Daniela Adriana Ion

Correlation between inflammatory biomarkers and metabolic disorders in HIV infected patients undergoing antiretroviral therapy

Correlation between inflammatory biomarkers and metabolic disorders in HIV infected patients undergoing antiretroviral therapy Raluca Mihăilescu, Victoria Aramă, Cătălin Tiliscan, Daniela Munteanu, Viorica Leoveanu, Mihaela Rădulescu, Adriana Hristea, Cristina Popescu, Ruxandra Moroti, Violeta Molagic, Raluca Năstase, Loredana Benea, Ana Maria Tudor, Mihai Lazăr, Anca-Ruxandra Negru, Irina Lăpădat, Ligia Ionescu, Mirela Cernat, Georgeta Jugănaru, Doina Cristea, Adriana Manea, Adrian Streinu-Cercel, Daniela Adriana Ion, Sorin Ștefan Aramă

Different Dynamics of Aquaporin 4 and Glutamate Transporter-1 Distribution in the Perineuronal and Perivascular Compartments during Ischemic Stroke

Aquaporin‐4 (AQP4) and glutamate transporter‐1 (GLT‐1) represent the major water and glutamate astrocyte buffering gateways in the brain. Utilizing perilesional ischemic human cortices, we have performed here for the first time an integrative assessment on both AQP4 and GLT‐1, and on their proximity to blood vessels and neurons. Counting the relative number of AQP4±/GLT‐1±/glial fibrillary acidic protein± cells showed that double‐positive variants were overall most frequent, and their number tended to decrease from organized and recent perilesional cortices to controls. AQP4/GLT‐1 colocalization showed higher coefficients for the perilesional cortices compared with controls, suggesting an increased water/glutamate‐buffering capability. Distance frequency analysis of AQP4/GLT‐1 in relationship to neurons showed that both markers were concentrated at 20–40 μm around the perikarya; with AQP4 being more abundant in close proximity, these differences were not being driven by changes in neuropil density alone. Our study suggests a dual, simultaneous astrocytic function depending on the relative distance to neurons and vessels, with increased water and glutamate‐buffering capability in the mid perineuronal space, and an increased water‐buffering capability in the immediate perineuronal space, even higher than around vessels. Thus, adding specific AQP4/GLT‐1 modulator agents selectively depending on the acute/chronic phase of stroke might increase the efficacy of existing treatments.

Insulin resistance and adipokines serum levels in a caucasian cohort of hiv-positive patients undergoing antiretroviral therapy: a cross sectional study

BackgroundInsulin resistance is frequent in human immunodeficiency virus (HIV) infection and may be related to antiretroviral therapy. Cytokines secreted by adipose tissue (adipokines) are linked to insulin sensitivity. The present study is aimed to assess the prevalence of insulin resistance (IR) and its association with several adipokines, in a non-diabetic Romanian cohort of men and women with HIV-1 infection, undergoing combination antiretroviral therapy (cART).MethodsA cross-sectional study was conducted in an unselected sample of 89 HIV-1-positive, non-diabetic patients undergoing stable cART for at least 6 months. Metabolic parameters were measured, including fasting plasma insulin, and circulating adiponectin, leptin, resistin, tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) levels. Insulin resistance was estimated by measuring the Quantitative Insulin Sensitivity Check Index (QUICKI), using a cut-off value of 0.33. A linear regression model was fitted to QUICKI to test the association of IR and adipokines levels.ResultsA total of 89 patients (aged 18–65, median: 28 years) including 51 men (57.3%) and 38 women (42.7%) were included in the study. Fifty nine patients (66.3%) were diagnosed with IR based on QUICKI values lower than the cut-off point. IR prevalence was 72.5% in men and 57.6% in women. The presence of the IR was not influenced by either the time of the HIV diagnosis or by the duration of cART. Decreased adiponectin and increased serum triglycerides were associated with increased IR in men (R=0.43, p=0.007). Hyperleptinemia in women was demonstrated to be associated with the presence of IR (R=0.33, p=0.03).ConclusionsGiven the significant prevalence of the IR in our young non-diabetic cohort with HIV infection undergoing antiretroviral therapy reported in our study and the consecutive risk of diabetes and cardiovascular events, we suggest that the IR management should be a central component of HIV-infection therapeutic strategy. As adipokines play major roles in regulating glucose homeostasis with levels varying according to the sex, we suggest that further studies investigating adipokines should base their analyses on gender differences.

Matrix metalloproteinase-9 expression in the nuclear compartment of neurons and glial cells in aging and stroke

Matrix metalloproteinases (MMPs) are well‐recognized denominators for extracellular matrix remodeling in the pathology of both ischemic and hemorrhagic strokes. Recent data on non‐nervous system tissue showed intracellular and even intranuclear localizations for different MMPs, and together with this, a plethora of new functions have been proposed for these intracellular active enzymes, but are mostly related to apoptosis induction and malign transformation. In neurons and glial cells, on human tissue, animal models and cell cultures, different active MMPs have been also proven to be located in the intra‐cytoplasmic or intra‐nuclear compartments, with no clear‐cut function. In the present study we show for the first time on human tissue the nuclear expression of MMP‐9, mainly in neurons and to a lesser extent in astrocytes. We have studied ischemic and hemorrhagic stroke patients, as well as aged control patients. Age and ischemic suffering seemed to be the best predictors for an elevated MMP‐9 nuclear expression, and there was no evidence of a clear‐cut extracellular proteolytic activity for this compartment, as revealed by intact vascular basement membranes and assessment of vascular densities. More, the majority of the cells expressing MMP‐9 in the nuclear compartment also co‐expressed activated‐caspase 3, indicating a possible link between nuclear MMP‐9 localization and apoptosis in neuronal and glial cells following an ischemic or hemorrhagic event. These results, besides showing for the first time the nuclear localization of MMP‐9 on a large series of human stroke and aged brain tissues, raise new questions regarding the unknown spectrum of the functions MMPs in human CNS pathology.

Variations in the expression of TIMP1, TIMP2 and TIMP3 in cutaneous melanoma with regression and their possible function as prognostic predictors

Regression in melanoma is a frequent biological event of uncertain prognostic value as the lesion exhibits heterogeneous phenotypical features, both at the morphological and immunohistochemical level. In the present study, we examined the expression of tissue inhibitors of metalloproteinases (TIMP1, TIMP2 and TIMP3) in melanoma with regression. We specifically examined the expression levels of these TIMPs in regressed components (RC) and non-regressed components (NRC) of the tumor and compared their expression levels with those in non-regressed melanomas. We found that TIMP1 was overexpressed in the NRC of melanomas with partial regression (PR) compared with the NRC in melanomas with segmental regression (SR) (P=0.011). TIMP2 was overexpressed in the NRC of melanomas with PR compared with the NRC in melanomas with SR (PR/SR, P=0.009); or compared with the NRC in melanomas with simultaneous SR-PR (P=0.002); or compared with melanomas without regression (absence of regression) (P=0.037). Moreover, TIMP3 was overexpressed in the NRC of all melanomas with SR as compared to the RC component (P=0.007). Our findings on the differential expression of TIMP1, TIMP2 and TIMP3 in melanomas with regression support the hypothesis that the morphological differences identified in the melanoma regression spectrum may have a correlation with prognosis. This may explain the controversial findings within the literature concerning the biological and prognostic role of regression in melanoma.

Serum adipokines and HIV viral replication in patients undergoing antiretroviral therapy.

INTRODUCTION Several studies have reported that cytokines secreted by adipose tissue (adipokines) may be linked to HIV replication. The aim of the study was to evaluate the relationship between HIV replication and serum levels of adipokines, in a Caucasian HIV-infected population of men and women undergoing complex antiretroviral therapy. METHODS A cross-sectional study was conducted in an unselected sample of 77 HIV-1-positive patients. Serum adipokines levels were measured including circulating adiponectin, leptin, resistin, tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6). Patients were divided into two groups: Group 1 - with undetectable viral load and Group 2 - with persistent HIV viral replication. Differences between groups ? were tested using independent-sample t-test for Gaussian variables and Mann-Whitney-Wilcoxon test for non-parametric variables. Pearsons chi-squared test was used for correlation analysis. RESULTS A total of 77 patients (age range: 17-65, mean: 32.5 years) including 44 men (57.1% men, age range: 17-63 years, mean: 34.1 years) and 33 women (42.9% women age range: 19-65 years, mean: 30.3 years) were included in the study. TNF-alpha had significantly higher serum levels in patients with detectable viral load (16.89 vs. 9.35 pg/mL), (p=0.043), but correlation analysis lacked statistical significance. Adiponectin had median serum levels of 9.22 ìg/mL in Group 1 vs. 16.50 ìg/mL in Group 2 but the results lacked statistical significance (p=0.059). Higher leptin, IL-6 and resistin serum levels were noted in patients with undetectable HIV viral load, without statistical significance. CONCLUSIONS The present study reported higher TNF-alpha serum levels in patients with persistent HIV viral load. We found no statistically significant correlations between adiponectin, leptin, resistin and IL-6 and HIV viral load in our Caucasian HIV-positive study population, undergoing antiretroviral therapy.

Body composition in HIV-infected patients receiving highly active antiretroviral therapy

Background: The development of combination antiretroviral therapies (cART) represents a significant advance in the treatment of (human immunodeficiency virus) HIV infection. However, several studies report that a large percentage of individuals with HIV, particularly those receiving cART, present body composition differences compared with the general population. The aim of this study was to explore body composition differences by dual-energy X-ray absorptiometry (DEXA), among HIV-positive patients receiving cART, in comparison to healthy controls. Methods: The cross-sectional study included 60 HIV-infected patients (all under 50 years old). We analyzed the association of antiretroviral medication use and different HIV-related factors, to the body composition parameters. Results: Our cohort had significantly lower fat mass and lower bone mass compared to non HIV-infected persons. Median time since HIV infection diagnosis was 5 years (interquartile range, [IQR], 2–10.25) and viral suppression was achieved in 49 (81.66%) patients. Treatment with protease inhibitors (PIs) was strongly correlated with low fat mass, reduced lean mass and loss of bone mineral density. Nucleoside reverse transcriptase inhibitors (NRTIs)-containing treatment was associated with decrease of lean tissue mass (LM). The prevalence of osteopenia was 41.67% at the lumbar spine (L1–L4) and 36.7% at the hip. We found osteoporosis in 10% of the patients at the lumbar spine. Reduced bone mass was associated, in the patient group, with the duration of PIs use and with smoking (in the males group). Conclusion: In our research, HIV-infected individuals compared to healthy controls had body composition differences, including fat mass atrophy and reduced bone mineral content.

Leptin expression in HIV-infected patients during antiretroviral therapy.

BACKGROUND Leptin is an adipokine with complex metabolic, neuroendocrine and immune functions. Our objective was to evaluate leptin serum levels in a cohort of Romanian HIV-infected patients undergoing antiretroviral therapy in relation to their immune-virological status, lipid and glucose metabolic abnormalities and the presence of metabolic syndrome (MS). METHODS We enrolled consecutive non-diabetic HIV-infected patients aged 18 and over on stable cART for at least 6 months. Blood samples were tested for: leptin, CD4 T cells count, HIV viral load and lipid panel. RESULTS A total of 90 HIV-infected patients were included in the study: 50 males (55.6%) with a mean age of 33.3 years and 40 females with a mean age of 30.4 years. Most patients (74.4%) had HIV viral load below the limit of detection and the median CD4 count for the cohort was 476 (410) cells/cmm. More than one third of the patients (41.1%) had hypoleptinemia. The prevalence of MS was 13.3%. Hypoleptinemia was significantly more frequent in men. In a subset of patients with undetectable HIV viral load, the median leptin value was 0.6 (6.07) ng/mL in patients with poor immune recovery (CD4 count ≤ 200/cmm) compared to 2 (3.07) ng/mL for those with better immune response (CD4 count > 200/cmm), without statistical significance. The median values of leptin were similar for persons with and without MS criteria. HDL-cholesterol values were positively correlated to leptin values in a linear regression model. CONCLUSION A significant proportion of patients in our study presented low levels of leptin; this finding was not associated with immune and virological parameters or the presence of MS. Hypoleptinemia was significantly correlated with lower levels of HDL-cholesterol, a key cardiovascular risk factor.

Potential association of obesity with IL6 G-174C polymorphism and TTV infections

Polymorphisms in IL6, ACE and ATR genes are associated with obesity. Torque Teno virus (TTV) seems to be able to interfere with production of some proinflammatory cytokines associated with obesity and related phenotypes. The aim of this study was to test the potential association between obesity, TTV infection and the IL6 G-174C (rs1800795), ACE I/D (rs4646994), AT1R A1166C (rs5186) polymorphisms. The polymorphisms and the presence of TTV were detected in blood samples from 150 obese and 150 normal-weight, healthy subjects using PCR based methods. IL6-174 CC genotype was more frequent in all obese patients (P=0.02) and in patients without TTV infections (P=0.03) than in controls. Obese women had more frequent TTV infections compared with normal-weight women (P=0.046). Obese subjects, regardless of gender (women P=0.03, men P=0.04), and healthy normal-weight men (P<0.01) carriers of AT1R C allele had higher triglycerides levels compared with non-carriers. The frequency of TTV in the control group (70.67%) was similar to data reported in other populations. The present study indicated that IL6-174 CC genotype and TTV infections in women could be associated with the common form of obesity.

The Association between Insulin Resistance and Proliferative Retinopathy in Type 1 Diabetes.

Abstract Introduction. Little is known about the relationship between insulin resistance and proliferative diabetic retinopathy in type 1 diabetes. The aim of this article is to explore the relationship between sight-threatening proliferative diabetic retinopathy and insulin resistance. Methods. This was a cross-sectional study that included 167 type 1 diabetes patients. Insulin resistance was assessed using eGDR (estimated glucose disposal rate) formula. Diabetic retinopathy was assessed by ophthalmoscopy using Early Treatment Diabetic Retinopathy classification. The association between eGDR and proliferative diabetic retinopathy was assessed in uni- and multivariate models using stepwise logistic regression of covariates. The contribution of individual predictors in the final regresion model was examined using Wald statistic. Results. Significantly lower eGDR’s values were observed in patients with proliferative diabetic retinopathy: 5.5 vs. 7 (p = 0.002). The results remained significant (p < 0.001) after adjusting for multiple covariates (sex, diabetes duration, body mass index, HDL cholesterol, LDL cholesterol, triglycerides, smoking). eGDR variable was retained in the final model of stepwise logistic regression (p < 0.001) and showed the strongest association with proliferative diabetic retinopathy (Wald = 12.73). Conclusions. In type 1 diabetes patients insulin resistance was the most important independent risk factor associated with diabetic proliferative retinopathy.