Increased plasma methylglyoxal level, inflammation, and vascular endothelial dysfunction in diabetic nephropathy

Objectives

To investigate the association of plasma levels of methylglyoxal (MG) and markers of inflammation/endothelial dysfunction with diabetic nephropathy (DN).

Design and methods

Plasma levels of MG, cytokines, and adhesion molecules were measured in type 2 diabetic patients (T2DM), T2DM patients with DN, and the controls.

Results

Plasma MG levels in DN were significantly higher than those in T2DM and the controls (312 ± 135 vs. 212 ± 73 and 312 ± 135 vs. 147 ± 78 nmol/L, respectively, P < 0.001). The plasma levels of MG were positively correlated with the fasting glucose, HbA1c, and urinary albumin/creatinine ratio (r = 0.754, P < 0.05). Plasma levels of IL-6, TNF-α, and adhesion molecules were markedly increased in DN compared to T2DM patients and the controls.

Conclusions

Increased plasma levels of MG, cytokines, and adhesion molecules are associated with DN. These markers may be useful in predicting the development of DN.     

Probabilistic neural networks for diagnosis of Alzheimer's disease using conventional and wavelet coherence

Recently, the authors presented an EEG (electroencephalogram) coherence study of the Alzheimer's disease (AD) and found statistically significant differences between AD and control groups. In this paper a probabilistic neural network (PNN) model is presented for classification of AD and healthy controls using features extracted in coherence and wavelet coherence studies on cortical connectivity in AD. The model is verified using EEGs obtained from 20 AD probable patients and 7 healthy/control subjects based on a standard 10-20 electrode configuration on the scalp. It is shown that extracting features from EEG sub-bands using coherence, as a measure of cortical connectivity, can discriminate AD patients from healthy controls effectively when a mixed band classification model is applied. For the data set used a classification accuracy of 100% is achieved using the conventional coherence and a spread parameter of the Gaussian function in a particular range found in this research.     

New diagnostic EEG markers of the Alzheimer’s disease using visibility graph

A new chaos–wavelet approach is presented for electroencephalogram (EEG)-based diagnosis of Alzheimer’s disease (AD) employing a recently developed concept in graph theory, visibility graph (VG). The approach is based on the research ideology that nonlinear features may not reveal differences between AD and control group in the band-limited EEG, but may represent noticeable differences in certain sub-bands. Hence, complexity of EEGs is computed using the VGs of EEGs and EEG sub-bands produced by wavelet decomposition. Two methods are employed for computation of complexity of the VGs: one based on the power of scale-freeness of a graph structure and the other based on the maximum eigenvalue of the adjacency matrix of a graph. Analysis of variation is used for feature selection. Two classifiers are applied to the selected features to distinguish AD and control EEGs: a Radial Basis Function Neural Network (RBFNN) and a two-stage classifier consisting of Principal Component Analysis (PCA) and the RBFNN. After comprehensive statistical studies, effective classification features and mathematical markers were discovered. Finally, using the discovered features and a two-stage classifier (PCA-RBFNN), a high diagnostic accuracy of 97.7% was obtained.     

Dynamic pressure–flow relationship of the cerebral circulation during acute increase in arterial pressure

The physiological mechanism(s) for the regulation of the dynamic pressure–flow relationship of the cerebral circulation are not well understood. We studied the effects of acute cerebral vasoconstriction on the transfer function between spontaneous changes in blood pressure (BP) and cerebral blood flow velocity (CBFV) in 13 healthy subjects (30 ± 7 years). CBFV was measured in the middle cerebral artery using transcranial Doppler. BP was increased stepwise with phenylephrine infusion at 0.5, 1.0 and 2.0 μg kg^–1 min^–1. Phenylephrine increased BP by 11, 23 and 37% from baseline, while CBFV increased (11%) only with the highest increase in BP. Cerebrovascular resistance index (BP/CBFV) increased progressively by 6, 17 and 23%, demonstrating effective steady-state autoregulation. Transfer function gain at the low frequencies (LF, 0.07–0.20 Hz) was reduced by 15, 14 and 14%, while the phase was reduced by 10, 17 and 31%. A similar trend of changes was observed at the high frequencies (HF, 0.20–0.35 Hz), but gain and phase remained unchanged at the very low frequencies (VLF, 0.02–0.07 Hz). Windkessel model simulation suggests that increases in steady-state cerebrovascular resistance and/or decreases in vascular compliance during cerebral vasoconstriction contribute to the changes in gain and phase. These findings suggest that changes in steady-state cerebrovascular resistance and/or vascular compliance modulate the dynamic pressure–flow relationship at the low and high frequencies, while dynamic autoregulation is likely to be dominant at the very low frequencies. Thus, oscillations in CBFV are modulated not only by dynamic autoregulation, but also by changes in steady-state cerebrovascular resistance and/or vascular compliance.     

Comparison among Ocular Response Analyzer, Corvis ST and Goldmann applanation tonometry in healthy children

AIM: To explore the relationship between different parameters of Ocular Response Analyzer (ORA) and Corvis ST (CST) in a sample of healthy Iranian school-aged children and the relationship between parameters of these 2 instruments against intraocular pressure (IOP), measured by the Goldmann applanation tonometer (GAT-IOP), age and gender, and find possible correlation between ORA and CST with GAT. METHODS: This cross-sectional study included 90 healthy children. A general interview and complete eye examination were performed. Following successful GAT-IOP measurement, ORA and CST were conducted. The CST parameters were A 1/2 length (A1L, A2L), A 1/2 velocity (A1V, A2V), highest concavity deformation amplitude (HCDA), radius of curvature (RoC), peak distance (PD), central corneal thickness (CCT) and IOP. The ORA parameters were corneal hysteresis (CH), corneal resistance factor (CRF), Goldmann-correlated IOP (IOP-G) and corneal compensated IOP (IOP-CC). Extracted data was analyzed using the Statistical Package for Social Science software. RESULTS: Totally 39 males with age of 9.08±1.60 (6-12)y and 51 females with age of 8.96±1.55 (6-13)y were included. Many CST parameters were significantly correlated with CH, CRF, IOP-G and IOP-CC. Some CST parameters had a significant correlation with GAT-IOP, including IOP-CST in both eyes and HCDA, A2L, PD, and RoC in the left eye, but none with age, except A2L in the right eye. The CRF measurement showed a significant correlation with GAT-IOP in both eyes and CH in the right eye, yet, none with age. Among all CST and ORA parameters, CCT-CST in both eyes and A1L in right eye had a significant correlation with gender, although this was a negligible negative correlation. Comparison of mean IOP values by different devices showed a significantly highest IOP overestimation by CST and lowest by IOP-CC compared with GAT. Also, IOP-G versus IOP-CST significantly had the lowest IOP overestimation among others. Overall, either low positive correlation or negligible correlation was found between IOP measurements by 3 instruments. CONCLUSION: The study finds the highest IOP overestimation by CST and lowest by IOP-CC compared with GAT. Overall, either low positive correlation or negligible correlation is found between IOP measurements by the 3 instruments.     

Hepatic insulin resistance,metabolic syndrome and cardiovascular disease

BackgroundThe metabolic syndrome is a constellation of common metabolic disorders that is associated with cardiovascular disease. Insulin resistance has a central role in the pathophysiology of metabolic syndrome.Recent advancesIt is now commonly accepted that chronic inflammation associated with visceral obesity induces insulin resistance in the liver. Chronic inflammation is characterized by the production of abnormal adipokines and cytokines such as TNF-α, FFA, IL-1, IL-6, leptin and resistin. These factors inhibit insulin signalling in hepatocytes by activating SOCS proteins, several kinases such as JNK, IKK-β and PKC and protein tyrosine phosphatases such as PTP1B and PTEN, that in turn impair insulin signalling at insulin receptor and insulin receptor substrate (IRS) level. Hepatic insulin resistance in turn causes impaired suppression of glucose production by insulin in hepatocytes leading to hyperglycemia. An important and early complication of hepatic insulin resistance is the induction of hepatic VLDL production, via changes in the rate of apoB synthesis and degradation and de novo lipogenesis, or increased FFA flux from adipose tissue into the liver. Insulin resistance also stimulates the production of CRP and PAI-1, both markers of an inflammatory state. All metabolic abnormalities related to hepatic insulin resistance have been shown to directly or indirectly promote atherosclerosis. Hyperglycemia induces a series of alterations including endothelial dysfunction, cellular proliferation, changes in extracellular matrix conformation and impairment of LDL receptor-mediated uptake decreasing the in vivo clearance of LDL. Small dense LDLs associated with high circulating VLDL have higher affinity to the intimal proteoglycans leading to the penetration of more LDL particles into the arterial wall. CRP can also accelerate atherosclerosis by increasing the expression of PAI-1 and adhesion molecules in endothelial cells, inhibition of nitric oxide formation and increasing LDL uptake into macrophages.ConclusionsOverall, growing evidence suggests that hepatic insulin resistance is sufficient to induce several components of the metabolic syndrome and promote progression to cardiovascular disease. Many unresolved questions remain however on the molecular and cellular mechanisms that trigger hepatic insulin resistance and promote the development of clinical metabolic syndrome.     

Evaluation of Alum-Naltrexone Adjuvant Activity,on Efficacy of Anti-Leishmania Immunization with Autoclaved Leishmania major (MRHO/IR/75/ER) Antigens in BALB/C Mice

Background

Naltrexone, an opioid receptor antagonist shifts the immune response toward a Th1 profile. In the current study, we evaluated the efficacy of the mixture of NTX and alum, as a new adjuvant, to enhance immune response and induce protection against Leishmania major in a mouse model.

Methods

BALB/c mice were immunized three times either autoclaved L. major promastigotes’ antigens alone or in combination with the adjuvant alum, naltrexone or the alum–naltrexone mixture. Both humoral and cellular immune responses were assessed two weeks after the last immunization and compared with control mice.

Results

The administration of alum- NTX in combination with the parasite antigen, significantly increased production of IFN-γ IFN-γ /IL-5 ratio, lymphocyte proliferation and improved DTH response against L. major. There was no significant difference in survival following challenge among groups.

Conclusion

Immunization with the alum– naltrexone mixture as an adjuvant, in combination with the autoclaved L. major promastigotes antigens, can enhance cellular immunity and shift the immune responses to a Th1 pattern.