Sameh Sarray

Serum IL-6, IL-10, and TNFα levels in pediatric sickle cell disease patients during vasoocclusive crisis and steady state condition

Vaso-occlusive crisis (VOC) is a significant complication of sickle cell disease (SCD), and altered production of pro-inflammatory and anti-inflammatory molecules contributed to its pathogenesis. In view of the association of chronic inflammation with VOC onset, and given the capacity of interleukin (IL)-10 as anti-inflammatory, and IL-6, and TNFα as pro-inflammatory cytokines, we tested the association of altered IL-10, IL-6, and TNFα secretion with VOC pathogenesis and its severity. Study subjects comprised 147 SCD patients with active VOC (VOC Group), and 63 pain-free SCD patients for at least 9 months before blood collection (Steady-state Group). Serum cytokine concentrations were determined by ELISA. IL-10 levels were significantly reduced, while IL-6 levels were increased in VOC compared to Steady-state groups; serum TNFα levels were comparable between both groups. There was enrichment of low IL-10, but high IL-6 and TNFα quartiles in VOC Group, which translated into increased VOC risk. In contrast, high IL-10, but low IL-6 and TNFα quartiles were seen in Steady-state Group. Correlation analysis demonstrated significant association between reduced IL-10 levels and the frequency, type, severity, and duration of VOC and requirement for hydroxyurea treatment, while IL-6 correlated with duration of VOC episodes. Our data support strong association of reduced IL-10 and increased IL-6 levels with VOC, and their modulation of VOC-related parameters.

Validity of adiponectin-to-leptin and adiponectin-to-resistin ratios as predictors of polycystic ovary syndrome

OBJECTIVE To evaluate the association of changes in adipokine ratios with polycystic ovary syndrome (PCOS) and related features as altered levels of the adipokines adiponectin, leptin, and resistin were linked with the pathogenesis of PCOS. DESIGN Case-control retrospective study. SETTING Outpatient obstetrics/gynecology and adult endocrinology clinics. PATIENT(S) Unrelated women with PCOS (n = 211) and age-matched control women (n = 215). INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Utility of adiponectin/leptin and adiponectin/resistin ratios as potential biomarkers of PCOS and associated features. RESULT(S) Significant differences in adiponectin but not leptin or resistin serum levels were seen between women with PCOS and control women. Ratios of adiponectin/leptin and adiponectin/resistin, but not leptin/resistin ratios, were statistically significantly different between PCOS cases and control women. Receiver operated characteristics area under the curve demonstrated sensitivity and specificity for adiponectin/leptin and adiponectin/resistin but not leptin/resistin ratios or individual adipokines as predictors of PCOS. Adiponectin/leptin and adiponectin/resistin ratios negatively correlated with body mass index, homeostatic model assessment, insulin resistance, and free insulin, testosterone, and sex hormone-binding globulin. In addition, adiponectin/resistin ratio negatively correlated with menarche. CONCLUSION(S) Ratios of adiponectin/leptin and adiponectin/resistin constitute novel predictor factors to explain PCOS and associated features and thus may present target for novel therapeutics in PCOS.

Contribution of Reduced Interleukin-10 Levels to the Pathogenesis of Osteomyelitis in Children with Sickle Cell Disease.

ABSTRACT Osteomyelitis is a significant complication of sickle cell disease (SCD), and several factors contribute to its pathogenesis, including altered expression of proinflammatory and anti-inflammatory cytokines. In view of the role of interleukin-10 (IL-10) as an anti-inflammatory cytokine, we tested the notion that SCD osteomyelitis is associated with a reduction in IL-10 secretion and, hence, precipitation of a proinflammatory state. Study subjects comprised 52 SCD patients with confirmed diagnosis of osteomyelitis and 165 age- and gender-matched SCD patients with negative histories of osteomyelitis. Results obtained showed that IL-10 serum levels in SCD osteomyelitis patients were significantly lower than those of control SCD patients. Receiver operating characteristic (ROC) analysis demonstrated that altered IL-10 serum levels predicted the development of osteomyelitis, and the mean area under ROC curves of IL-10 was 0.810 among SCD patients with osteomyelitis. A systematic shift in IL-10 serum levels toward lower values was seen in osteomyelitis cases, with an increased osteomyelitis risk associated with decreased IL-10 levels. Multivariate logistic regression analyses confirmed the independent association of reduced IL-10 with osteomyelitis after controlling for sickle hemoglobin (HbS), fetal hemoglobin (HbF), platelet count, and white blood cell (WBC) count. These data support the strong association of decreased IL-10 levels with osteomyelitis, thereby supporting a role for IL-10 in osteomyelitis follow-up.

Differential association of DENND1A genetic variants with polycystic ovary syndrome in Tunisian but not Bahraini Arab women

BACKGROUND AND AIM Polycystic ovary syndrome (PCOS) is a common endocrine disorder, and results from interaction between modifiable and non-modifiable factors, including genetic predisposition. Previous genome-wide association studies and meta-analysis identified DENND1A as PCOS susceptibility locus in some, but not all populations. We investigated whether the association of DENND1A gene variants with PCOS was similar between Tunisian and Bahraini Arab women. SUBJECTS AND METHODS This was retrospective case-control study. Study subjects comprised 320 women with PCOS, and 446 age-and ethnically-matched control women. Genotyping of DENND1A rs10818854, rs2479106, and rs10986105 variants was done by real-time PCR. RESULTS Minor allele frequency of rs10818854 and rs10986105 DENND1A variants were significantly higher among women with PCOS. Setting homozygous wild-type genotype carrier as reference, rs10818854 and rs10986105 were associated with increased risk of PCOS, which persisted after controlling for key covariates, while reduced PCOS risk was seen with only rs2479106 under the additive model. This assigned PCOS susceptibility and protective nature to these genotypes, respectively. Both rs10818854 and rs10986105 were positively associated with HOMA-IR and AMH in women with PCOS. Haploview analysis revealed limited linkage disequilibrium between the tested DENND1A variants. Extensive diversity in haplotypes assignment was seen, with most haplotypes (99.5%) captured by 5 haplotypes. Taking GAT haplotype as reference, AAG, and GAG haplotypes were positively, while GAT haplotype was negatively associated with PCOS. CONCLUSION The association of DENND1A rs10818854 and rs10986105 variants with PCOS in Tunisian but not Bahraini women confirms the dependence of this association on the ethnic/racial origin of study subjects.

Levels of CD40L and other inflammatory biomarkers in obese and non-obese women with polycystic ovary syndrome.

We investigated whether changes in sCD40L, hs‐CRP, IL‐6, and TNF‐α levels are associated with polycystic ovary syndrome (PCOS).

Elevation in Circulating Soluble CD40 Ligand Concentrations in Type 2 Diabetic Retinopathy and Association with its Severity

BACKGROUND To investigate the relationship between changes in circulating soluble CD40 ligand (sCD40L) levels and the presence and severity of type 2 diabetic retinopathy (DR). SUBJECTS AND METHODS sCD40L plasma concentrations were measured in 205 type 2 diabetes (T2DM) patients without DR (DWR; n=50) and with DR (n=155), the latter subdivided into non-proliferative diabetic retinopathy [NPDR; n=98 (63.2%)], or proliferative retinopathy [PDR; n=57 (36.8%)] patients. RESULTS Receiver operating characteristic analysis provided good discriminatory power for sCD40L as predictor of DR presence, with high sensitivity and specificity. Categorizing DWR and DR patients into sCD40L quartiles, based on sCD40L concentrations in T2DM without DR, demonstrated statistically significant gradual increase in DR risk with increasing sCD40L levels. sCD40L levels were significantly higher in DR compared to DWR patients. Plasma sCD40L levels differed significantly according to DR severity, and correlated with diabetes duration, dyslipedimea, nephropathy, and presence of DR, but not with gender, age, SBP, DBP, FPG, HbA1c, T2DM medications. Linear regression analysis confirmed the association of increased sCD40L levels with DR, independent of others parameters; mean plasma sCD40L levels differing significantly according to DR severity. CONCLUSION Plasma sCD40L levels were positively associated with DR. The significant finding here is that sCD40L levels can be predictors of DR severity.

Association of VEGFA variants with altered VEGF secretion and type 2 diabetes: A case-control study

HighlightsWe evaluated the association of VEGFA variants with altered VEGF levels and T2DM.Increased and reduced T2DM risk was associated with specific VEGFA genotypes.VEGFA haplotypes that conferred T2DM susceptibility and protection were identified.This study support a role for VEGFA as T2DM candidate locus. Background Vascular endothelial growth factor (VEGF) contributes to type 2 diabetes (T2DM) pathogenesis, and genetic variations in VEGFA gene were suggested to influence VEGF secretion and T2DM pathogenesis. Aim To evaluate the association of specific VEGFA variants with altered VEGF levels, and with T2DM among Tunisians. Subjects and methods A retrospective case‐control study, performed on 815 T2DM patients, and 805 healthy controls. VEGF levels were measured by ELISA, genotyping of VEGFA variants was done by allelic exclusion method (real‐time PCR). Results MAF of rs1570360, rs2010963, rs25648, rs833068, rs3025036, and rs3025039 were significantly different between T2DM cases and controls. Increased T2DM risk was associated with rs699947, rs1570360, and rs3025020, while reduced T2DM risk was seen with rs1547651, rs2010963, rs25648, rs3025036, and rs3025039 genotypes, thus assigning T2DM susceptibility and protection, respectively. Reduced VEGF levels were associated with rs833061, rs2010963, and rs3025039 heterozygosity and rs3025036 major allele homozygosity in T2DM cases, while increased VEGF levels were seen in rs833070 homozygous major allele genotype. Both rs699947 and rs1570360 positively, while rs2010963 and rs3025036 negatively correlated with fasting glucose. In addition, rs699947 positively correlated with LDL‐cholesterol, and rs3025039 positively correlated with diabetes duration, but negatively with HbA1c and serum triglycerides. Haploview analysis identified Block 1 containing 8 loci, and Block 2 with the remaining 3 loci. Haplotypes ACTGCCGG and AACGGCGA (Block 1) were negatively associated with T2DM, while haplotype CCC was positively and haplotype CGC (Block 2) were negatively associated with T2DM. Conclusion This study confirms the contribution of altered VEGF secretion, resulting from genetic variation in VEGFA gene into T2DM pathogenesis, hence supporting role for VEGFA as T2DM candidate locus.

Assessing C reactive protein/albumin ratio as a new biomarker for polycystic ovary syndrome: a case–control study of women from Bahraini medical clinics

Objective Polycystic ovary syndrome (PCOS) is an endocrine disorder affecting approximately one in seven women who experience androgen excess, menstrual cycle irregularities, frequent anovulation and a tendency for central obesity and insulin resistance. Chronic subclinical inflammation is now recognised as being common in the context of PCOS, which led to the postulation that PCOS may fundamentally be an inflammatory process. This study aimed to: (1) evaluate serum C reactive protein (CRP)/albumin ratio as a potential predictive biomarker for PCOS; (2) compare the relationship between CRP/albumin and PCOS to variables classically associated with the syndrome. Design Case–control study. Setting Adult obstetrics/gynaecology, endocrinology and outpatient clinics; university hospital in Bahrain. Participants 200 premenopausal women with a diagnosis of PCOS, and 119 ethnically matched eumenorrheic premenopausal women. Main outcome measures CRP/albumin ratio, anthropometric measures, insulin resistance, androgen excess. Results Independent of body mass index (BMI), receiver operating characteristic curve for CRP/albumin ratio as a selective biomarker for PCOS was 0.865 (95% CI 0.824 to 0.905), which was more sensitive than CRP alone. Binary regression analysis showed that CRP/albumin ratio outperformed classical correlates, Free Androgen Index and insulin resistance, in predicting PCOS for every BMI category. Conclusion CRP/albumin ratio, a marker for inflammation related to metabolic dysfunction, was found to have a stronger association with PCOS than either androgen excess or insulin resistance. Inflammation is known to be influenced by adiposity, but relative to controls, women with PCOS have higher levels of CRP/albumin irrespective of BMI. These findings support the view that inflammation plays a central role in the pathophysiology of PCOS.