In diabetes mellitus, vascular complications such as atherosclerosis are a major cause of death. The key underlying pathomechanisms are unclear. However, hyperglycemic oxidative stress derived from ...NADPH oxidase (Nox), the only known dedicated enzyme to generate reactive oxygen species appears to play a role. Here we identify the Nox1 isoform as playing a key and pharmacologically targetable role in the accelerated development of diabetic atherosclerosis.
Human aortic endothelial cells exposed to hyperglycemic conditions showed increased expression of Nox1, oxidative stress, and proinflammatory markers in a Nox1-siRNA reversible manner. Similarly, the specific Nox inhibitor, GKT137831, prevented oxidative stress in response to hyperglycemia in human aortic endothelial cells. To examine these observations in vivo, we investigated the role of Nox1 on plaque development in apolipoprotein E-deficient mice 10 weeks after induction of diabetes mellitus. Deletion of Nox1, but not Nox4, had a profound antiatherosclerotic effect correlating with reduced reactive oxygen species formation, attenuation of chemokine expression, vascular adhesion of leukocytes, macrophage infiltration, and reduced expression of proinflammatory and profibrotic markers. Similarly, treatment of diabetic apolipoprotein E-deficient mice with GKT137831 attenuated atherosclerosis development.
These studies identify a major pathological role for Nox1 and suggest that Nox1-dependent oxidative stress is a promising target for diabetic vasculopathies, including atherosclerosis.
Cyclo-oxygenase (COX) inhibitors are among the most commonly used drugs in the western world for their anti-inflammatory and analgesic effects. However, they are also well-known to increase the risk ...of coronary events. This area is of renewed significance given alarming new evidence suggesting this effect can occur even with acute usage. This contrasts with the well-established usage of aspirin as a mainstay for cardiovascular prophylaxis, as well as overwhelming evidence that COX inhibition induces vasodilation and is protective for vascular function. Here, we present an updated review of the preclinical and clinical literature regarding the cardiotoxicity of COX inhibitors. While studies to date have focussed on the role of COX in influencing renal and vascular function, we suggest an interaction between prostanoids and T cells may be a novel factor, mediating elevated cardiovascular disease risk with NSAID use.
Until recently, most of the biological effects of nitric oxide (NO) have been attributed to its uncharged state (NO ), yet NO can also exist in the reduced state as nitroxyl (HNO or NO− ). Putatively ...generated from both NO synthase (NOS)-dependent and -independent sources, HNO is rapidly emerging as a novel entity with distinct pharmacology and therapeutic advantages over its redox sibling, NO . Thus, unlike NO , HNO can target cardiac sarcoplasmic ryanodine receptors to increase myocardial contractility, can interact directly with thiols and is resistant to both scavenging by superoxide ( O2− ) and tolerance development. HNO donors are protective in the setting of heart failure in which NO donors have minimal impact. Here, we discuss the unique pharmacology of HNO versus NO and highlight the therapeutic potential of HNO donors in the treatment of cardiovascular disease.
Hypertension is a major, independent risk factor for atherosclerotic cardiovascular disease. However, this pathology can arise through multiple pathways, which could influence vascular disease ...through distinct mechanisms. An overactive sympathetic nervous system is a dominant pathway that can precipitate in elevated blood pressure. We aimed to determine how the sympathetic nervous system directly promotes atherosclerosis in the setting of hypertension. We used a mouse model of sympathetic nervous system-driven hypertension on the atherosclerotic-prone apolipoprotein E-deficient background. When mice were placed on a western type diet for 16 weeks, we showed the evolution of unstable atherosclerotic lesions. Fortuitously, the changes in lesion composition were independent of endothelial dysfunction, allowing for the discovery of alternative mechanisms. With the use of flow cytometry and bone marrow imaging, we found that sympathetic activation caused deterioration of the hematopoietic stem and progenitor cell niche in the bone marrow, promoting the liberation of these cells into the circulation and extramedullary hematopoiesis in the spleen. Specifically, sympathetic activation reduced the abundance of key hematopoietic stem and progenitor cell niche cells, sinusoidal endothelial cells and osteoblasts. Additionally, sympathetic bone marrow activity prompted neutrophils to secrete proteases to cleave the hematopoietic stem and progenitor cell surface receptor CXCR4. All these effects could be reversed using the β-blocker propranolol during the feeding period. These findings suggest that elevated blood pressure driven by the sympathetic nervous system can influence mechanisms that modulate the hematopoietic system to promote atherosclerosis and contribute to cardiovascular events.
Roughly one quarter of active upper limb prosthetic technology is rejected by the user, and user surveys have identified key areas requiring improvement: function, comfort, cost, durability, and ...appearance. Here we present the first systematic, clinical assessment of a novel prosthetic hand, the SoftHand Pro (SHP), in participants with transradial amputation and age-matched, limb-intact participants. The SHP is a robust and functional prosthetic hand that minimizes cost and weight using an underactuated design with a single motor. Participants with limb loss were evaluated on functional clinical measures before and after a 6-8 hour training period with the SHP as well as with their own prosthesis; limb-intact participants were tested only before and after SHP training. Participants with limb loss also evaluated their own prosthesis and the SHP (following training) using subjective questionnaires. Both objective and subjective results were positive and illuminated the strengths and weaknesses of the SHP. In particular, results pre-training show the SHP is easy to use, and significant improvement in the Activities Measure for Upper Limb Amputees in both groups following a 6-8 hour training highlights the ease of learning the unique features of the SHP (median improvement: 4.71 and 3.26 and p = 0.009 and 0.036 for limb loss and limb-intact groups, respectively). Further, we found no difference in performance compared to participant's own commercial devices in several clinical measures and found performance surpassing these devices on two functional tasks, buttoning a shirt and using a cell phone, suggesting a functional prosthetic design. Finally, improvements are needed in the SHP design and/or training in light of poor results in small object manipulation. Taken together, these results show the promise of the SHP, a flexible and adaptive prosthetic hand, and pave a path forward to ensuring higher functionality in future.
Current prosthetic hands are frequently rejected in part due to limited functionality and versatility. We assessed the feasibility of a novel prosthetic hand, the SoftHand Pro (SHP), whose design ...combines soft robotics and hand postural synergies. Able-bodied subjects (n = 23) tracked cursor motion by opening and closing the SHP and performed a grasp-lift-hold-release (GLHR) task with a sensorized cylindrical object of variable weight. The SHP control was driven by electromyographic (EMG) signals from two antagonistic muscles. Although the time to perform the GLHR task was longer for the SHP than native hand for the first few trials (10.2 ± 1.4 s and 2.13 ± 0.09 s, respectively), performance was much faster on subsequent trials (~5 s). The SHP steady-state grip force was significantly modulated as a function of object weight (p <; 0.001). For the native hand, however, peak and steady-state grip forces were modulated to a greater extent (+68% and +91%, respectively). These changes were mediated by the modulation of EMG amplitude and co-contraction. These data suggest that the SHP has a promise for prosthetic applications and point-to-design modifications that could improve the SHP.
It is now becomingly increasingly evident that the functions of the mammalian Y chromosome are not circumscribed to the induction of male sex. While animal studies have shown variations in the Y are ...strongly accountable for blood pressure (BP), this is yet to be confirmed in humans. We have recently shown modulation of adaptive immunity to be a significant mechanism underpinning Y-chromosome-dependent differences in BP in consomic strains. This is paralleled by studies in man showing Y chromosome haplogroup is a significant predictor for coronary artery disease through influencing pathways of immunity. Furthermore, recent studies in mice and humans have shown that Y chromosome lineage determines susceptibility to autoimmune disease. Here we review the evidence in animals and humans that Y chromosome lineage influences hypertension and cardiovascular disease risk, with a novel focus on pathways of immunity as a significant pathway involved.
Multivitamin/mineral products (MVMs) are the dietary supplements most commonly used by US adults. During manufacturing, some ingredients are added in amounts exceeding the label claims to compensate ...for expected losses during the shelf life. Establishing the health benefits and harms of MVMs requires accurate estimates of nutrient intake from MVMs based on measures of actual rather than labeled ingredient amounts.
Our goals were to determine relations between analytically measured and labeled ingredient content and to compare adult MVM composition with Recommended Dietary Allowances (RDAs) and Tolerable Upper Intake Levels.
Adult MVMs were purchased while following a national sampling plan and chemically analyzed for vitamin and mineral content with certified reference materials in qualified laboratories. For each ingredient, predicted mean percentage differences between analytically obtained and labeled amounts were calculated with the use of regression equations.
For 12 of 18 nutrients, most products had labeled amounts at or above RDAs. The mean measured content of all ingredients (except thiamin) exceeded labeled amounts (overages). Predicted mean percentage differences exceeded labeled amounts by 1.5-13% for copper, manganese, magnesium, niacin, phosphorus, potassium, folic acid, riboflavin, and vitamins B-12, C, and E, and by ∼25% for selenium and iodine, regardless of labeled amount. In contrast, thiamin, vitamin B-6, calcium, iron, and zinc had linear or quadratic relations between the labeled and percentage differences, with ranges from -6.5% to 8.6%, -3.5% to 21%, 7.1% to 29.3%, -0.5% to 16.4%, and -1.9% to 8.1%, respectively. Analytically adjusted ingredient amounts are linked to adult MVMs reported in the NHANES 2003-2008 via the Dietary Supplement Ingredient Database (http://dsid.usda.nih.gov) to facilitate more accurate intake quantification.
Vitamin and mineral overages were measured in adult MVMs, most of which already meet RDAs. Therefore, nutrient overexposures from supplements combined with typical food intake may have unintended health consequences, although this would require further examination.
Vascular inflammation and disease progression, such as atherosclerosis, are in part a consequence of haemodynamic forces generated by changes in blood flow. The haemodynamic forces, such as shear ...stress or stretch, interact with vascular endothelial cells, which transduce the mechanical stimuli into biochemical signals via mechanosensors, which can induce an upregulation in pathways involved in inflammatory signaling. However, it is unclear how these mechanosensors respond to shear stress and most significantly what cellular mechanisms are involved in sensing the haemodynamic stimuli. This review explores the transition from shear forces, stretch and pressure to endothelial inflammation and the process of mechanotransduction, specifically highlighting evidence to suggest that caveolae play as a role as mechanosensors.
Hospital-based studies have shown that mortality rates in individuals with diabetic foot ulcers are about twice those observed in individuals with diabetes without foot ulcers.
To assess the etiology ...and management of chronic diabetic foot ulcers.
Literature review.
Systematic review of the literature discussing management of diabetic foot ulcers. Since there were only a few randomized controlled trials on this topic, articles were selected to attempt to be comprehensive rather than a formal assessment of study quality.
Chronic nonhealing foot ulcers occur in approximately 15% of patients with diabetes. Many factors contribute to impaired diabetic wound healing. Risk factors include peripheral neuropathy, peripheral arterial disease, limited joint mobility, foot deformities, abnormal foot pressures, minor trauma, a history of ulceration or amputation, and impaired visual acuity. With the current treatment for nonhealing diabetic foot ulcers, a significant number of patients require amputation.
Diabetic foot ulcers are optimally managed by a multidisciplinary integrated team. Offloading and preventative management are important. Dressings play an adjunctive role. There is a critical need to develop novel treatments to improve healing of diabetic foot ulcers. The goal is to have wounds heal and remain healed.
Diabetic neuropathy and peripheral arterial disease are major factors involved in a diabetic foot ulcer. Despite current treatment modalities for nonhealing diabetic foot ulcers, there are a significant number of patients who require amputations. No known therapy will be effective without concomitant management of ischemia, infection, and adequate offloading.
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