Thyroid hormone (TH) is critical for tissue differentiation at early stages of development, induces physiological hypertrophy and regulates the expression of important contractile proteins such as myosin heavy chain (MHC) isoform and calcium cycling proteins. Furthermore, TH seems to control the response to stress by regulating important cardioprotective molecules such as heat shock proteins (HSPs). Thus, the present study investigated whether TH administration immediately after acute myocardial infarction can favourably remodel the post-infarcted myocardium. Acute myocardial infarction was induced in rats by coronary artery ligation (AMI, n=10), while SHAM-operated animals served as controls (SHAM, n = 8). TH was administered for 13 weeks (AMI-THYR, n = 9). Cardiac contractile function and left ventricular (LV) chamber remodelling was assessed by serial echocardiography and in Langendorff heart preparations. AMI significantly reduced LV ejection fraction (EF%); 30.0 (s.e.m, 2.3) Vs. 73.8 (1.8) in SHAM, P < 0.05. In addition, +dp/dt and -dp/dt (in mmHg/s) were 4,051 (343) and 2,333 (118) respectively for SHAM Vs. 2,102 (290) and 1,368 (181) for AMI, P < 0.05. With TH treatment, EF% was increased to 49.5 (2.7) in AMI-THYR, P < 0.05, while +dp/dt and -dp/dt (in mmHg/s) were 3,708 (231) and 2,035 (95) for AMI-THYR, P < 0.05 Vs. AMI. A marked elevation of the expression of beta-MHC and a reduced ratio of SERCA/Phospholamban were found in viable myocardium of AMI hearts, which was prevented by TH. Furthermore, heat shock protein 70 myocardial content was decreased in AMI hearts and was significantly increased after TH treatment. An ellipsoidal reshaping of LV chamber was observed with TH; cardiac sphericity index, (ratio of long/short axis, SI), was 1.98 (0.03) for SHAM, 1.52 (0.05) for AMI and 1.72(0.02) for AMI-THYR, P < 0.05. In conclusion, long-term TH administration immediately after AMI results in sustained improvement of cardiac haemodynamics.

In 2015, it can be said that the diabetic foot is no longer the Cinderella of diabetic complications. Thirty years ago there was little evidence-based research taking place on the diabetic foot, and there were no international meetings addressing this topic. Since then, the biennial Malvern Diabetic Foot meetings started in 1986, the American Diabetes Association founded their Foot Council in 1987, and the European Association for the Study of Diabetes established a Foot Study Group in 1998. The first International Symposium on the Diabetic Foot in The Netherlands was convened in 1991, and this was soon followed by the establishment of the International Working Group on the Diabetic Foot that has produced useful guidelines in several areas of investigation and the management of diabetic foot problems. There has been an exponential rise in publications on diabetic foot problems in high impact factor journals, and a comprehensive evidence-base now exists for many areas of treatment. Despite the extensive evidence available, it, unfortunately, remains difficult to demonstrate that most types of education are efficient in reducing the incidence of foot ulcers. However, there is evidence that education as part of a multi-disciplinary approach to diabetic foot ulceration plays a pivotal role in incidence reduction. With respect to treatment, strong evidence exists that offloading is the best modality for healing plantar neuropathic foot ulcers, and there is also evidence from two randomized controlled trials to support the use of negative-pressure wound therapy in complex post-surgical diabetic foot wounds. Hyperbaric oxygen therapy exhibits the same evidence level and strength of recommendation. International guidelines exist on the management of infection in the diabetic foot. Many randomized trials have been performed, and these have shown that the agents studied generally produced comparable results, with the exception of one study in which tigecycline was shown to be clinically inferior to ertapenem ± vancomycin. Similarly, there are numerous types of wound dressings that might be used in treatment and which have shown efficacy, but no single type (or brand) has shown superiority over others. Peripheral artery disease is another major contributory factor in the development of ulceration, and its presence is a strong predictor of non-healing and amputation. Despite the proliferation of endovascular procedures in addition to open revascularization, many patients continue to suffer from severely impaired perfusion and exhaust all treatment options. Finally, the question of the true aetiopathogenesis of Charcot neuroarthropathy remains enigmatic, although much work is currently being undertaken in this area. In this area, it is most important to remember that a clinically uninfected, warm, insensate foot in a diabetic patient should be considered as a Charcot foot until proven otherwise, and, as such, treated with offloading, preferably in a cast.

Thyroid hormone administration early after infarction attenuates cardiac remodeling and significantly improves myocardial performance.

Aliskiren had a favorable effect on endothelial function and EPCs, reduced arterial stiffness, and improved LV twisting and untwisting. These effects were independent of BBP lowering, as they were not observed after the achievement of similar values of BBP with HCTZ.

Background: Anaemia is a common finding in diabetes, particularly in those patients with albuminuria or renal dysfunction and is associated with impaired erythropoietin (EPO) secretion. This review focuses on mechanisms involved in the regulation of erythropoiesis in diabetic patients in an effort to elucidate the competing effects of the renin angiotensin system (RAS) blockade and sodium-glucose cotransporter-2 (SGLT2) inhibitors on haemoglobin concentration and hematocrit values. Summary: The RAS shows significant activation in diabetic subjects. Angiotensin II, its active octapeptide, causes renal tubulointerstitial hypoxia, which stimulates hypoxia-inducible factors (HIF) and increases EPO secretion and erythropoiesis. As expected, drugs that inactivate RAS, such as angiotensin converting enzyme inhibitors or angiotensin receptor blockers (ACEi/ARB) are associated with a significant hematocrit-lowering effect and/or anaemia in various clinical conditions, including diabetes. Dual blockade by a combination of ACEi and ARB in diabetic patients achieves a better RAS inhibition, but at the same time a worse drop of haemoglobin concentration. Increased glucose reabsorption by SGLTs in diabetic subjects generates a high-glucose environment in renal tubulointerstitium, which may impair HIF-1, damage renal erythropoietin-producing cells (REPs) and decrease EPO secretion and erythropoiesis. SGLT2 inhibitors, which inhibit glucose reabsorption, may attenuate glucotoxicity in renal tubulointerstitium, allowing REPs to resume their function and increase EPO secretion. Indeed, EPO levels increase within a few weeks after initiation of therapy with all known SGLT2 inhibitors, followed by increased reticulocyte count and a gradual elevation of haemoglobin concentration and hematocrit level, which reach zenith values after 2-3 months. Key Messages: The competing effects of RAS blockade and SGLT2 inhibitors on erythropoiesis may have important clinical implications. The rise of hematocrit values by SGLT2 inhibitors given on top of RAS blockade in recent outcome trials may significantly contribute to the cardiorenal protection attained. The relative contribution of each system to erythropoiesis and outcome remains to be revealed in future studies.

The present study investigated whether changes in thyroid hormone (TH) signalling can occur after acute myocardial infarction (AMI) with possible physiological consequences on myocardial performance. TH may regulate several genes encoding important structural and regulatory proteins particularly through the TRa1 receptor which is predominant in the myocardium. AMI was induced in rats by ligating the left coronary artery while sham-operated animals served as controls. This resulted in impaired cardiac function in AMI animals after 2 and 13 weeks accompanied by a shift in myosin isoforms expression towards a fetal phenotype in the non-infarcted area. Cardiac hypertrophy was evident in AMI hearts after 13 weeks but not at 2 weeks. This response was associated with a differential pattern of TH changes at 2 and 13 weeks; T 3 and T 4 levels in plasma were not changed at 2 weeks but T 3 was significantly lower and T 4 remained unchanged at 13 weeks. A twofold increase in TRa1 expression was observed after 13 weeks in the non-infarcted area, P!0.05 versus sham operated, while TRa1 expression remained unchanged at 2 weeks. A 2.2-fold decrease in TRb1 expression was found in the non-infarcted area at 13 weeks, P!0.05, while no change in TRb1 expression was seen at 2 weeks. Parallel studies with neonatal cardiomyocytes showed that phenylephrine (PE) administration resulted in 4.5-fold increase in the expression of TRa1 and 1.6-fold decrease in TRb1 expression versus untreated, P!0.05. In conclusion, cardiac dysfunction which occurs at late stages after AMI is associated with increased expression of TRa1 receptor and lower circulating tri-iodothyronine levels. Thus, apo-TRa1 receptor state may prevail contributing to cardiac fetal phenotype. Furthermore, down-regulation of TRb1 also contributes to fetal phenotypic changes. a1-adrenergic signalling is, at least in part, involved in this response. 156 415-424 European Journal of Endocrinology

Foot infections are common among diabetic patients with peripheral neuropathy and/or peripheral arterial disease, and it can be the pivotal event leading to a minor or major amputation of the lower extremity. Treatment of diabetic foot infections, especially deep-seated ones, remains challenging, in part because impaired blood perfusion and the presence of biofilms can impair the effectiveness of systemic antibiotics. The local application of antibiotics is an emerging field in the treatment of diabetic foot infections, with demonstrable advantages. These include delivery of high concentrations of antibiotics in the affected area, limited systemic absorption, and thus negligible side effects. Biodegradable vehicles, such as calcium sulfate beads, are the prototypical system, providing a good elution profile and the ability to be impregnated with a variety of antibiotics. These have largely superseded the nonbiodegradable vehicles, but the strongest evidence available is for calcium bead implantation for osteomyelitis management. Natural polymers, such as collagen sponge, are an emerging class of delivery systems, although thus far, data on diabetic foot infections are limited. There is recent interest in the novel antimicrobial peptide pexiganan in the form of cream, which is active against most of the microorganisms isolated in diabetic foot infections. These are promising developments, but randomized trials are required to ascertain the efficacy of these systems and to define the indications for their use. Currently, the role of topical antibiotic agents in treating diabetic foot infections is limited and outside of routine practice.

It is now recognized that changes occurring during cardiac remodeling may influence the tolerance of the myocardium to ischemic stress. Therefore, the present study investigated the response of the post-infarcted heart to ischemia in an experimental model of ischemia and reperfusion injury and the possible underlying mechanisms. Acute myocardial infarction (AMI) was induced in Wistar male rats by ligating the left coronary artery (AMI, n = 13), while sham-operated rats were used as controls (SHAM, n = 11). At 2 weeks, cardiac dysfunction was observed in AMI, as indicated by the reduction of the left ventricular EF%. Isolated hearts were then subjected to 30 min of zero-flow global ischemia followed by 45 min of reperfusion. Ischemic contracture was significantly depressed in AMI hearts. Postischemic left ventricular end diastolic pressure (LVEDP45) in mmHg and LDH release in IU/g were markedly decreased; LVEDP45 was 52.1 (7.5) for AMI vs 96.6 (7.5),P < 0.05 and LDH release was 7.5 (1.0) in AMI vs 11.4 (0.56) in SHAM, P < 0.05. This response was associated with 2-fold increase in HSP70 expression in AMI hearts (noninfarcted segment), P < 0.05 vs SHAM and 1.7 fold increase in the expression of the phospho-HSP27, P < 0.05, while the expression of PKCepsilon was shown to be 1.4-fold less in AMI, P < 0.05. In conclusion, the post-infarcted heart seems to be resistant to ischemiareperfusion injury and heat shock protein 70 and 27 may be involved in this response.