLP-1RAs point to liraglutide and semaglutide as first-choice for the management of T2D, which has been confirmed by a recently published consensus report on the treatment of T2D from the American Diabetes Association and the European Association for the Study of Diabetes. The pricing of exenatide QW will most likely be a key determinant for its place in the future management of T2D.

Purpose: The study purpose was to investigate the acceptability and utility of, and preference for, wearable activity trackers (WATs) amongst cancer survivors living in regional and remote areas of Western Australia., Methods: Twenty participants were recruited (Mean age = 63 years, SD = 13) to test two to three trackers from five available models (Fitbit Alta, Garmin Vivofit 2, Garmin Vivosmart, Polar loop 2 and Polar A300). Participants wore each device for two weeks, followed by a one-week washout period between devices. Interviews were conducted with participants to explore user perceptions and experiences. Interview transcripts were analysed using thematic analysis., Results: Four main themes emerged: (i) Consciousness raising; (ii) Prompts and Feedback; (iii) Accuracy and registry of activities; and, (iv) WAT preferences and features., Conclusions: WATs were acceptable and useful to cancer survivors. WATs increased self-awareness of physical activity, provided real time feedback in relation to step goals, and reinforced progress and efforts towards goals. The aesthetics of the WATs were deemed crucial in determining preference and likelihood of use., Implications for Cancer Survivors: Future interventions may do well to have two different WATs available for participants to choose from, according to activity preferences, aesthetic preferences, and display size., Competing Interests: The authors have declared that no competing interests exist.

Patients with chronic obstructive pulmonary disease (COPD) are at risk of developing osteoporosis, as the COPD in itself as well as continued smoking and treatment with systemic corticosteroid all increase the risk of developing osteoporosis. Other risk factors for osteoporosis are low vitamin D levels, malnutrition and physical inactivity. All patients who have risk factors in the form of severe COPD, and all patients with COPD in active treatment with systemic corticosteroid and/or other risk factors should be examined with a DEXA-scan. Treatment of osteoporosis in patients with COPD does not differ from general recommendations.

Introduction: Persons with type 1 diabetes require intensive insulin therapy to achieve glycaemic control, but side effects, including hypoglycaemia and weight gain, may reduce treatment compliance. We hypothesise that add-on treatment of the short-acting glucagon-like peptide-1 receptor agonist, exenatide, to insulin therapy in persons with type 1 diabetes will reduce insulin requirements, glycaemic excursions and body weight and improve glycaemic control without increasing the risk of hypoglycaemia. The present article describes a protocol developed to test this hypothesis., Methods and Analysis: One-hundred adult persons with type 1 diabetes for more than 1 year, insufficient glycaemic control (glycated haemoglobin A1c (HbA1c) between 58 and 86 mmol/mol) and body mass index >22.0 kg/m 2 will be randomised to either exenatide 10 µg three times per day (at meal times) or placebo as add-on therapy to regular basal-bolus insulin treatment for 26 weeks. Primary endpoint is change in HbA1c between the two groups at end of treatment. Secondary endpoints include change in glycaemic excursions (assessed by continuous glucose monitoring); insulin dose; hypoglycaemic and adverse events; body weight, lean body and fat mass; dietary patterns; quality of life and treatment satisfaction; cardiovascular-disease risk profile; metabolomics; and arginine-tested plasma glucose, glucagon and C-peptide levels., Ethics and Dissemination: The study is approved by the Danish Medicines Agency, the Regional Scientific Ethics Committee of the Capital Region of Denmark and the Data Protection Agency. The study will be carried out under the surveillance and guidance of the good clinical practice (GCP) unit at Copenhagen University Hospital Bispebjerg in accordance with the ICH-GCP guidelines and the Helsinki Declaration. Positive, negative as well as inconclusive results will be sought disseminated at scientific meetings and in international peer-reviewed scientific journals., Trial Registration Number: NCT03017352., Competing Interests: Competing interests: NJJ and TV have no competing interests. TFD has received research support from Novo Nordisk and AstraZeneca, and has received lecture fees from Novo Nordisk. AL has received lecture fees from Novo Nordisk, Boehringer Ingelheim and Eli Lilly. HUA owns stocks in Novo Nordisk and serves in advisory boards for Novo Nordisk and Astra Zeneca. FKK has served on scientific advisory panels and/or speaker’s bureaus for, served as a consultant to and/or received research support from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Gubra, MSD/Merck, Novo Nordisk, Sanofi and Zealand Pharma., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

A large overdose of insulin is a serious health matter. Information concerning administration and duration of intravenous (IV) glucose, other treatment options or complications besides hypoglycaemia following large insulin overdoses is not readily apparent from the literature. A systematic search, compilation and review of case reports on insulin overdoses, published 1986-2017, was performed in PubMed, EMBASE, Cochrane and PROSPERO databases. Of 1523 published articles, 45 cases of insulin overdoses were included with a total median insulin dose of 900 international units (IU) (range 26-4800 IU). Hospitalization occurred in 44 cases with a median hospitalization duration of 94 hr (range 12-721 hr), and one-third (n = 15) admitted to the intensive care unit. First-line treatment was IV glucose treatment in 95% of cases. Treatment options besides IV glucose that were reported beneficial included glucagon IV or intramuscular (IM), octreotide IV or IM, surgical excision, hydrocortisone IV and oral intake of complex carbohydrates. Prevalent complications were intermittent cerebral impairment (73%), hypokalaemia (49%), other electrolyte disturbances (42%), and hepatic disturbances (7%) and cardiac toxicity (e.g. cardiac arrhythmia) (9%). Long-term consequences were one case of lasting hypoglycaemic encephalopathy and one death. In conclusion, following large insulin overdoses, in-hospital admission and treatment with IV glucose may be needed for up to a week. Monitoring of electrolytes and hepatic and cardiac functions seems important. Several experimental treatment options may be considered in addition to glucose administration. With appropriate pre- and in-hospital treatment, cases with severe hypoglycaemia and neurologic complications may have a favourable outcome., (© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Cellular-scale imaging of the mechanical properties of tissue has helped to reveal the origins of disease; however, cellular-scale resolution is not readily achievable in intact tissue volumes. Here, we demonstrate volumetric imaging of Young's modulus using ultrahigh-resolution optical coherence elastography, and apply it to characterizing the stiffness of mouse aortas. We achieve isotropic resolution of better than 15 μm over a 1-mm lateral field of view through the entire depth of an intact aortic wall. We employ a method of quasi-static compression elastography that measures volumetric axial strain and uses a compliant, transparent layer to measure surface axial stress. This combination is used to estimate Young's modulus throughout the volume. We demonstrate differentiation by stiffness of individual elastic lamellae and vascular smooth muscle. We observe stiffening of the aorta in regulator of G protein signaling 5-deficient mice, a model that is linked to vascular remodeling and fibrosis. We observe increased stiffness with proximity to the heart, as well as regions with micro-structural and micro-mechanical signatures characteristic of fibrous and lipid-rich tissue. High-resolution imaging of Young's modulus with optical coherence elastography may become an important tool in vascular biology and in other fields concerned with understanding the role of mechanics within the complex three-dimensional architecture of tissue., (Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Globally, an increasing and aging population is contributing to the prevalence of cancer. To be effective, cancer care needs to involve the coordination of multidisciplinary specialties, and also needs to be affordable, accessible, and capable of producing optimal patient outcomes. Porter and Teisberg (2006) have postulated that shifting current healthcare strategies from volume-based to patient-centric care redirects economic competition to providing treatments which promote the best patient outcomes while driving down costs. Therefore, the value in value-based healthcare (VBH) is defined as patient outcome per currency spent on providing care. Based on the experiences of healthcare organizations currently transitioning to the value-based system, this review details actionable guidelines to transition current cancer care practices to the value-based system in four main steps: by defining universal clinical and patient-reported measures, creating cancer-specific units that provide the full care cycle, establishing a data capture model to routinely determine the value of the care delivered, and continually improving treatment strategies through research. As healthcare providers in more developed countries move to value-based care, those located in less developed countries should also be assisted in their transition to relieve the cancer burden globally., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Nosocomial pneumonia in relation to tracheotomy is a well-known complication. The aim of the present study was to study prophylactic antibiotics at the time of tracheotomy as a protective factor against nosocomial pneumonia., Methods: A retrospective follow-up study was conducted on otorhinolaryngeal cancer patients requiring a surgical tracheotomy over a four-year period. Data were extracted from a digital record system. The inclusion criteria included a cancer diagnosis in the otorhinolaryngeal area; and the tracheotomy had to be the primary operation. A total of 88 patients were eligible for inclusion, forming a group without antibiotics (n = 53) treatment and a group with antibiotics (n = 35) treatment., Results: In the group without antibiotics, 67% (n = 34) developed pneumonia (not including aspirational) versus 44% (n = 14) in the group with antibiotics (p = 0.04). The 30-day mortality was 10% (n = 9), and the one-year mortality was 58% (n = 42) for the total population, with no statistically significant differences between the groups. Pneumonia after tracheotomy prolonged the hospitalisation time regardless of grouping. In the group without antibiotics, the median was seven days for patients without pneumonia compared with 12.5 days for patients with pneumonia (p < 0.01). Within the group with antibiotics, the median was ten days for the patients without pneumonia versus 16 days for those with pneumonia (p = 0.02)., Conclusion: The present study indicates that prophylactic antibiotics administration at the time of tracheotomy lowers the incidence of pneumonia in otorhinolaryngeal cancer patients., Funding: not relevant., Trial Registration: not relevant.

A common characteristic of axonopathy is the abnormal accumulation of cytoskeletal proteins. We recently reported that streptozotocin (STZ)-induced type 1 diabetes produced a change in the morphology of sympathetic nerve fibers supplying rat plantar metatarsal arteries (PMAs). Here we investigated whether these morphological changes are associated with axonal accumulation of the type III intermediate filament peripherin and the microtubule protein β-tubulin III, as both are implicated in axonal remodeling. PMAs from hyperglycemic STZ-treated rats receiving a low dose of insulin (STZ-LI) were compared with those from normoglycemic STZ-treated rats receiving a high dose of insulin (STZ-HI) and vehicle-treated controls. Western blotting revealed an increase in protein expression level for peripherin in PMAs from STZ-LI rats but no change in that for β-tubulin III. In addition, there was an increase in the number of peripherin immunoreactive nerve fibers in the perivascular nerve plexus of PMAs from STZ-LI rats. Co-labeling for peripherin and neuropeptide Y (a marker for sympathetic axons) revealed that peripherin immunoreactivity increased in sympathetic axons. None of these changes were detected in PMAs from STZ-HI rats, indicating that increased peripherin in sympathetic axons of STZ-LI rats is likely due to hyperglycemia and provides a marker of diabetes-induced nerve damage.

In humans neural control of arterial vessels supplying skin in the extremities is particularly vulnerable to the effects of diabetes. Here the streptozotocin (STZ) rat model of type 1 diabetes was used to compare effects on neurovascular function in plantar metatarsal arteries (PMAs), which supply blood to skin of hind paw digits, with those in mesenteric arteries (MAs). Twelve weeks after STZ (60 mg/kg ip), wire myography was used to assess vascular function. In PMAs, lumen dimensions were unchanged but both nerve-evoked contractions and sensitivity to α(1) (phenylephrine, methoxamine)- and α(2) (clonidine)-adrenoceptor agonists were reduced. The density of perivascular nerve fibers was also reduced by ~25%. These changes were not observed in PMAs from STZ-treated rats receiving either a low dose of insulin that did not greatly reduce blood glucose levels or a high dose of insulin that markedly reduced blood glucose levels. In MAs from STZ-treated rats, nerve-evoked increases in force did not differ from control but, because lumen dimensions were ~20% larger, nerve-evoked increases in effective transmural pressure were smaller. Increases in effective transmural pressure produced by phenylephrine or α,β-methylene ATP in MAs from STZ-treated rats were not smaller than control, but the density of perivascular nerve fibers was reduced by ~10%. In MAs, the increase in vascular dimensions is primarily responsible for reducing effectiveness of nerve-evoked constrictions. By contrast, in PMAs decreases in both the density of perivascular nerve fibers and the reactivity of the vascular muscle appear to explain impairment of neurovascular transmission.

Despite reduced sympathetic activity below the level of a spinal cord injury (SCI), venoconstriction during autonomic dysreflexia increases venous return to the heart. Here, contractions of isometrically mounted tail veins from rats with spinal transection at T4 performed 8 - 10 weeks earlier are compared with those from sham-operated rats. After SCI, lumen diameter was reduced by ∼30% and the contractions evoked by electrical stimulation of the perivascular axons were larger than control. This augmentation of neurovascular transmission was not associated with enhanced sensitivity to α-adrenoceptor agonists or to adenosine-5'-triphosphate (ATP) although contractions to depolarization with K(+) were larger after SCI. The percentage reduction in nerve-evoked contraction after SCI produced by the α(1)-adrenoceptor antagonist prazosin (10 nM) was unchanged but that by the α(2)-adrenoceptor antagonist rauwolscine (0.1 μM) was reduced. The relative contribution of P2-purinoceptors to nerve-evoked contractions after α-adrenoceptor blockade, revealed by adding suramin (0.1 mM), was unchanged. The greater depolarization-induced contraction and the reduced contribution of α(2)-adrenoceptors to nerve-evoked contraction suggest that changes in the venous smooth muscle underlie the potentiation of neurovascular transmission after SCI. Furthermore, the smaller lumen diameter after SCI will increase the pressure that the veins exert on the luminal contents when they are neurally activated.