Diabetes-specific microvascular disease is a leading cause of blindness, renal failure and nerve damage, and diabetes-accelerated atherosclerosis leads to increased risk of myocardial infarction, stroke and limb amputation. Four main molecular mechanisms have been implicated in glucose-mediated vascular damage. All seem to reflect a single hyperglycaemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain. This integrating paradigm provides a new conceptual framework for future research and drug discovery.

http://www.chem.uwec.edu/Chem454/BiochemDiabetes.pdf

Biochemistry and molecular cell biology of diabetic complications

Mechanisms underlying inflammation in neurodegeneration.

Ischemia and reperfusion-elicited tissue injury contributes to morbidity and mortality in a wide range of pathologies, including myocardial infarction, ischemic stroke, acute kidney injury, trauma, circulatory arrest, sickle cell disease and sleep apnea. Ischemia-reperfusion injury is also a major challenge during organ transplantation and cardiothoracic, vascular and general surgery. An imbalance in metabolic supply and demand within the ischemic organ results in profound tissue hypoxia and microvascular dysfunction. Subsequent reperfusion further enhances the activation of innate and adaptive immune responses and cell death programs. Recent advances in understanding the molecular and immunological consequences of ischemia and reperfusion may lead to innovative therapeutic strategies for treating patients with ischemia and reperfusion-associated tissue inflammation and organ dysfunction.

/pdf/ischemia-and-reperfusion-from-mechanism-to-translation-1v2cagcnsb.pdf

Ischemia and reperfusion—from mechanism to translation

Endothelial Cells in Physiology and in the Pathophysiology of Vascular Disorders

In both type 1 and type 2 diabetes, the late diabetic complications in nerve, vascular endothelium, and kidney arise from chronic elevations of glucose and possibly other metabolites including free fatty acids (FFA). Recent evidence suggests that common stress-activated signaling pathways such as nuclear factor-kappaB, p38 MAPK, and NH2-terminal Jun kinases/stress-activated protein kinases underlie the development of these late diabetic complications. In addition, in type 2 diabetes, there is evidence that the activation of these same stress pathways by glucose and possibly FFA leads to both insulin resistance and impaired insulin secretion. Thus, we propose a unifying hypothesis whereby hyperglycemia and FFA-induced activation of the nuclear factor-kappaB, p38 MAPK, and NH2-terminal Jun kinases/stress-activated protein kinases stress pathways, along with the activation of the advanced glycosylation end-products/receptor for advanced glycosylation end-products, protein kinase C, and sorbitol stress pathways, plays a key role in causing late complications in type 1 and type 2 diabetes, along with insulin resistance and impaired insulin secretion in type 2 diabetes. Studies with antioxidants such as vitamin E, alpha-lipoic acid, and N-acetylcysteine suggest that new strategies may become available to treat these conditions.

/pdf/oxidative-stress-and-stress-activated-signaling-pathways-a-3134ynljka.pdf

Oxidative Stress and Stress-Activated Signaling Pathways: A Unifying Hypothesis of Type 2 Diabetes

Effects of pregnancy on glomerular dynamics: Micropuncture study in the rat

Roughly 3% of patients worldwide with a new diagnosis of type 2 diabetes mellitus (T2DM) already have an overt nephropathy at diagnosis and about 20-30% of the remaining ones develop a complication of this kind later in life. The early identification of kidney disease in diabetic patients is important as it slows its progression, which is important not only because this reduces the need for renal replacement therapy, but also because it decreases the high rate of mortality and morbidity associated with a reduction in kidney function. The increasing prevalence of type 2 diabetes and the consequent greater probability of finding different types of kidney diseases in diabetic patients frequently gives rise to overlapping diagnoses, a definition encompassing the differential diagnosis between diabetic and non-diabetic kidney disease. The issue is made more complex by the acknowledgement of the increasing frequency of presentations of what is termed "diabetic kidney disease" without relevant proteinuria, in particular in T2DM patients. Distinguishing between diabetes related and non-diabetes related forms of kidney disease in diabetic patients is not only a semantic question, as different diseases require different clinical management. However, while the urologic and macrovascular complications of diabetes, as well as overlapping parenchymal damage, can be diagnosed by means of imaging studies, often only a kidney biopsy will make a differential diagnosis possible. In fact, the coexistence of typical diabetic lesions, such as nodular glomerulopathy or glomerulosclerosis, with different glomerular, vascular and tubulo-interstitial alterations has been extensively described, and an analysis of the dominant histological pattern can contribute to determining what therapeutic approach should be adopted. However, due to the high frequency of kidney diseases, and to the fact that T2DM patients are often affected by multiple comorbidities, a kidney biopsy is not generally performed in T2DM patients. What follows is a review aiming to discuss the diagnostic work-up, on the base of clinical, laboratory and imaging criteria, and evaluate the present indications and alternatives to renal biopsy.

https://www.mdpi.com/1422-0067/22/11/5425/pdf

Kidney biopsy in type 2 diabetic patients: Critical reflections on present indications and diagnostic alternatives

Antifungal prophylaxis may be required in high-risk patients undergoing liver transplantation and for that reason we aimed to verify its role and its related impact on the graft. From January 2006 throughout 2012, 250 liver transplants were evaluated and 54 patients identified as being at higher risk were randomly selected to undergo the following schedule: 28 patients received liposomal amphotericin B and 26 received caspofungin. We evaluated, throughout 12 months, renal and liver function tests, bacterial and fungal infection episodes, and intensive care unit (ICU) stay, as well as the Th1 and Th2 cytokine network. Differences were analyzed according to non-parametric tests (two-tailed p values). Neither of the groups showed episodes of invasive fungal infection during the 12 months follow-up; however, patients receiving prophylaxis with liposomal amphotericin B had reduced episodes of bacterial infections coupled with an improved immune system response compared with those receiving caspofungin. Finally, a reduced stay in the ICU was also observed. In conclusion, even if the results of liposomal amphotericin B and caspofungin prophylaxis strategies did not differ in terms of invasive fungal infection rate, patients receiving prophylaxis with liposomal amphotericin B had a reduced ICU stay and an improved Th2 status, as well as a reduced number of post-transplant bacterial infections. Further studies are required to better address and evaluate these findings.

Antifungal prophylaxis with liposomal amphotericin B and caspofungin in high-risk patients after liver transplantation: impact on fungal infections and immune system.

We determine the feasibility of laparoscopic revision surgery in children following previous open and laparoscopic antireflux operations. To give an objective overview about this topic, we analyzed the outcome of 15 children (8 girls and 7 boys) who had undergone attempted laparoscopic revision between 4 and 72 months (median 16 months) after a previous antireflux operation. Seven patients had previously undergone an open antireflux procedure (4 Nissen fundoplication; 3 Thal procedure) and 8 a laparoscopic procedure (5 Nissen; 3 Toupet's procedure). Two of these children were mentally handicapped. The indications for revision were: recurrent reflux, 5; valve migration, 5; valve dismount, 5. Eight procedures comprised construction of a new Nissen fundoplication and in 7 cases a Toupet's procedure was performed. Revision was successfully completed laparoscopically in 10 cases, 7 of 8 patients following a previous laparoscopic procedure and in 3 of 7 following a previous open operation. Operating time ranged between 70 and 140 minutes (median 90 minutes). No perioperative complications occurred in either group. All patients were discharged within 3 to 4 days after the redo procedure. Follow-up time varied between 6 months and 7 yrs. Preoperative symptoms were relieved in all patients and all antireflux medication has been discontinued, except in two cases that still had rare symptoms. Although technically challenging, laparoscopic reoperation for recurrent gastroesophageal reflux disease can be performed safely and with good results, in the hands of experienced endoscopic surgeons. Reoperation is likely to be more difficult following failure of an open procedure than after failure of a laparoscopic one. Concerning the type of procedure, redo surgery is more difficult to perform after Nissen's than after Toupet's or Thal's procedure.

Ciro Esposito

Papers

Effects of pregnancy on glomerular dynamics: Micropuncture study in the rat

Kidney biopsy in type 2 diabetic patients: Critical reflections on present indications and diagnostic alternatives

Antifungal prophylaxis with liposomal amphotericin B and caspofungin in high-risk patients after liver transplantation: impact on fungal infections and immune system.

Laparoscopic reoperation following unsuccessful antireflux surgery in childhood.

Acute effects of cyclosporine on glomerular dynamics--micropuncture study in the rat.