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Skeletal muscle haemodynamics and circulating adenosine triphosphate (ATP) responses during hypoxia and exercise are blunted in older (OA) vs. young (YA) adults, which may be associated with impaired red blood cell (RBC) ATP release. Rho-kinase inhibition improves deoxygenation-induced ATP release from OA isolated RBCs. We tested the hypothesis that Rho-kinase inhibition (via fasudil) in vivo would improve local haemodynamic and ATP responses during hypoxia and exercise in OA. Healthy YA (25 ± 3 years; n = 12) and OA (65 ± 5 years; n = 13) participated in a randomized, double-blind, placebo-controlled, crossover study on two days (≥5 days between visits). A forearm deep venous catheter was used to administer saline/fasudil and sample venous plasma ATP ([ATP]

Metformin has been associated with modest weight reduction in the non-pregnant population. Our hypothesis is that metformin exposure will lead to a higher incidence of appropriate weight gain during pregnancy.This was a retrospective cohort study in a single center between 2009 and 2019. We included all pregnant women with type 2 diabetes or prediabetes. We compared women exposed to metformin in any trimester. The primary outcome was appropriate weight gain defined by the Institute of Medicine guidelines. Secondary outcomes included excessive weight gain, weight loss, suspected fetal growth restriction (FGR), and mean birth weight. Adjusted odds ratios or group differences were calculated using logistic or linear regression, controlling for confounders.Of 41,472 deliveries during the study period, 511 pregnancies met inclusion criteria. 284 pregnancies had no metformin exposure; 227 did have metformin exposure, of which 169 (72.2%) were initiated on metformin in the first trimester. Women exposed to metformin in any trimester were statistically not more likely to have appropriate weight gain (aOR 1.53 (95% CI 1.00-2.34,Metformin exposure in pregnancy was associated with less excess weight gain and a higher rate of weight loss. There was no difference in FGR or mean birth weight in metformin exposed neonates. This suggests that metformin may help avoid excess weight gain and its associated comorbidities.

Many institutions implemented policy changes to protect patients and clinicians during the COVID-19 pandemic. This study examines how institutional policy changes and patient behaviors affected perinatal outcomes. We hypothesized that obstetric practice changes occurred and that these changes affected perinatal outcomes.We conducted a retrospective cohort study of singleton pregnancies delivered at a single institution with low incidence of COVID-19. Deliveries occurring from December 15, 2019 through March 14, 2020 were designated as the pre-COVID-19 group. Those occurring from March 15, 2020, through June 15, 2020, were designated the COVID-19 group. The primary outcome is a perinatal composite defined as delivery ≥ 41 weeks, hypertensive disorder of pregnancy at term, unplanned Cesarean delivery, term neonatal intensive care unit admission, 42-day maternal readmission, and 7-day neonatal readmission. Additional maternal, neonatal, and delivery composites also were analyzed, and we evaluated all individual outcomes secondarily.Of 2,268 deliveries, 1,210 occurred during the COVID-19 period. Four of the 1,210 (0.3%) were diagnosed with COVID-19. Women during the COVID-19 period were more likely to present in spontaneous labor and less likely to undergo induction. Maternal and neonatal length of stay was also shorter. There was no difference in the perinatal composite between the 2 groups (36.3% vs 36.7% [OR 1.05; 95% CI, 0.86-1.21]). There was a significant increase in deliveries occurring at or after 41 weeks (4.7% vs 6.9% [OR 1.83; 95% CI, 1.00-3.34]). There was no difference in maternal, neonatal, and delivery composites or the outcomes assessed individually.We demonstrated significant changes in clinical practice secondary to policy changes and patient behaviors during the COVID-19 pandemic. As an institution that globally adopted ARRIVE (A Randomized Trial of Induction Versus Expectant Management) practices, we noted fewer inductions, more women presenting in labor and more women delivering at or after 41 weeks. We also noted a shorter length of hospital stay for the mother-baby dyad. Overall, these changes in clinical practice did not affect perinatal outcomes.

The vascular endothelium senses and integrates numerous inputs to regulate vascular tone. Recent evidence reveals complex signal processing within the endothelium, yet little is known about how endothelium-dependent stimuli interact to regulate blood flow. We tested the hypothesis that combined stimulation of the endothelium with adenosine triphosphate (ATP) and acetylcholine (ACh) elicits greater vasodilation and attenuates α(1)-adrenergic vasoconstriction compared with combination of ATP or ACh with the endothelium-independent dilator sodium nitroprusside (SNP). We assessed forearm vascular conductance (FVC) in young adults (6 women, 7 men) during local intra-arterial infusion of ATP, ACh, or SNP alone and in the following combinations: ATP + ACh, SNP + ACh, and ATP + SNP, wherein the second dilator was coinfused after attaining steady state with the first dilator. By design, each dilator evoked a similar response when infused separately (ΔFVC, ATP: 48 ± 4; ACh: 57 ± 6; SNP: 53 ± 6 mL·min(−1)·100 mmHg(−1); P ≥ 0.62). Combined infusion of the endothelium-dependent dilators evoked greater vasodilation than combination of either dilator with SNP (ΔFVC from first dilator, ATP + ACh: 45 ± 9 vs. SNP + ACh: 18 ± 7 and ATP + SNP: 26 ± 4 mL·min(−1)·100 mmHg(−1), P < 0.05). Phenylephrine was subsequently infused to evaluate α(1)-adrenergic vasoconstriction. Phenylephrine elicited less vasoconstriction during infusion of ATP or ACh versus SNP (ΔFVC, −25 ± 3 and −29 ± 4 vs. −48 ± 3%; P < 0.05). The vasoconstrictor response to phenylephrine was further diminished during combined infusion of ATP + ACh (−13 ± 3%; P < 0.05 vs. ATP or ACh alone) and was less than that observed when either dilator was combined with SNP (SNP + ACh: −26 ± 3%; ATP + SNP: −31 ± 4%; both P < 0.05 vs. ATP + ACh). We conclude that endothelium-dependent agonists interact to elicit vasodilation and limit α(1)-adrenergic vasoconstriction in humans. NEW & NOTEWORTHY The results of this study highlight the vascular endothelium as a critical site for integration of vasomotor signals in humans. To our knowledge, this is the first study to demonstrate that combined stimulation of the endothelium with ATP and ACh results in enhanced vasodilation compared with combination of either ATP or ACh with an endothelium-independent dilator. Furthermore, we show that ATP and ACh interact to modulate α(1)-adrenergic vasoconstriction in human skeletal muscle in vivo.

Albert algebras, a specific kind of Jordan algebra, are naturally distinguished objects among commutative non-associative algebras and also arise naturally in the context of simple affine group schemes of type $F_4$, $E_6$, or $E_7$. We study these objects over an arbitrary base ring $R$, with particular attention to the case of the integers. We prove in this generality results previously in the literature in the special case where $R$ is a field of characteristic different from 2 and 3., v2: section 12 on number of generators is new, Theorem 13.5 now holds for semi-local rings (and even a somewhat wider class)

KEY POINTS During exercise, blood flow to working skeletal muscle increases in parallel with contractile activity such that oxygen delivery is sufficient to meet metabolic demand. K+ released from active skeletal muscle fibres could facilitate vasodilatation in proportion to the degree of muscle fibre recruitment. Once released, K+ stimulates inwardly rectifying K+ (KIR ) channels on the vasculature to elicit an increase in blood flow. In the present study, we demonstrate that KIR channels mediate the rapid vasodilatory response to an increase in exercise intensity. We also show that KIR channels augment vasodilatation during exercise which demands greater muscle fibre recruitment independent of the total amount of work performed. These results suggest that K+ plays a key role in coupling the magnitude of vasodilatation to the degree of contractile activity. Ultimately, the findings from this study help us understand the signalling mechanisms that regulate muscle blood flow in humans. ABSTRACT Blood flow to active skeletal muscle is augmented with greater muscle fibre recruitment. We tested whether activation of inwardly rectifying potassium (KIR ) channels underlies vasodilatation with elevated muscle fibre recruitment when work rate is increased (Protocol 1) or held constant (Protocol 2). We assessed forearm vascular conductance (FVC) during rhythmic handgrip exercise under control conditions and during local inhibition of KIR channels (intra-arterial BaCl2 ). In Protocol 1, healthy volunteers performed mild handgrip exercise for 3 min, then transitioned to moderate intensity for 30 s. BaCl2 eliminated vasodilatation during the first contraction at the moderate workload (ΔFVC, BaCl2 : -1 ± 17 vs. control: 30 ± 28 ml min-1 100 mmHg-1 ; n = 9; P = 0.004) and attenuated the 30 s area under the curve by 56 ± 14% (n = 9; P

KEY POINTS The ability of contracting skeletal muscle to attenuate sympathetic vasoconstriction (functional sympatholysis) is critical for maintaining blood flow during exercise-mediated sympathoexcitation. Functional sympatholysis and endothelial function are impaired with ageing, resulting in compromised blood flow and oxygen delivery to contracting skeletal muscle during exercise. In the present study, intra-arterial infusion of ACh or ATP to augment endothelium-dependent signalling during exercise attenuated α1 -adrenergic vasoconstriction in the contracting muscle of older adults. The vascular signalling mechanisms capable of functional sympatholysis are preserved in healthy ageing, and thus the age-related impairment in functional sympatholysis probably results from the loss of a functional signal (e.g. plasma [ATP]) as opposed to an intrinsic endothelial dysfunction. ABSTRACT The ability of contracting skeletal muscle to attenuate sympathetic α-adrenergic vasoconstriction ('functional sympatholysis') is impaired with age. In young adults, increasing endothelium-dependent vasodilatory signalling during mild exercise augments sympatholysis. In the present study, we tested the hypothesis that increasing endothelium-dependent signalling during exercise in older adults can improve sympatholysis. In 16 older individuals (Protocol 1, n = 8; Protocol 2, n = 8), we measured forearm blood flow (Doppler ultrasound) and calculated changes in vascular conductance (FVC) to local intra-arterial infusion of phenylephrine (PE; α1 -agonist) during (i) infusion of an endothelium-dependent vasodilator alone (Protocol 1: ACh or Protocol 2: low dose ATP); (ii) mild handgrip exercise (5% maximum voluntary contraction; MVC); (iii) moderate handgrip exercise (15% MVC); and (iv) mild or moderate handgrip exercise + infusion of ACh or ATP to augment endothelium-dependent signalling. PE caused robust vasoconstriction in resting skeletal muscle during control vasodilator infusions (ΔFVC: ACh: -31 ± 3 and ATP: -30 ± 4%). PE-mediated vasoconstriction was not attenuated by mild or moderate intensity exercise (ΔFVC: 5% MVC: -30 ± 9; 15% MVC: -33 ± 8%; P > 0.05 vs. control ACh and ATP), indicative of impaired sympatholysis, and ACh or ATP infusion during mild exercise did not impact this response. However, augmentation of endothelium-dependent signalling via infusion of ACh or ATP during moderate intensity exercise attenuated PE-mediated vasoconstriction (ΔFVC: -13 ± 1 and -19 ± 5%, respectively; P

KEY POINTS In humans, the vasodilatory response to skeletal muscle contraction is mediated in part by activation of inwardly rectifying potassium (KIR ) channels. Evidence from animal models suggest that KIR channels serve as electrical amplifiers of endothelium-dependent hyperpolarization (EDH). We found that skeletal muscle contraction amplifies vasodilatation to the endothelium-dependent agonist ACh, whereas there was no change in the vasodilatory response to sodium nitroprusside, an endothelium-independent nitric oxide donor. Blockade of KIR channels reduced the exercise-induced amplification of ACh-mediated vasodilatation. Conversely, pharmacological activation of KIR channels in quiescent muscle via intra-arterial infusion of KCl independently amplified the vasodilatory response to ACh. This study is the first in humans to demonstrate that specific endothelium-dependent vasodilatory signalling is amplified in the vasculature of contracting skeletal muscle and that KIR channels may serve as amplifiers of EDH-like vasodilatory signalling in humans. ABSTRACT The local vasodilatory response to muscle contraction is due in part to the activation of inwardly rectifying potassium (KIR ) channels. Evidence from animal models suggest that KIR channels function as 'amplifiers' of endothelium-dependent vasodilators. We tested the hypothesis that contracting muscle selectively amplifies endothelium-dependent vasodilatation via activation of KIR channels. We measured forearm blood flow (Doppler ultrasound) and calculated changes in vascular conductance (FVC) to local intra-arterial infusion of ACh (endothelium-dependent dilator) during resting conditions, handgrip exercise (5% maximum voluntary contraction) or sodium nitroprusside (SNP; endothelium-independent dilator) which served as a high-flow control condition (n = 7, young healthy men and women). Trials were performed before and after blockade of KIR channels via infusion of barium chloride. Exercise augmented peak ACh-mediated vasodilatation (ΔFVC saline: 117 ± 14; exercise: 236 ± 21 ml min-1 (100 mmHg)-1 ; P < 0.05), whereas SNP did not impact ACh-mediated vasodilatation. Blockade of KIR channels attenuated the exercise-induced augmentation of ACh. In eight additional subjects, SNP was administered as the experimental dilator. In contrast to ACh, exercise did not alter SNP-mediated vasodilatation (ΔFVC saline: 158 ± 35; exercise: 121 ± 22 ml min-1 (100 mmHg)-1 ; n.s.). Finally, in a subset of six subjects, direct pharmacological activation of KIR channels in quiescent muscle via infusion of KCl amplified peak ACh-mediated vasodilatation (ΔFVC saline: 97 ± 15, KCl: 142 ± 16 ml min-1 (100 mmHg)-1 ; respectively; P < 0.05). These findings indicate that skeletal muscle contractions selectively amplify endothelium-dependent vasodilatory signalling via activation of KIR channels, and this may be an important mechanism contributing to the normal vasodilatory response to exercise in humans.

The American College of Obstetrics and Gynecology (ACOG) has recommended every hospital disclose their level of maternal care (LOMC) to categorize the capabilities of their birthing center and regionalize perinatal care. Of the 98 birthing centers in Wisconsin, 44% have self-disclosed their LOMC. In many states, disclosing LOMC is mandated but, despite evidence and professional association recommendations, Wisconsin relies on voluntary self-reporting. We surveyed all birthing centers in Wisconsin to better understand the barriers to disclosing their LOMC.An anonymous survey was sent to all 98 birthing centers in Wisconsin. Survey recipients were hospital administrators, nursing supervisors, or physician directors of obstetric units. The survey sought information on perceived barriers to completing self-assessments and disclosing their hospital's LOMC. Quantitative descriptive statistics were used for data analysis.Of 98 birth centers in Wisconsin, 40 (40.8%) responded. Fifteen of the 40 responses were from birthing centers that have not yet disclosed their LOMC. Of these, 93% were unsure how to disclose, 73% found the paperwork confusing, and 80% did not have the time or staff to complete the paperwork. Respondents did not report lack of departmental support, concerns about losing business or reputation, or future physician recruitment as barriers. Of all respondents, 77.5% were aware of ACOG's LOMC recommendations, but only 35% thought disclosing their LOMC would be beneficial to maternal care.Birthing centers in Wisconsin need further guidance on how to complete a self-assessment of their LOMC. In order to increase self-disclosure of LOMC, statewide perinatal organizations will need to continue to emphasize the benefits of releasing this information. Organizations should also provide additional support to level 1 and 2 birthing centers and improve maternal and neonatal care overall.

Metformin has been found to have a role in promoting vascular remodeling and angiogenesis which may reduce the risk of developing preeclampsia. Prior studies have shown a decrease in the incidence of hypertensive disorders of pregnancy in patients with type 2 and gestational diabetes taking metformin. We hypothesize metformin exposure decreases the risk of developing hypertension in patients with type 2 diabetes.Retrospective cohort study from 2009 to 2019 of singleton pregnancies was complicated by type 2 diabetes. We compared patients who received metformin throughout pregnancy to those with no metformin exposure. The primary outcome was a hypertension composite defined as gestational hypertension, preeclampsia with or without severe features, HELLP syndrome, or eclampsia. Individual hypertensive outcomes and neonatal outcomes were secondarily evaluated. Logistic regression was used to adjust for confounding variables.A total of 254 pregnancies were included. Women exposed to metformin were significantly less likely to develop hypertension composite compared with nonexposed women (22.7 vs. 33.1%, aOR 0.53, 95% CI 0.29-0.96). The incidence of preeclampsia with severe features was also significantly lower in those who received metformin compared with those who did not (12.1 vs. 20.7%, aOR 0.38, 95% CI 0.18-0.81). There were no differences in preterm birth prior to 34 or 37 weeks, fetal growth restriction, or birth weight between the study groups. A subgroup analysis of women without chronic hypertension also had a significantly lower risk of developing preeclampsia with severe features (7.6 vs. 17.8%, aOR 0.35, 95% CI 0.13-0.94).Metformin exposure was associated with a decreased risk of composite hypertensive disorders of pregnancy in patients with pregestational type 2 diabetes. These data suggest that there may be benefit to metformin administration beyond glycemic control in this patient population.· Metformin use showed a decreased risk of a hypertension composite.. · Results were consistent in patients without chronic hypertension.. · Metformin may show benefit beyond glycemic control in women with type 2 diabetes..

PURPOSE OF REVIEW: Bone elongation is a complex process driven by multiple intrinsic (hormones, growth factors) and extrinsic (nutrition, environment) variables. Bones grow in length by endochondral ossification in cartilaginous growth plates at ends of developing long bones. This review provides an updated overview of the important factors that influence this process. RECENT FINDINGS: Insulin-like growth factor-1 (IGF-1) is the major hormone required for growth and a drug for treating pediatric skeletal disorders. Temperature is an underrecognized environmental variable that also impacts linear growth. This paper reviews the current state of knowledge regarding the interaction of IGF-1 and environmental factors on bone elongation. SUMMARY: Understanding how internal and external variables regulate bone lengthening is essential for developing and improving treatments for an array of bone elongation disorders. Future studies may benefit from understanding how these unique relationships could offer realistic new approaches for increasing bone length in different growth-limiting conditions.

Burrowing crayfishes are poorly understood animals that face conservation and management issues due to a lack of distribution and ecological data. Within Pennsylvania, the burrowing crayfish Cambarus dubius has a limited distribution and its conservation status within the state is unranked. An assessment was conducted in southwestern Pennsylvania to assess the conservation status of C. dubius throughout its historic range. GIS-landscape data was used to analyze potential predictors of presence/absence. Six historic sites and 790 new sites were sampled for the presence of C. dubius. Of the 796 sites sampled, C. dubius was collected from 61 sites. Active crayfish burrows were present at 137 additional sites; these are predicted to be those of C. dubius due to the structure of the burrows. Additional biological and ecological data on C. dubius are also provided. The global model produced from logistic regression analysis was unable to predict variables of presence/absence; suggestions for additional variables to better predict presence/absence of C. dubius are provided. Collections also yielded populations of Lacunicambarus thomai within the range of C. dubius and are the easternmost within Pennsylvania.

Preeclampsia (PE) is a pregnancy complication of abnormally elevated blood pressure and organ damage where endothelial function is impaired. Wall shear stress (WSS) strongly effects endothelial cell morphology and function but in PE the WSS values are unknown. WSS calculations from ultrasound inaccurately assume cylindrical arteries and patient specific computational fluid dynamics (CFD) typically require time-consuming 3D imaging such as CT or MRI. Two-dimensional (2D) B-mode ultrasound images were lofted together to create simplified three-dimensional (3D) geometries of the brachial artery (BA) that incorporate artery curvature and non-circular cross sections. This process was efficient and on average took 120 ± 10 s. Patient specific CFD was then performed to quantify BA WSS for a small cohort of PE (n = 5) and normotensive pregnant patients (n = 5) and compared against WSS calculations assuming a cylindrical artery. For several WSS metrics (time averaged WSS (TAWSS), peak systolic WSS, oscillatory shear index (OSI), OSI/TAWSS and relative residence time) CFD on the simplified arterial geometries calculated large spatial differences in WSS that assuming a cylindrical artery cannot calculate. Bland–Altman and intra-class correlation (ICC) analyses found assuming a cylindrical artery both underestimated (p

KEY POINTS Increasing blood flow (hyperaemia) to exercising muscle helps match oxygen delivery and metabolic demand. During exercise in hypoxia, there is a compensatory increase in muscle hyperaemia that maintains oxygen delivery and tissue oxygen consumption. Nitric oxide (NO) and prostaglandins (PGs) contribute to around half of the augmented hyperaemia during hypoxic exercise, although the contributors to the remaining response are unknown. In the present study, inhibiting NO, PGs, Na+ /K+ -ATPase and inwardly rectifying potassium (KIR ) channels did not blunt augmented hyperaemia during hypoxic exercise beyond previous observations with NO/PG block alone. Furthermore, although inhibition of only Na+ /K+ -ATPase and KIR channels abolished hyperaemia during hypoxia at rest, it had no effect on augmented hyperaemia during hypoxic exercise. This is the first study in humans to demonstrate that Na+ /K+ -ATPase and KIR channel activation is required for augmented muscle hyperaemia during hypoxia at rest but not during hypoxic exercise, thus providing new insight into vascular control. ABSTRACT Exercise hyperaemia in hypoxia is augmented relative to the same exercise intensity in normoxia. During moderate-intensity handgrip exercise, endothelium-derived nitric oxide (NO) and vasodilating prostaglandins (PGs) contribute to ∼50% of the augmented forearm blood flow (FBF) response to hypoxic exercise (HypEx), although the mechanism(s) underlying the remaining response are unclear. We hypothesized that combined inhibition of NO, PGs, Na+ /K+ -ATPase and inwardly rectifying potassium (KIR ) channels would abolish the augmented hyperaemic response in HypEx. In healthy young adults, FBF responses were measured (Doppler ultrasound) and forearm vascular conductance was calculated during 5 min of rhythmic handgrip exercise at 20% maximum voluntary contraction under regional sympathoadrenal inhibition in normoxia and isocapnic HypEx (O2 saturation ∼80%). Compared to control, combined inhibition of NO, PGs, Na+ /K+ -ATPase and KIR channels (l-NMMA + ketorolac + ouabain + BaCl2; Protocol 1; n = 10) blunted the compensatory increase in FBF during HypEx by ∼50% (29 ± 6 mL min-1 vs. 62 ± 8 mL min-1 , respectively, P 0.05). However, the blocked condition in both protocols abolished the hyperaemic response to hypoxia at rest (P

Key points Intravascular ATP attenuates sympathetic vasoconstriction (sympatholysis) similar to what is observed in contracting skeletal muscle of humans, and may be an important contributor to exercise hyperaemia. Similar to exercise, ATP-mediated vasodilatation occurs via activation of inwardly rectifying potassium channels (KIR ), and synthesis of nitric oxide (NO) and prostaglandins (PG). However, recent evidence suggests that these dilatatory pathways are not obligatory for sympatholysis during exercise; therefore, we tested the hypothesis that the ability of ATP to blunt α1 -adrenergic vasoconstriction in resting skeletal muscle would be independent of KIR , NO, PGs and Na+ /K+ -ATPase activity. Blockade of KIR channels alone or in combination with NO, PGs and Na+ /K+ -ATPase significantly reduced the vasodilatatory response to ATP, although intravascular ATP maintained the ability to attenuate α1 -adrenergic vasoconstriction. This study highlights similarities in the vascular response to ATP and exercise, and further supports a potential role of intravascular ATP in blood flow regulation during exercise in humans. Abstract Exercise and intravascular ATP elicit vasodilatation that is dependent on activation of inwardly rectifying potassium (KIR ) channels, with a modest reliance on nitric oxide (NO) and prostaglandin (PG) synthesis. Both exercise and intravascular ATP attenuate sympathetic α-adrenergic vasoconstriction (sympatholysis). However, KIR channels, NO, PGs and Na+ /K+ -ATPase activity are not obligatory to observe sympatholysis during exercise. To further determine similarities between exercise and intravascular ATP, we tested the hypothesis that inhibition of KIR channels, NO and PG synthesis, and Na+ /K+ -ATPase would not alter the ability of ATP to blunt α1 -adrenergic vasoconstriction. In healthy subjects, we measured forearm blood flow (Doppler ultrasound) and calculated changes in vascular conductance (FVC) to intra-arterial infusion of phenylephrine (PE; α1 -agonist) during ATP or control vasodilatator infusion, before and after KIR channel inhibition alone (barium chloride; n = 7; Protocol 1); NO (l-NMMA) and PG (ketorolac) inhibition alone, or combined NO, PGs, Na+ /K+ -ATPase (ouabain) and KIR channel inhibition (n = 6; Protocol 2). ATP attenuated PE-mediated vasoconstriction relative to adenosine (ADO) and sodium nitroprusside (SNP) (PE-mediated ΔFVC: ATP: -16 ± 2; ADO: -38 ± 6; SNP: -59 ± 6%; P 0.05 vs. control). These findings demonstrate that intravascular ATP modulates α1 -adrenergic vasoconstriction via pathways independent of KIR channels, NO, PGs and Na+ /K+ -ATPase in humans, consistent with a role for endothelium-derived hyperpolarization in functional sympatholysis.

Key points Red blood cells (RBCs) release ATP in response to deoxygenation, which can increase blood flow to help match oxygen supply with tissue metabolic demand. This release of ATP is impaired in RBCs from older adults, but the underlying mechanisms are unknown. In this study, improving RBC deformability in older adults restored deoxygenation-induced ATP release, whereas decreasing RBC deformability in young adults reduced ATP release to the level of that of older adults. In contrast, treating RBCs with a phosphodiesterase 3 inhibitor did not affect ATP release in either age group, possibly due to intact intracellular signalling downstream of deoxygenation as indicated by preserved cAMP and ATP release responses to pharmacological Gi protein activation in RBCs from older adults. These findings are the first to demonstrate that the age-related decrease in RBC deformability is a primary mechanism of impaired deoxygenation-induced ATP release, which may have implications for treating impaired vascular control with advancing age. Abstract In response to haemoglobin deoxygenation, red blood cells (RBCs) release ATP, which binds to endothelial purinergic receptors and stimulates vasodilatation. This ATP release is impaired in RBCs from older vs. young adults, but the underlying mechanisms are unknown. Using isolated RBCs from young (24 ± 1 years) and older (65 ± 2 years) adults, we tested the hypothesis that age-related changes in RBC deformability (Study 1) and cAMP signalling (Study 2) contribute to the impairment. RBC ATP release during normoxia ( P O 2 ∼112 mmHg) and hypoxia ( P O 2 ∼20 mmHg) was quantified with the luciferin-luciferase technique following RBC incubation with Y-27632 (Rho-kinase inhibitor to increase deformability), diamide (cell-stiffening agent), cilostazol (phosphodiesterase 3 inhibitor), or vehicle control. The mean change in RBC ATP release from normoxia to hypoxia in control conditions was significantly impaired in older vs. young (∼50% vs. ∼120%; P 0.05). Cilostazol did not change ATP release in either age group (P > 0.05), and RBC cAMP and ATP release to pharmacological Gi protein activation was similar in both groups (P > 0.05). We conclude that decreased RBC deformability is a primary contributor to age-related impairments in RBC ATP release, which may have implications for impaired vascular control with advancing age.

Transesophageal echocardiography (TEE) imaging has become an essential component of many open and interventional cardiac procedures and has increasing use in monitoring for noncardiac procedures, partly because of an aging population. Whether expected or not, encountering difficulty when inserting the TEE probe presents the anesthesiologist with a conundrum. Repeated insertion attempts increase the risk of a serious complication; however, proceeding without TEE may be unacceptable to the proceduralist or surgeon. The aim of this review is to present the spectrum of complications possible with TEE, propose several evidence-based insertion tips, examine potential alternative cardiac imaging options, and finally, propose a roadmap for providers who encounter difficulty when placing a TEE probe.

Limb length inequality results from many types of musculoskeletal disorders. Asymmetric weight bearing from a limb length discrepancy of less than 2% can have debilitating consequences such as back problems and early-onset osteoarthritis. Existing treatments include invasive surgeries and/or drug regimens that are often only partially effective. As a noninvasive alternative, we previously developed a once daily limb-heating model using targeted heat on one side of the body for 2 weeks to unilaterally increase bone length by up to 1.5% in growing mice. In this study, we applied heat for 1 week to determine whether these small differences in limb length are functionally significant, assessed by changes in hindlimb weight bearing. We tested the hypothesis that heat-induced limb length asymmetry has a functional impact on weight bearing in mouse hindlimbs. Female 3-week-old C57BL/6 mice (N = 12 total) were treated with targeted intermittent heat for 7 days (40 C for 40 min/day). High-resolution x-ray (N = 6) and hindlimb weight bearing data (N = 8) were acquired at the start and end of the experiments. There were no significant left-right differences in starting tibial length or hindlimb weight bearing. After 1-week heat exposure, tibiae (t = 7.7, p

Dietary nitrate ( NO 3 − ) is converted to nitrite ( NO 2 − ) and can be further reduced to the vasodilator nitric oxide (NO) amid a low O 2 environment. Accordingly, dietary NO 3 − increases hind limb blood flow in rats during treadmill exercise; however, the evidence of such an effect in humans is unclear. We tested the hypothesis that acute dietary NO 3 − (via beetroot [BR] juice) increases forearm blood flow (FBF) via local vasodilation during handgrip exercise in young adults ( n = 11; 25 ± 2 years). FBF (Doppler ultrasound) and blood pressure (Finapres) were measured at rest and during graded handgrip exercise at 5%, 15%, and 25% maximal voluntary contraction (MVC) lasting 4 min each. At the highest workload (25% MVC), systemic hypoxia (80% SaO 2 ) was induced and exercise continued for three additional minutes. Subjects ingested concentrated BR (12.6 mmol nitrate ( n = 5) or 16.8 mmol nitrate ( n = 6) and repeated the exercise bout either 2 (12.6 mmol) or 3 h (16.8 mmol) postconsumption. Compared to control, BR significantly increased FBF at 15% MVC (184 ± 15 vs. 164 ± 15 mL/min), 25% MVC (323 ± 27 vs. 286 ± 28 mL/min), and 25% + hypoxia (373 ± 39 vs. 343 ± 32 mL/min) and this was due to increases in vascular conductance (i.e., vasodilation). The effect of BR on hemodynamics was not different between the two doses of BR ingested. Forearm VO 2 was also elevated during exercise at 15% and 25% MVC. We conclude that acute increases in circulating NO 3 − and NO 2 − via BR increases muscle blood flow during moderate‐ to high‐intensity handgrip exercise via local vasodilation. These findings may have important implications for aging and diseased populations that demonstrate impaired muscle perfusion and exercise intolerance.

Systolic BP and large elastic artery stiffness both increase with age and are reduced by dietary sodium restriction. Production of the natriuretic hormone marinobufagenin, an endogenous α1 Na+,K+-ATPase inhibitor, is increased in salt-sensitive hypertension and contributes to the rise in systolic BP during sodium loading.The hypothesis was that dietary sodium restriction performed in middle-aged/older adults (eight men and three women; 60 ± 2 years) with moderately elevated systolic BP (139 ± 2/83 ± 2 mmHg) would reduce urinary marinobufagenin excretion as well as systolic BP and aortic pulse-wave velocity (randomized, placebo-controlled, and crossover design). This study also explored the associations among marinobufagenin excretion with systolic BP and aortic pulse-wave velocity across conditions of 5 weeks of a low-sodium (77 ± 9 mmol/d) and 5 weeks of a normal-sodium (144 ± 7 mmol/d) diet.Urinary marinobufagenin excretion (weekly measurements; 25.4 ± 1.8 versus 30.7 ± 2.1 pmol/kg per day), systolic BP (127 ± 3 versus 138 ± 5 mmHg), and aortic pulse-wave velocity (700 ± 40 versus 843 ± 36 cm/s) were lower during the low- versus normal-sodium condition (all P0.05). Across all weeks, marinobufagenin excretion was related with systolic BP (slope=0.61, P0.001) and sodium excretion (slope=0.46, P0.001). These associations persisted during the normal- but not the low-sodium condition (both P0.005). Marinobufagenin excretion also was associated with aortic pulse-wave velocity (slope=0.70, P=0.02) and endothelial cell expression of NAD(P)H oxidase-p47phox (slope=0.64, P=0.006).These results show, for the first time in humans, that dietary sodium restriction reduces urinary marinobufagenin excretion and that urinary marinobufagenin excretion is positively associated with systolic BP, aortic stiffness (aortic pulse-wave velocity), and endothelial cell expression of the oxidant enzyme NAD(P)H oxidase. Importantly, marinobufagenin excretion is positively related to systolic BP over ranges of sodium intake typical of an American diet, extending previous observations in rodents and humans fed experimentally high-sodium diets.

While a certain degree of structural and functional intra-lobular heterogeneity of sinusoidal endothelial cells has been observed in rodents, little information is available about the zonal characteristics of sinusoidal endothelial cells in the human liver acinus. We have therefore examined the intra-acinar distribution of a panel of endothelial markers in the normal human liver, including: (a) structural markers of continuous and sinusoidal endothelia (PECAM-1, CD-34 protein, VE-cadherin, 1F10 antigen), (b) functional markers specific for sinusoidal endothelial cells, as previously determined in the laboratory (CD4 protein, the lipopolysaccharide-binding protein receptor (CD 14), aminopeptidase N, ICAM-1, receptors II and III for the Fc fragment of immunoglobulins G), (c) endothelial cell-matrix adhesion proteins and leukocyte-endothelial cell adhesion molecules. We observed a heterogeneous distribution for: (a) the 1F10 antigen, whose distribution in the human liver acinus was restricted to vessels situated along the axis of acinar zone 1, (b) the lipopolysaccharide-binding protein receptor and the receptor III for the Fc fragment of IgG, not expressed or only barely expressed in acinar zone 1. The distribution of the other markers tested did not display significant intra-lobular variation. Our in situ results suggest the existence of a degree of zonal heterogeneity in the structural and functional characteristics of sinusoidal endothelial cells in the human liver acinus. This might contribute to the constitution of distinct microenvironments within the human liver parenchyma.

We define Lie multiplication derivations of an arbitrary non-associative algebra A over any commutative ring and, following McCrimmon [15], describe them completely if A is alternative. Using this description, we propose a new definition of inner derivations for alternative algebras, among which Schafer’s standard derivations [19, 20] and McCrimmon’s associator derivations [15] occupy a special place, the latter being particularly useful to resolve diculties in characteristic 3. We also show that octonion algebras over any commutative ring have only associator derivations. 2000 Mathematics Subject Classification. Primary 17D05; Secondary 17A36, 17A45, 17B40

There is always an unexplored ethical dimension over and above the list of causes of major industrial accidents, be them human errors, organizational or technical failures. This results in a cascade of bad decisions being taken at the organizational, human and technical levels, which cause tragic accidents, often with loss of human life. However, no one wants these accidents to occur, and there are often very qualified people who work in these organizations. A myriad of legislation was born from these major industrial accidents, each law or regulation more complex than the last, but they do not seem to be sufficient to cure the outbreak of various errors. Perhaps the prescribed treatment is simply inappropriate or the dose is not well administered! To manage risks properly, it will not only be necessary to develop techniques but also to develop processes, at the personnel level as well as at the organizational level, which will take human nature into account. Appropriate mechanisms will also have to be set up to reconcile “public interest” and “risk management”. It will thus be necessary to define, implement and improve a series of processes and most importantly, provide guidance to managers. It is necessary to continue improving the risk analysis methods, to continue training in the field of risk management for numerous stakeholders, to reinforce legislation on risk management and most importantly, to base risk management on ethical principles.

But Le but de cette etude est d’evaluer les modifications a long terme du diametre pupillaire apres insertion d’un implant phaque Artisan® pour la correction d’une forte ametropie myopique. Patients et methodes Nous avons inclus 14 yeux de 7 patients dans cette etude. Nous avons determine le diametre pupillaire en ambiance photopique, en ambiance scotopique apres 10 minutes d’adaptation dans l’obscurite, puis apres dilatation pharmacologique. Les mesures du diametre pupillaire dans ces trois conditions ont ete realisees en utilisant l’image du segment anterieur capturee par le topographe-aberrometre OPD-scan® (Nidek). Resultats Le suivi moyen etait de 46 mois apres la chirurgie. Le diametre pupillaire moyen mesure en ambiance photopique etait de 2,94 ± 0,33 mm (extremes de 2,54 a 3,6 mm). Le diametre pupillaire moyen mesure en ambiance scotopique etait inferieur a 6 mm chez tous les patients (4,68 ± 0,59 mm, avec un diametre pupillaire scotopique maximal de 5,67 mm). Le diametre pupillaire moyen apres dilatation pharmacologique etait egalement diminue (5,39 ± 1,08 mm), avec une dilatation pupillaire superieure a 7 mm chez un seul patient. Conclusion La diminution du diametre pupillaire a long terme apres insertion d’un implant Artisan® pourrait contribuer a preserver la qualite de vision en condition scotopique chez ces patients. Le mecanisme le plus probable serait une restriction mecanique de la dilatation pupillaire par l’implant.

Background and objectives Metabolomics is a relatively new field of “-omics” research, focusing on high-throughput identification of small molecular weight metabolites. Diet has both acute and chronic effects on metabolic profiles; however, alterations in response to dietary sodium restriction (DSR) are completely unknown. The goal of this study was to explore changes in urine metabolites in response to DSR, as well as their association with previously reported improvements in vascular function with DSR. Design, setting, participants, & measurements Using stored urine samples from a 10-week randomized placebo-controlled crossover study of DSR in 17 middle-aged/older adults (six men and 11 women; mean age 62±8 years) who had moderately elevated systolic BP (130–159 mmHg) and were otherwise healthy, a liquid chromatography/mass spectrometry–based analysis of 289 metabolites was performed. This study identified metabolites that were significantly altered between the typical (153±29 mmol/d) and low (70±29 mmol/d) sodium conditions, as well as their baseline (typical sodium) association with responsiveness to previously reported improvements in vascular endothelial function (brachial artery flow-mediated dilation) and large elastic artery stiffness (aortic pulse wave velocity). Results Of the 289 metabolites surveyed, 10 were significantly altered (nine were upregulated and one was downregulated) during the low sodium condition, and eight of these exceeded our prespecified clinically significant threshold of a >40% change. These metabolites were involved in biologic pathways broadly related to cardiovascular risk, nitric oxide production, oxidative stress, osmotic regulation, and metabolism. One metabolite, serine, was independently (positively) associated with previously reported improvements in the primary vascular outcome of brachial artery flow-mediated dilation. Conclusions This proof-of-concept study provides the first evidence that DSR is a stimulus that induces significant changes in urinary metabolomic profiles. Moreover, serine was independently associated with corresponding changes in vascular endothelial function after DSR. Larger follow-up studies will be required to confirm and further elucidate the metabolic pathways that are altered in response to DSR.

The normal ability of contracting skeletal muscle to blunt sympathetic vasoconstriction is impaired in older adults, potentially contributing to the age-associated impairment in skeletal muscle blo...

High blood concentrations of C-reactive protein (CRP) have been associated with elevated risk of colorectal cancer in several prospective studies including the European Prospective Investigation into Cancer and Nutrition (EPIC), but it is unknown whether these observations reflect a causal relationship. We aimed to investigate whether CRP genetic variants associated with lifelong higher CRP concentrations translate into higher colorectal cancer risk. We conducted a prospective nested case-control study within EPIC including 727 cases diagnosed between 1992 and 2003 and 727 matched controls selected according to an incidence-density sampling protocol. Baseline CRP concentrations were measured in plasma samples by a high sensitivity assay. Tagging single nucleotide polymorphisms (SNPs) in the CRP gene (rs1205, rs1800947, rs1130864, rs2808630, rs3093077) were identified via HapMap. The causal effect of CRP on colorectal cancer risk was examined in a Mendelian Randomization approach utilizing multiple CRP genetic variants as instrumental variables. The SNPs rs1205, rs1800947, rs1130864 and rs3093077 were significantly associated with CRP concentrations and were incorporated in a CRP allele score which was associated with 13% higher CRP concentrations per allele count (95% confidence interval 8-19%). Using the CRPscore as instrumental variable, genetically twofold higher CRP concentrations were associated with higher risk of colorectal cancer (odds ratio 1.74, 95% confidence interval 1.06-2.85). Similar observations were made using alternative definitions of instrumental variables. Our findings give support to the hypothesis that elevated circulating CRP may play a direct role in the etiology of colorectal cancer. © 2014 UICC.

The *-polynomial identities of minimal degree of M n (F) are determined for n = 2, 4, * the symplectic involution.

Sympathetic stimulation of postjunctional α-adrenergic receptors elicits vasoconstriction in resting skeletal muscle that is blunted during exercise in an intensity dependent manner. This ‘sympatho...