Apligraf consists of bovine collagen dermis seeded with allogeneic male fibroblasts and keratinocytes. It is been shown to promote healing, but the length of persistence and pathological features have not been characterized previously in acute wounds. Forty-eight deep dermal wounds were created and Apligraf, a split-skin graft (SSG), or a dressing was applied. Biopsies of wounds were taken for immunohistochemical analysis and polymerase chain reaction was performed to detect the Y chromosome from Apligraf cells in 14 female wounds. Male allogeneic DNA was detected in wounds for the first 4 weeks. All subsequent time points were negative apart from one biopsy at 6 weeks. The wounds took 4-9 weeks to heal, with the Apligraf exhibiting no features of engraftment. This was in contrast to the rapid healing seen in the SSG control group. Histology revealed a more intense cellular infiltrate, but less vascularization below Apligraf compared with controls. Evidence of an epidermal-mesenchymal interaction was observed. This is the first article to elucidate the survival of Apligraf allogeneic cells in acute wounds in immunocompetent human subjects for up to 6 weeks and demonstrates that in the management of acute surgical wounds, Apligraf has a role only as a temporary biological dressing.

Metformin is quite frequently used off-label in type 1 diabetes to limit insulin dose requirement. Guidelines recommend that it can improve glucose control in those who are overweight and obese but evidence in support of this is limited. Recently-published findings from the REducing with MetfOrmin Vascular Adverse Lesions (REMOVAL) trial suggest that metformin therapy in type 1 diabetes can reduce atherosclerosis progression, weight and LDL-cholesterol levels. This provides a new perspective on metformin therapy in type 1 diabetes and suggests a potential role for reducing the long-term risk of cardiovascular disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-017-4364-6) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Type 2 diabetes (T2D) carries risks of both cardiovascular (CV) (myocardial infarction, stroke, and peripheral vascular disease) and microvascular (retinopathy/nephropathy/neuropathy) complications. Glucose-lowering is an effective strategy for preventing microvascular complications, but the extent to which it can reduce CV complications is less certain. Glucagon-like peptide-1 (GLP-1) agonists are potent glucose-lowering agents but also have potentially beneficial effects on other traditional (body weight, blood pressure (BP), and LDL cholesterol) and non-traditional risk factors (low grade inflammation and endothelial dysfunction). The results of four large CV outcome trials with GLP-1 agonists are now available. These have compared lixisenatide (ELIXA), liraglutide (LEADER), semaglutide (SUSTAIN-6), and long-acting exenatide (EXSCEL) with placebo and standard of care over 2-4 years; four others (including with dulaglutide and albiglutide) are ongoing. LEADER and SUSTAIN-6 have demonstrated reductions in rates of major adverse CV events with active GLP-1 treatment but ELIXA and EXSCEL have not. In this review, we discuss the mechanisms by which GLP-1 receptor agonists act on the CV system and the design and conduct of these trials. Contrary to the assertions that (a) all GLP-1 agonists reduce CV disease in T2D but to different extents or (b) the magnitude of CV protection is predominantly related to glucose-lowering, we argue that CV benefit is specific to agents that provide longer acting agonism at the GLP-1 receptor. The mechanisms involve reduction in body weight and BP, and lowering of LDL-cholesterol and glucose, but pleiotropic effects-including suppression of low grade inflammation, vasodilation, and natriuresis-are also likely relevant.

We determined the physiological and anatomical properties of systems mediating renal nerve inhibition elicited by electrical and chemical stimulation of the cervical dorsolateral funiculus of the anesthetized spinally transected rat. Stimulus-response characteristics suggested that this system was well suited for a role in tonic inhibition of sympathetic activity. Inhibition was elicited from a region of the cervical spinal cord extending from a lateral position near the accessory nerve to the dorsal columns. Inhibition could not be elicited by spinal stimulation before lesions had been placed rostral to stimulation sites in the lateral funiculi. Inhibition was blocked by similarly placed lesions caudal to stimulation sites. Therefore, this system may course in the lateral funiculus, and it may be tonically active in intact rats. Renal sympathetic activity could be inhibited by electrical stimulation caudal to large, chronic, spinal lesions. Therefore, some component of the inhibitory system was either antidromically activated or propriospinal. Glutamate applied to the dorsolateral surface of the cervical spinal cord elicited inhibition indistinguishable from that elicited by electrical stimulation, which suggested that neurons with somas located superficially at cervical levels may be responsible for some component of the spinally elicited inhibition.

Spinal transection approximately doubles renal sympathetic activity (RSA) in rats. These experiments localized spinal pathways inhibiting RSA and determined the effects of transection-elicited renal sympathetic hyperactivity on renal circulation and renal function. Experiments were conducted in chloralose-anesthetized, paralyzed, artificially respired, male Sprague-Dawley rats. RSA was measured from an electrode on the left renal nerve. Renal arterial blood flow (RABF), glomerular filtration rate, urine flow rate, and renal sodium and potassium excretions were also measured. Localized lesions of the cervical spinal cord indicated that spinal generators of RSA were inhibited by pathways descending in the dorsal cervical cord. Autoregulation of RABF prevented transection-elicited increases in RSA from affecting renal vascular resistance. Renal sodium and potassium excretions were dramatically reduced after spinal transection, although these reductions were ameliorated somewhat by fixing posttransection renal arterial pressure at pretransection levels. We conclude that the vascular effects of transection-elicited elevations in RSA are minimized by autoregulation of RABF and that posttransection changes in renal function result from changes in both arterial pressure and RSA.