Electroencephalography functional connectivity-A biomarker for painful polyneuropathy.

BACKGROUND AND PURPOSE: Advanced analysis of electroencephalography (EEG) data has become an essential tool in brain research. Based solely on resting state EEG signals, a data-driven, predictive and explanatory approach is presented to discriminate painful from non-painful diabetic polyneuropathy (DPN) patients. METHODS: Three minutes long, 64 electrode resting-state recordings were obtained from 180 DPN patients. The analysis consisted of a mixture of traditional, explanatory and machine learning analyses. First, the 10 functional bivariate connections best differentiating between painful and non-painful patients in each EEG band were identified and the relevant receiver operating characteristic was calculated. Later, those connections were correlated with selected clinical parameters. RESULTS: Predictive analysis indicated that theta and beta bands contain most of the information required for discrimination between painful and non-painful polyneuropathy patients, with area under the receiver operating characteristic curve values of 0.93 for theta and 0.89 for beta bands. Assessing statistical differences between the average magnitude of functional connectivity values and clinical pain parameters revealed that painful DPN patients had significantly higher cortical functional connectivity than non-painful ones (p = 0.008 for theta and p = 0.001 for alpha bands). Moreover, intra-band analysis of individual significant functional connections revealed a positive correlation with average reported pain in the previous 3 months in all frequency bands. CONCLUSIONS: Resting state EEG functional connectivity can serve as a highly accurate biomarker for the presence or absence of pain in DPN patients. This highlights the importance of the brain, in addition to the peripheral lesions, in generating the clinical pain picture. This tool can probably be extended to other pain syndromes.

Renal safety and survival among acutely ill hospitalized patients treated by blockers of the Renin-Angiotensin axis or loop diuretics: a single-center retrospective analysis.

BACKGROUND: Concern exists regarding the renal safety of blocking the renin-angiotensin system (RAS) during acute illness, especially in the presence of volume depletion and hemodynamic instability. METHODS: We explored the impact of loop diuretics and RAS blockers on the likelihood of developing acute kidney injury (AKI) or acute kidney functional recovery (AKR) among inpatients. Adjusted odds ratio for AKI, AKR and mortality was calculated, using logistic regression models, with subgroup analysis for patients with estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2, corrected for blood pressure measurements. RESULTS: 53,289 patients were included. RAS blockade was associated with reduced adjusted odds ratio for both AKI (0.76, CI 0.70-0.83) AKR (0.55, 0.52-0.58), and mortality within 30 days (0.44, 0.41-0.48), whereas loop diuretics were associated with increased risk of AKI (3.75, 3.42-4.12) and mortality (1.71, 1.58-1.85) and reduced AKR (0.71, 0.66-0.75). Comparable impact of RAS blockers and loop diuretics on renal outcomes and death was found among 6,069 patients with eGFR < 30 ml/min/1.73m2. RAS inhibition and diuretics tended to increase the adjusted odds ratios for AKI and to reduce the likelihood of AKR in hypotensive patients. CONCLUSIONS: Reduced blood pressure, RAS blockers and diuretics affect the odds of developing AKI or AKR among inpatients, suggesting possible disruption in renal functional reserve (RFR). As long as blood pressure is maintained, RAS inhibition seems to be safe and renoprotective in this population, irrespective of kidney function upon admission, and is associated with reduced mortality.

Combination of hyperglycaemia and hyperlipidaemia induces endothelial dysfunction: Role of the endothelin and nitric oxide systems.

Endothelial dysfunction (ED) is a key feature of diabetes and is a major cause of diabetic vasculopathy. Diabetic patients who also exhibit hyperlipidaemia suffer from accelerated vascular complications. While the deleterious effects of high glucose levels (HG) and hyperlipidaemia alone on ED are well established, the effects of combined hyperlipidaemia and HG have not been thoroughly studied. Therefore, the current study examines whether HG and hyperlipidaemia exert synergistic ED, and explores the mechanisms underlying this phenomenon. We applied multi-disciplinary approaches including cultured HUVECs and HMEC-1 as well as knockout mice CByJ.129S7(B6)-Ldlrtm1Her/J (LDLR-/- ) to investigate the mechanisms underlying combined HG and hyperlipidaemia-induced ED. Incremental doses of glucose in the presence or absence of OxLDL were added to HUVECs and HMEC-1. After 5 days, the status of nitric oxide (NO) and endothelin (ET)-1 systems as well as their signal transduction were assessed using Western blot, ELISA and immunoreactive staining. The effects of chronic combination of HG and hyperlipidaemia on endothelial integrity and function as well as alterations in circulatory NO and ET-1 systems were examined in knockout mice LDLR-/- and their wild-type. HUVEC cells exposed to HG and OxLDL displayed enhanced ET-1 production, more than HG or OxLDL when added alone. Overproduction of ET-1 stems from up-regulation of endothelin converting enzyme (ECE)-1 as observed under these conditions. In contrast, combination of HG and OxLDL dramatically decreased both total endothelial NO synthase (eNOS) by 60%, and activated eNOS (peNOS) by 80%. Moreover, NRF2 decreased by 42% and its active form (pNRF2) by 56%, as compared to baseline. Likewise, ETB levels decreased by 64% from baseline on endothelial cells. Furthermore, diabetic LDLR-/- mice displayed a higher blood pressure, plasma triglycerides, cholesterol, ET-1 and NO2/NO3 levels, when compared with normoglycemic LDLR-/- and BALB mice. Combined hyperglycaemia and hyperlipidaemia activates the ET system and attenuates the nitric oxide system with the Nrf2 signalling pathway. These findings suggest that perturbations in these paracrine systems may contribute to ED.

Renal Functional Recovery Confounding the Assessment of Contrast Nephropathy: Propensity Score Analysis.

BACKGROUND: Large data analyses confirm the relative safety of contrast-enhanced computed tomography (CT), except for those with advanced renal failure. However, the prevalence of post-contrast acute kidney injury may be masked by acute kidney functional recovery (AKR) in unstable inpatients, irrespective of contrast-enhanced imaging. METHODS: In this work we aimed to assess AKI and AKR along with need for dialysis and mortality, among inpatients undergoing contrast-enhanced or non-enhanced CT. We performed a large-scale retrospective data analysis using propensity score matching (PSM) that compared patients undergoing contrast-enhanced and non-enhanced imaging. We also performed a subgroup analysis of subjects stratified by baseline renal function. RESULTS: A total of 41,456 patients were analyzed. PSM resulted in well-balanced groups. AKR occurred substantially more often than AKI among hospitalized patients following CT imaging, especially among those with low baseline renal function. Yet, in this population, whereas the rate of AKI significantly increased, the rate of AKR significantly decreased following contrast-enhanced studies as compared to patients that underwent non-enhanced CT. A significantly higher proportion of patients with baseline advanced renal failure that underwent contrast-enhanced imaging required dialysis. CONCLUSIONS: The increased incidence of AKI and AKR as seen in patients with lower pre-imaging kidney function possibly suggests that both entities reflect impaired renal functional reserve. Unstable kidney function in inpatients, as demonstrated by rates of AKR and AKI, is an important confounder which requires attention in similar observational studies on the renal effects of contrast media and of various other renal injurious events.

Endothelin-1 levels are decreased in pediatric Type 1 diabetes and negatively correlate with the carotid intima media thickness.

AIMS: Better understanding of the timeline and risk factors for the appearance of complications in pediatric Type-1-diabetes is key for developing prevention strategies. We studied endothelial markers and their determinants in adolescents with Type-1-diabetes at different time points from diagnosis. METHODS: A cross-sectional study of 58 adolescents, mean age 15.0 ± 2.4 years; 20 with recent-onset Type-1-diabetes, 20 with over 7 years of Type-1-diabetes and 18 controls. Clinical and biochemical data were collected. Fingertip arterial reactive hyperemia (EndoPAT) and carotid intima-media-thickness (cIMT) were measured to assess endothelial function and structure. RESULTS: Compared to controls, individuals with prolonged Type-1-diabetes had higher mean cIMT (0.49 ± 0.07 mm vs. 0.43 ± 0.05 mm p = 0.021) and maximal cIMT (0.61 ± 0.08 mm 0.52 ± 0.08 mm, p = 0.025). Endothelin-1 levels were significantly lower in subjects with prolonged Type-1-diabetes (1.2 ± 1.0 pg/ml) compared to controls (3.0 ± 1.7, p = 0.008 pg/ml); they negatively correlated with the mean cIMT (c = - 0.291, p = 0.031) and mean 6 months hemoglobin A1c (c = - 0.301, p = 0.022) and positively correlated with mean c-peptide levels (c = 0.356, p = 0.006) and the weekly exercise time (c = 0.485, p < 0.001). Endothelin-1 levels did not correlate with EndoPAT results. CONCLUSIONS: Our results suggest that the early years after the diagnosis of Type-1-diabetes are an important window for prevention of arterial damage in the pediatric population. The trajectories of relationships of Endothelin-1 with metabolic and vascular measures were opposite from the anticipated, yet consistent. Endothelin-1 related indirectly to adverse measures and directly to favorable measures. Decreased Endothelin-1 levels might reflect early stages in endothelial impairment in Type-1-diabetes, yet its' exact role in the development of complications is yet to be unraveled.

Renal functional recovery among inpatients: A plausible marker of reduced renal functional reserve.

Renal functional reserve (RFR) reflects the ability of the kidney to enhance glomerular filtration rate (GFR) in response to a protein load. Chronic kidney disease (CKD) leads to diminished RFR, since the capacity for whole-body GFR to increase through hyperfiltration of remaining nephrons is limited. Evaluating 41,456 inpatients following computerised tomography we reported many exhibiting acute kidney injury (AKI) but more patients with recovering kidney function (AKR), presumably reflecting resolution of their critical conditions. The incidences of AKI and AKR were closely co-associated and were both inversely correlated with baseline kidney function. We discuss this phenomenon, arguing that AKR among inpatients with an acute illness, like AKI, may often reflect underlying subtle CKD with diminished RFR.

[RADIOCONTRAST NEPHROPATHY: MYTHS OR REALITY? THE VALUE OF PROPENSITY MATCHING APPLIED FOR LARGE DATA RETROSPECTIVE ANALYSES].

INTRODUCTION: Reviewed are three studies we conducted, assessing the risk of contrast nephropathy in hospitalized patients undergoing computerized tomography. These were retrospective large data analyses at a single tertiary care facility, using meticulous and compound propensity score matching and inverse probability of treatment weighting. These studies indicate that overall, the risk of contrast nephropathy is likely negligible, with the exception of patients with grades 4-5 renal failure at baseline (eGFR<30 ml/min/1.73m2), with an odds ratio of 1.51 to develop AKI, associated with increased mortality as compared with patients undergoing non-enhanced imaging. We also assessed the incidence and magnitude of improved kidney function (acute kidney recovery) around imaging, underscoring its potential to mask subclinical AKI. These studies illustrate the strengths of large data analysis with advanced statistical tools.

[INTERNAL MEDICINE: "WHAT MAKES THE DESERT BEAUTIFUL - IS A WELL HIDDEN SOMEWHERE"].

INTRODUCTION: In recent years, the status of Internal Medicine has been constantly wearing down. There has been a dramatic decrease in the number of internal medicine students and residents planning to pursue careers in internal medicine. This is mainly due to a higher workload, as well as physical and professional exhaustion leading to work dissatisfaction and provision of suboptimal patient care. Therefore, an increased tendency towards selecting a career in internal medicine sub-specialties has been noted. In this paper, we will present an open and sincere talk with three young internal medicine specialists, who willingly decided to keep working in internal medicine departments despite the challenging work environment. We will discuss the burnout associated with poor work-life/home balance and disruptive work environment and suggest measurements that may enhance the educational and professional experience and career satisfaction and increase the well-being of internal medicine specialists in the future. We aim to promote awareness to the importance of maintaining high-quality senior physicians working in Internal Medicine departments.

Skin well-being in diabetes: Role of macrophages.

Macrophages are key players in wound healing- along with mediating the acute inflammatory response, macrophages activate cutaneous epithelial cells and promote tissue repair. Diabetes complications, including diabetic chronic wounds, are accompanied by persistent inflammation and macrophage malfunction. Several studies indicate that hyperglycemia induces various alterations that affect macrophage function in wound healing including epigenetic changes, imbalance between pro- and anti-inflammatory modulators, and insensitivity to proliferative stimuli. In this review, we briefly summarize recent studies regarding those alterations and their implications on skin well-being in diabetes.

Near-drowning: new perspectives for human hypoxic acute kidney injury.

Concepts regarding hypoxic acute kidney injury (AKI) are derived from widely used warm ischemia-reflow (WIR) models, characterized by extensive proximal tubular injury and associated with profound inflammation. However, there is ample clinical and experimental data indicating that hypoxic AKI may develop without total cessation of renal blood flow, with a different injury pattern that principally affects medullary thick limbs in the outer medulla. This injury pattern likely reflects an imbalance between blood and oxygen supply and oxygen expenditure, principally for tubular transport. Experimental models of hypoxic AKI other than WIR are based on mismatched oxygen delivery and consumption, particularly within the physiologically hypoxic outer medulla. However, evidence for such circumstances in human AKI is lacking. Recent analysis of the clinical course and laboratory findings of patients following near-drowning (ND) provides a rare glimpse into such a scenario. This observation supports the role of renal hypoxia in the evolution of AKI, as renal impairment could be predicted by the degree of whole-body hypoxia (reflected by lactic acidosis). Furthermore, there was a close association of renal functional impairment with indices of reduced oxygen delivery (respiratory failure and features of intense sympathetic activity) and of enhanced oxygen consumption for active tubular transport (extrapolated from the calculated volume of consumed hypertonic seawater). This unique study in humans supports the concept of renal oxygenation imbalance in hypoxic AKI. The drowning scenario, particularly in seawater, may serve as an archetype of this disorder, resulting from reduced oxygen delivery, combined with intensified oxygen consumption for tubular transport.

Biomarker evidence for distal tubular damage but cortical sparing in hospitalized diabetic patients with acute kidney injury (AKI) while on SGLT2 inhibitors.

BACKGROUND: Inhibitors of sodium-glucose co-transporter-2 (SGLT2i) were found to improve renal outcome in diabetic patients in large prospective randomized trials. Yet, SGLT2i may acutely reduce kidney function through volume depletion, altered glomerular hemodynamics or intensified medullary hypoxia leading to acute tubular injury (ATI). The aim or this study was to prospectively assess the pathophysiology of acute kidney injury (AKI) in patients hospitalized while on SGLT2i, differing ATI from pre-renal causes using renal biomarkers. METHODS: Serum and urine Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Kidney Ischemia Molecule (KIM)-1, markers of distal and proximal tubular injury, respectively, were determined in 46 diabetic patients who were on SGLT2i upon hospitalization with an acute illness. RESULTS: Serum and urine NGAL, but not KIM-1, were significantly increased in 21 of the patients who presented with AKI upon admission, as compared with 25 patients that maintained kidney function. Both serum and urinary NGAL correlated with the degree of impaired renal function, which in many cases was likely the result of additional acute renal perturbations, such as sepsis. CONCLUSIONS: Increased urinary and serum NGAL indicates that ATI, principally affecting distal tubular segments, may develop in some of the patients hospitalized with an acute illness and AKI while on SGLT2i. It is suggested that intensified medullary hypoxia by SGLT2i might be detrimental in this injury. By contrast, concomitantly unaltered KIM-1 might reflect improved cortical oxygenation by SGLT2i, and may explain an overall reduced risk of AKI with SGLT1i in large series. The independent potential of SGLT2i to inflict medullary hypoxic damage should be explored further.

Mortality in Patients with Polymyositis and Dermatomyositis in an Israeli Population.

BACKGROUND: The reported mortality rates of patients with polymyositis and dermatomyositis are highly variable worldwide. The excess mortality of patients with polymyositis/dermatomyositis has not been evaluated in an Israeli population. OBJECTIVES: To investigate the overall mortality in a large and well-established cohort of patients with polymyositis/dermatomyositis as compared to the mortality expected in the matched general population in a tertiary medical center. METHODS: In this retrospective cohort study, the mortality of 166 patients with polymyositis/dermatomyositis was compared to age- and sex-matched control subjects in the general population. All-cause standardized mortality ratios (SMRs) were estimated. RESULTS: Overall, 47 (28.3%) deaths were observed among patients with polymyositis/dermatomyositis during a mean follow-up period of 5.8 ± 4.8 years, which was 7 times higher than in the control group (SMR 7.4, 95% confidence interval [95%CI] 5.5-9.8). The SMRs were comparable in patents with polymyositis (7.7, 95%CI 4.8-12.3) and dermatomyositis (7.2, 95%CI 5.0-10.3). The 1-, 5-, 10-, and 15-year overall survival rates were 90.0%, 82.8%, 51.5%, and 26.1%, respectively, in patients with polymyositis, and 80.3%, 59.6%, 40.0%, and 17.1%, respectively, in patients with dermatomyositis. CONCLUSIONS: The overall mortality among Israeli patients with polymyositis/dermatomyositis is 7.4 times greater than for the general population. Although long-term mortality was comparable between patients with dermatomyositis and polymyositis, patients in the former group died at a notably earlier stage.

Increased Intra-abdominal Pressure Induces Acute Kidney Injury in an Experimental Model of Congestive Heart Failure.

BACKGROUND: Congestive heart failure (CHF) entails a complex interaction between the heart and the kidney that represents a clinical entity called cardiorenal syndrome (CRS). One of the mechanisms underlying CRS includes increased intra-abdominal pressure (IAP). We examined the effect of elevated IAP on kidney function in rats with low- and high-output CHF. METHODS AND RESULTS: Rats with compensated and decompensated CHF induced by means of aortocaval fistula, rats with myocardial infraction (MI) induced by means of left anterior descending artery ligation, and sham control rats were subjected to either 10 or 14 mm Hg IAP. Urine flow (V), Na+ excretion (UNaV), glomerular filtration rate (GFR), and renal plasma flow (RPF) were determined. The effects of pretreatment with tadalafil (10 mg/kg orally for 4 days) on the adverse renal effects of IAP were examined in decompensated CHF and MI. Basal V and GFR were significantly lower in rats with decompensated CHF compared with sham control rats. Decompensated CHF rats and MI rats subjected to 10 and 14 mm Hg IAP exhibited more significant declines in V, UNaV, GFR and RPF than compensated and sham controls. Elevated IAP also induced tubular injury, as evidenced by significantly increased absolute urinary excretion of neutrophil gelatinase-associated lipocalin. In addition, in a nonquantitative histologic analysis, elevated IAP was associated with increase in necrosis and cell shedding to the tubule lumens, especially in the decompensated CHF subgroup. Pretreatment of decompensated CHF rats and MI rats with tadalafil ameliorated the adverse renal effects of high IAP. CONCLUSIONS: Elevated IAP contributes to kidney dysfunction in high- and low-cardiac output CHF. IAP induces both hemodynamic alterations and renal tubular dysfunction. These deleterious effects are potentially reversible and can be ameliorated with the use of phosphodiesterase-5 inhibition.

Regulation of Macrophage Apoptosis and Atherosclerosis by Lipid-Induced PKCδ Isoform Activation.

RATIONALE: Activation of monocytes/macrophages by hyperlipidemia associated with diabetes mellitus and obesity contributes to the development of atherosclerosis. PKCδ (protein kinase C δ) expression and activity in monocytes were increased by hyperlipidemia and diabetes mellitus with unknown consequences to atherosclerosis. OBJECTIVE: To investigate the effect of PKCδ activation in macrophages on the severity of atherosclerosis. METHODS AND RESULTS: PKCδ expression and activity were increased in Zucker diabetic rats. Mice with selective deletion of PKCδ in macrophages were generated by breeding PKCδ flox/flox mice with LyzM-Cre and ApoE-/- mice (MPKCδKO/ApoE-/- mice) and studied in atherogenic (AD) and high-fat diet (HFD). Mice fed AD and HFD exhibited hyperlipidemia, but only HFD-fed mice had insulin resistance and mild diabetes mellitus. Surprisingly, MPKCδKO/ApoE-/- mice exhibited accelerated aortic atherosclerotic lesions by 2-fold versus ApoE-/- mice on AD or HFD. Splenomegaly was observed in MPKCδKO/ApoE-/- mice on AD and HFD but not on regular chow. Both the AD or HFD increased macrophage number in aortic plaques and spleen by 1.7- and 2-fold, respectively, in MPKCδKO/ApoE-/- versus ApoE-/- mice because of decreased apoptosis (62%) and increased proliferation (1.9-fold), and not because of uptake, with parallel increased expressions of inflammatory cytokines. Mechanisms for the increased macrophages in MPKCδKO/ApoE-/- were associated with elevated phosphorylation levels of prosurvival cell-signaling proteins, Akt and FoxO3a, with reduction of proapoptotic protein Bim associated with PKCδ induced inhibition of P85/PI3K. CONCLUSIONS: Accelerated development of atherosclerosis induced by insulin resistance and hyperlipidemia may be partially limited by PKCδ isoform activation in the monocytes, which decreased its number and inflammatory responses in the arterial wall.

Exogenous Insulin Infusion Can Decrease Atherosclerosis in Diabetic Rodents by Improving Lipids, Inflammation, and Endothelial Function.

OBJECTIVE: The objective of this study is to evaluate whether exogenously induced hyperinsulinemia may increase the development of atherosclerosis. APPROACH AND RESULTS: Hyperinsulinemia, induced by exogenous insulin implantation in high-fat fed (60% fat HFD) apolipoprotein E-deficient mice (ApoE-/-) mice, exhibited insulin resistance, hyperglycemia, and hyperinsulinemia. Atherosclerosis was measured by the accumulation of fat, macrophage, and extracellular matrix in the aorta. After 8 weeks on HFD, ApoE-/- mice were subcutaneously implanted with control (sham) or insulin pellet, and phlorizin, a sodium glucose cotransporters inhibitor (1/2)inhibitor, for additional 8 weeks. Intraperitoneal glucose tolerance test showed that plasma glucose levels were lower and insulin and IGF-1 (insulin-like growth factor-1) levels were 5.3- and 3.3-fold higher, respectively, in insulin-implanted compared with sham-treated ApoE-/- mice. Plasma triglyceride, cholesterol, and lipoprotein levels were decreased in mice with insulin implant, in parallel with increased lipoprotein lipase activities. Atherosclerotic plaque by en face and complexity staining showed significant reductions of fat deposits and expressions of vascular adhesion molecule-1, tumor necrosis factor-α, interleukin 6, and macrophages in arterial wall while exhibiting increased activation of pAKT and endothelial nitric oxide synthase (P<0.05) comparing insulin-implanted versus sham HFD ApoE-/- mice. No differences were observed in atherosclerotic plaques between phlorizin-treated and sham HFD ApoE-/- mice, except phlorizin significantly lowered plasma glucose and glycated hemoglobin levels while increased glucosuria. Endothelial function was improved only by insulin treatment through endothelial nitric oxide synthase/nitric oxide activations and reduced proinflammatory (M1) and increased anti-inflammatory (M2) macrophages, which were inhibited by endothelial nitric oxide synthase inhibitor. CONCLUSIONS: Exogenous insulin decreased atherosclerosis by lowering inflammatory cytokines, macrophages, and plasma lipids in HFD-induced hyperlipidemia, insulin resistant and mildly diabetic ApoE-/- mice.

SHP-1 activation inhibits vascular smooth muscle cell proliferation and intimal hyperplasia in a rodent model of insulin resistance and diabetes.

AIMS/HYPOTHESIS: Accelerated migration and proliferation of vascular smooth muscle cells (VSMCs) enhances arterial restenosis after angioplasty in insulin resistance and diabetes. Elevation of Src homology 2-containing protein tyrosine phosphatase 1 (SHP-1) induces apoptosis in the microvasculature. However, the role of SHP-1 in intimal hyperplasia and restenosis has not been clarified in insulin resistance and diabetes. METHODS: We used a femoral artery wire injury mouse model, rodent models with insulin resistance and diabetes, and patients with type 2 diabetes. Further, we modulated SHP-1 expression using a transgenic mouse that overexpresses SHP-1 in VSMCs (Shp-1-Tg). SHP-1 agonists were also employed to study the molecular mechanisms underlying the regulation of SHP-1 by oxidised lipids. RESULTS: Mice fed a high-fat diet (HFD) exhibited increased femoral artery intimal hyperplasia and decreased arterial SHP-1 expression compared with mice fed a regular diet. Arterial SHP-1 expression was also decreased in Zucker fatty rats, Zucker diabetic fatty rats and in patients with type 2 diabetes. In primary cultured VSMCs, oxidised LDL suppressed SHP-1 expression by activating Mek-1 (also known as Map2k1) and increased DNA methylation of the Shp-1 promoter. VSMCs from Shp-1-Tg mice exhibited impaired platelet-derived growth factor (PDGF)-stimulated tyrosine phosphorylation with a concomitant decrease in PDGF-stimulated VSMC proliferation and migration. Similarly, HFD-fed Shp-1-Tg mice and mice treated with the SHP-1 inducer, Icariside II, were protected from the development of intimal hyperplasia following wire injury. CONCLUSIONS/INTERPRETATION: Suppression of SHP-1 by oxidised lipids may contribute to the excessive VSMC proliferation, inflammatory cytokine production and intimal hyperplasia observed in arteries from diabetes and insulin resistance. Augmenting SHP-1 levels is a potential therapeutic strategy to maintain stent patency in patients with insulin resistance and diabetes.

High density lipoprotein modulates osteocalcin expression in circulating monocytes: a potential protective mechanism for cardiovascular disease in type 1 diabetes.

BACKGROUND: Cardiovascular disease (CVD) is a major cause of mortality in type 1 diabetes (T1D). A pro-calcific drift of circulating monocytes has been linked to vascular calcification and is marked by the surface expression of osteocalcin (OCN). We studied OCN+ monocytes in a unique population with ≥50 years of T1D, the 50-Year Joslin Medalists (J50M). METHODS: CD45 bright/CD14+/OCN+ cells in the circulating mononuclear blood cell fraction were quantified by flow cytometry and reported as percentage of CD45 bright cells. Mechanisms were studied by inducing OCN expression in human monocytes in vitro. RESULTS: Subjects without history of CVD (n = 16) showed lower levels of OCN+ monocytes than subjects with CVD (n = 14) (13.1 ± 8.4% vs 19.9 ± 6.4%, p = 0.02). OCN+ monocytes level was inversely related to total high density lipoprotein (HDL) cholesterol levels (r = -0.424, p = 0.02), large (r = -0.413, p = 0.02) and intermediate (r = -0.445, p = 0.01) HDL sub-fractions, but not to small HDL. In vitro, incubation with OxLDL significantly increased the number of OCN+ monocytes (p < 0.01). This action of OxLDL was significantly reduced by the addition of HDL in a concentration dependent manner (p < 0.001). Inhibition of the scavenger receptor B1 reduced the effects of both OxLDL and HDL (p < 0.05). CONCLUSIONS: Low OCN+ monocytes levels are associated with lack of CVD in people with long duration T1D. A possible mechanism for the increased OCN+ monocytes could be the elevated levels of oxidized lipids due to diabetes which may be inhibited by HDL. These findings suggest that circulating OCN+ monocytes could be a marker for vascular disease in diabetic patients and possibly modified by HDL elevation.

Dysregulation of wound healing mechanisms in diabetes and the importance of negative pressure wound therapy (NPWT).

Diabetes is a serious disease with severe side effects and comorbidities. Diabetic foot with its chronic nonhealing ulcers, or diabetic foot ulcers, as they are commonly called, can be devastating, even leading to amputation. Many therapies exist to assist and improve wound healing. One exciting discovery is the use of negative pressure wound therapy (NPWT) as an adjunct to standard treatment. Few studies have substantively explored the molecular mechanisms of NPWT and why we see improved wound healing, a concept that demands more research. The following commentary summarizes the current literature regarding NPWT as well as some of the vast body of work that focuses on the physiologic mechanisms of wound healing in diabetics in general.

Remarkable differences in the epidemiology of pemphigus among two ethnic populations in the same geographic region.

BACKGROUND: The epidemiology of pemphigus in different ethnic populations exposed to similar environments is unknown. Trends in the incidence of pemphigus based on an immunopathologically validated cohort have not been investigated. OBJECTIVES: We sought to estimate the incidence of pemphigus in Israel and to investigate differences between the 2 major ethnic populations. METHODS: Pemphigus incidence was retrospectively estimated from January 2000 to December 2015 in 2 Israeli regions with a total population of 1.56 million inhabitants. RESULTS: One hundred eighty patients with pemphigus (mean age, 54.70 ± 16 years) were identified. The overall estimated incidence was 7.2 per million inhabitants per year (95% confidence interval, 6.2-8.3). The incidence in the Jewish population was threefold higher than that in Arabs (9.6 vs 3.2 cases per million per year, respectively; P < .0001) and higher among women than men (9 vs 5.3 cases per million per year, respectively; P < .0001). The incidence decreased from 8.4 cases per million per year in 2000 to 2005 to 7.0 and 6.0 (95% confidence interval, 4.5-7.9) in 2006 to 2010 and 2011 to 2015, respectively (P = .068). LIMITATIONS: This study was limited by the retrospective design and the small population. CONCLUSIONS: The incidence of pemphigus in Israel is among the highest reported worldwide and is significantly more frequent among Jews.