Association of matrix metalloproteinase-2 gene variants with diabetic nephropathy risk.

BACKGROUND: Diabetic nephropathy is a highly destructive microvascular complication of diabetes. Genetic predisposition is involved in the pathogenesis of diabetic nephropathy, with multiple allelic polymorphisms associated with the development and progression of the disease, thereby increasing the overall risk. To date, no study is available that shows the association of matrix metalloproteinase-2 (MMP-2) gene polymorphisms with diabetic nephropathy risk. Thus, we investigated the potential genetic influence of MMP-2 promoter variants in the development of diabetic nephropathy in type 2 diabetic patients. METHODS: In total, 726 type 2 diabetic patients and 310 healthy controls were included in the study and genotyped for MMP-2, -1306C/T, -790T/G, -1575G/T and -735C/T by real-time PCR. The analysis of the outcomes was performed assuming three genetic models. The threshold for statistical significance was set at 0.05. RESULTS: The results showed that the minor allele frequency of the -790T/G variant was significantly higher in patients with and without nephropathy compared to controls. Furthermore, the distribution analysis revealed a significant association of the -790T/G variant, in all genetic models, with increased risk of diabetic nephropathy that persisted after adjusting for key covariates. No significant associations between MMP-2, -1306C/T, -1575G/T, -735C/T and the risk of diabetic nephropathy were detected. Haplotype analysis identified two risk haplotypes GCGC and GTAC associated with diabetic nephropathy. CONCLUSIONS: The present study is the first to demonstrate the allelic and genotypic association of the MMP-2-790T/G variant and two haplotypes with an increased risk of diabetic nephropathy in a Tunisian population with type 2 diabetes.

Interleukin 10 (IL-10) gene variants and haplotypes in Tunisian women with polycystic ovary syndrome (PCOS): a case-control study.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder that affects women in their child-bearing age, and is associated with insulin resistance and type 2 diabetes. The etiology of PCOS involves multiple factors including genetic, metabolic and immunological factors. Interleukin - 10 (IL-10), as an anti-inflammatory cytokine, plays a critical role in this regard. We investigated the potential role of IL-10 gene variants in the development of PCOS in Tunisian population. METHODS AND RESULTS: 115 cases and 120 controls were recruited in the current case control study. Rotterdam consensus criteria were used to diagnose PCOS patients. Genotyping for IL-10, rs1800896, rs1800871 and rs1800872 variants, was performed by real time PCR. The results obtained showed that the minor allele frequency of rs1800896, rs1800871and rs1800872 were comparable between PCOS cases and control subjects (P = 0.30, P = 0.71, and P = 0.57 respectively). The distribution analysis revealed an unsignificant association of the three tested variants, in all genetic models. Haplotype analysis identified one haplotype CCA with a protective role in PCOS development (P = 0.05; OR (95% CI) = 0.56 (0.32 - 0.99)). This association did not persist after adjustment for multiples covariates (Pc = 0.154). CONCLUSIONS: Our study is the first to show how ethnicity influences the association of IL-10 gene variants with PCOS susceptibility. No allelic nor genetic association were observed between the tested variants and PCOS in Tunisian women, however, a particular IL-10 haplotype with a protective effect for PCOS was identified.

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

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.

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.

Differential Association of FTO Gene variants and Haplotypes with the Susceptibility to Polycystic Ovary Syndrome According To Obesity in Women with PCOS.

We explored the relation between FTO single gene variants (rs1861868, rs9939973, rs1421085, rs1121980, rs17817449, rs8050136, rs9939609, rs9930506, and rs8044769) and polycystic ovary syndrome (PCOS), in particular, according to the obesity status. This retrospective population-based case-control study involved women with PCOS (583) and 713 eumenorrheic control women; genotyping was done by real-time PCR. Significantly higher minor allele frequency (MAF) of rs9939973, rs17817449, rs9939609, and rs9930506 and lower MAF of rs1121980 were seen in PCOS cases. Lower risk of PCOS was associated with rs1121980 and rs8050136 heterozygous and minor allele-homozygous genotypes, while an elevated risk of PCOS was seen with minor allele-homozygous rs9939973, rs17817449, and r9939609 heterozygous and genotypes and minor allele-homozygous rs9930506 and rs8044769 genotype. While none of the tested FTO SNPs variants was associated with PCOS in normal body weight/lean subjects, rs9939973, rs9939609, and rs9930506 were negatively associated with PCOS in overweight subjects. In comparison, rs1861868 was negatively, while rs8044769 was positively associated with PCOS in obese subjects. Haplotype analysis identified haplotypes GACCTCTAT, AACCTCTAT, AACCTATAT and AGTTGCAGC, and GACCTCTAC to be positively associated with PCOS, while haplotypes GGTTGAAGC, GACCTATAT, GGTTGCAGC, and GATCTATAT were negatively associated with PCOS. Apart from GGTTGAAGC, these haplotypes remained associated with altered risk of PCOS after adjusting for covariates. In addition to rs17817449, rs9939609, rs9930506, and rs1121980, this study is the first to demonstrate association of rs9939973 and rs8044769 with altered risk of PCOS and the first to confirm the BMI dependency on the association of FTO variants with PCOS. This underscores the role of FTO gene variants as predisposing factors of PCOS.

Genetic variation in progesterone receptor gene and ovarian cancer risk: A case control study.

BACKGROUND: Previous studies examined the association of genetic variation in progesterone receptor (PR) gene (PGR) with ovarian cancer, possibly by altering the expression of PR-B isoform, but with mixed outcome. OBJECTIVE: This study evaluated the association of PGR variants with ovarian cancer and associated features. METHODS: This was a retrospective case-control study, which involved 82 women with ovarian cancer and 95 cancer-free women who served as controls. Genotyping was done by Taqman® SNP genotyping by qRT-PCR. The PGR variants tested were rs471767 (A > G), rs590688 (G > C), and rs10895068 (G > A). Stratification analyses were used for testing the correlation between the PGR variants with ovarian cancer susceptibility according to menstruation status, FIGO classification, pathological grade, and chemotherapy. RESULTS: Significantly lower minor allele frequency (MAF) of rs10895068 was seen among ovarian cancer patients, thereby imparting disease protective nature to this variant. Significant association of rs10895068 genotypes with ovarian cancer was seen under the dominant model, but not other genetic models. FIGO classification correlated positively with rs471767 and rs10895068, while rs10895068 correlated positively with lymph node positivity. Three-locus haplotype analysis identified ACA and HCG haplotypes to be negatively associated with the risk of ovarian cancer. CONCLUSIONS: This report confirms the contribution of PGR variants, specifically the rs10895068 (+331G/A) the etiology of ovarian cancer.

Association of MMP-2 genes variants with diabetic retinopathy in Tunisian population with type 2 diabetes.

AIMS: Few studies investigated the association of genetic difference in metalloproteinase-2 (MMP-2) gene with diabetic retinopathy but with mixed outcome. To investigate the association between a set of MMP-2 genetic variants and the risk of diabetic retinopathy in an Arab Tunisian population with type 2 diabetes. SUBJECTS AND METHODS: A retrospective case-control study comprising a total of 779 type 2 diabetes patients with or without diabetic retinopathy was conducted. Genotyping was prepared by TaqMan® SNP genotyping qRT-PCR. The variants used were rs243865 (C/T), rs243864 (T/G), rs243866 (G/T) and rs2285053 (C/T). RESULTS: The minor allele frequency (MAF) of the rs243864 MMP-2 variant was significantly higher among diabetic retinopathy patients. Setting homozygous wild type genotype carrier as reference, the rs243864T/G allele was associated with increased risk of diabetic retinopathy under the dominant, recessive, and additive models which persisted when key covariates were controlled for, while a reduced risk of diabetic retinopathy progression was seen after adjustment between non-proliferative and proliferative diabetic patients. Furthermore, the heterozygous genotype GT of the rs243866 variant is positively associated with the risk of proliferative diabetic retinopathy in the additive model. A limited linkage disequilibrium (LD) was revealed between the four-matrix metalloproteinase-2 variants. Four-loci haplotype analysis identified, GCTC, TTTC, and GCTT haplotypes to be positively associated with the risk of diabetic retinopathy. CONCLUSION: Our findings demonstrate that the MMP-2 variant rs243864 and 243866 are related to the susceptibility to diabetic retinopathy and the progression of the disease in an Arab Tunisian population with type 2 diabetes.

Analysis of differential expression of hypoxia-inducible microRNA-210 gene targets in mild and severe preeclamptic patients.

Preeclampsia (PE) is a multi-system disorder that is specific to human pregnancy. Inadequate oxygenation of uterus and placenta is considered as one of the leading causes for the disease. MicroRNA-210(miR-210) is one of the prime molecules that has emerged in response to hypoxia. The objective of this study was to determine miR-210 expression patterns in plasma from severe PE and mild PE patients, and how that affects the expression of miR-210 target genes. The expression levels of miR-210 were validated using reverse transcription-quantitative PCR in plasma of severe PE (15) and mild PE (15) patients in comparison to controls subjects (15) with normal pregnancy. Then, the association between miR-210 and its downstream genes was validated by using human miR-210 targets RT2 profiler PCR Array. Both the categories (mild and severe) showed significantly high miR-210 expression levels. Also out of the 84 hypoxia miR-210 associated genes screened using mRNA, 18 genes were found to be differentially expressed in severe PE whereas 16 genes in mild PE cases with varying magnitude. All the genes in both the PE groups were found downregulated in comparison to controls. These downregulated genes expressed in both the cases were shown to be participating in immunosuppression, apoptosis, cell growth, signaling, angiogenesis, DNA repair. This study provides novel data on the genes that work downstream of miR-210 and how dysregulated expression of miR-210 can affect their expression and in turn functioning which can be associated with PE risk and severity. This study is the very first to determine the effect of miR-210 expression levels on associated genes in plasma samples.

Association of matrix metalloproteinase-2 gene polymorphisms with susceptibility to type 2 diabetes: A case control study.

AIMS: Genetic variations mediating MMP-2 expression may result in individual differences in susceptibility to particular diseases. Our aim was to investigate the possible association of certain MMP-2 gene variants with the susceptibility of type 2 diabetes (T2D) in a Tunisian population. SUBJECTS AND METHODS: A retrospective case-control study involving 310 normoglycemic control subjects and 791 T2D patients was conducted. Genotyping of MMP-2 variants was performed by real time PCR. RESULTS: Minor allele frequencies (MAF) of the rs243865 and the rs243866 MMP-2, were significantly different between T2D cases and controls. Setting homozygous wild-type genotype carrier as reference, a reduced risk of T2D was seen with the rs243865 and the rs243866 genotypes. Haploview analysis revealed limited linkage disequilibrium between the tested MMP-2 and variants, with most haplotypes (99.5%) captured by 7 MMP-2 haplotypes. Taking the GCCC haplotype as reference for MMP-2 (OR = 1.00), a reduced frequency of TTCC haplotypes (P = 0.04) and the GTCC haplotype (P = 3.5 ·â€¯10-5) was noted in T2D which indicates a protective nature of these two haplotypes for T2D development. CONCLUSION: To the best of our knowledge, the present study is the first to demonstrate a consistent association of the rs243865 and rs243866 genotype with a protection for T2D.

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.

Apolipoprotein E genetic polymorphism influence the susceptibility to nephropathy in type 2 diabetes patients.

BACKGROUND: An association between Apolipoprotein E (Apo E) alleles and genotypes and diabetic nephropathy (DN) was suggested, but with inconsistent results. We tested the relationship between serum lipids, Apo E alleles and genotypes with type 2 diabetes (T2DM), and DN pathogenesis. METHODS: Study subjects comprised 1389 normoglycemic controls, and 1422 T2DM patients, of whom 825 were normoalbuminuric (DWN), and 597 presented with nephropathy (DN). RESULTS: Significantly lower Apo ε2, and higher Apo ε4 allele frequencies was seen among T2DM patients than controls. Significantly higher frequency of ε3/ε4, and lower frequencies of ε3/ε3, ε2/ε3, and ε4/ε4 carriers was seen among T2DM cases. Apo ε2-carrying individuals were more frequently found in controls than in patients, while significantly higher frequency of ε4-carrying genotypes was seen in T2DM cases. Significantly higher ε2, and lower ε3 allele frequencies were noted for DN group compared to DWN group. Significantly higher frequency of ε2-containing ε2/ε3 and ε2/ε4, and lower frequencies of ε3/ε3 carriers was seen among DN cases. Apo ε3/ε3 was associated with higher total cholesterol, LDL-cholesterol, and triglyceride levels in DN patients, and significantly higher triglyceride levels were seen in ε2/ε3-carrying DN patients. Logistic regression analysis confirmed the association of Apo ε3-containing ε3/ε3, ε2/ε3, and ε3/ε4, and Apo ε2-containing ε2/ε4 with DN, after controlling for key covariates. CONCLUSION: The results of this case-control study provide evidence that the ε2 and ε3 alleles of APOE modify lipid profile, and constitute independent risk factors of DN in type 2 diabetes. The molecular mechanisms underlying this risk is discussed.

Maternal HLA-DR, HLA-DQ, and HLA-DP loci are linked with altered risk of recurrent pregnancy loss in Lebanese women: A case-control study.

PROBLEM: We investigated the association between idiopathic recurrent pregnancy loss (RPL) and HLA-DPB1, HLA-DQB1, and HLA-DRB1 alleles and DPB1-DQB1-DRB1 haplotypes. METHOD OF STUDY: Case-control retrospective study involved 93 Lebanese women with unexplained RPL, and 113 multiparous Lebanese women with two or more successful pregnancies, and no miscarriages who served as controls. DPB1, DQB1, and DRB1 genotyping was performed by PCR-SSP. RESULTS: Expected and observed DRB1, DQB1, and DPB1 frequencies were comparable, and HLA genotype frequencies were in Hardy-Weinberg equilibrium. Significantly higher frequencies of DRB1*04:01:01 and DRB1*08:01:01, and decreased DRB1*07:01:01 frequency were seen in RPL cases than in controls. On the other hand, the distribution of DQB1 alleles was comparable between cases and control groups. Significantly lower frequencies of DPB1*04:01:01 and DPB1*14:01:01 were seen in women with RPL than control subjects. While the frequency DPB1*02:01:01 was markedly higher in RPL cases than in controls, the difference was not significant. DPB1-DQB1-DRB1 haplotype analysis identified haplotype DPB1*04:01:01-DQB1*03:02:01-DRB1*04:01:01 to be positively associated, while haplotype DPB1*04:01:01-DQB1*02:01:01-DRB1*07:01:01 to be negatively associated with RPL. Of these two haplotypes, only DPB1*04:01:01-DQB1*02:01:01-DRB1*07:01:01 remained significant after correction for multiple tests (Pc  = .0008). CONCLUSION: Our results confirm an association of select DRB1 and DPB1 alleles with RPL in Lebanese women, and the first to identify DPB1-DQB1-DRB1 linked with altered RPL susceptibility, further highlighting the immunological/inflammatory nature of RPL.

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.

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.

Lebectin and lebecetin, two C-type lectins from snake venom, inhibit alpha5beta1 and alphaV-containing integrins.

Integrins are essential protagonists in the complex multistep process of cancer progression and metastasis. We recently reported that lebectin, a novel C-type lectin from Macrovipera lebetina venom, displays an anti-integrin activity. In this study, we extend this observation to lebecetin, a second C-type lectin isolated from the same venom and previously reported as a potent inhibitor of platelet aggregation. Both venom lectins appear to exert their effect on cell adhesion, migration, invasion and proliferation by inhibiting alpha5beta1 and alphav-containing integrins. Moreover, the inhibition of alpha5beta1 and alphav integrins is likely due to the binding of venom peptides, as both lebectin and lebecetin co-immunoprecipitate with these integrins. Lebectin and lebecetin are thus the first examples of venom C-type lectins inhibiting an integrin other than the collagen receptor alpha2beta1.

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

PROBLEM: We investigated whether changes in sCD40L, hs-CRP, IL-6, and TNF-α levels are associated with polycystic ovary syndrome (PCOS). METHOD OF STUDY: Case-control study involving 143 women with and 165 women without PCOS. RESULT(S): Reduced sCD40L, and increased hs-CRP and IL-6, but not TNF-α, levels were seen between cases and controls. ROC analysis demonstrated high sensitivity and specificity for sCD40L and hs-CRP as PCOS predictors. Altered sCD40L levels were associated with PCOS, irrespective of body weight. Significant differences in IL-6 levels were seen between non-obese subjects and for TNF-α in obese subjects. sCD40L correlated negatively with age, insulin, HOMA-IR, LH, free testosterone, FAI, and hirsutism, but positively with SHBG. CRP correlated positively with BMI, insulin, HOMA-IR, free testosterone, and hirsutism. IL-6 correlated positively with hirsutism. TNF-α correlated positively with age, but negatively with insulin and HOMA-IR. CONCLUSION: CD40L, more than IL-6, or TNF-α, constitutes a predictor to explain PCOS and associated features.

The high-molecular weight multimer form of adiponectin is a useful marker of polycystic ovary syndrome in Bahraini Arab women.

BACKGROUND & AIMS: We tested if decreased total and high molecular weight (HMW)-adiponectin, and altered HMW/total adiponectin ratio (HMWR) constitute reliable markers of polycystic ovary syndrome (PCOS) among Bahraini Arab women. METHODS: Case-control study involving 122 Bahraini Arab women with PCOS and 89 ethnically-matched control women. PCOS was evaluated according to 2003 Rotterdam criteria. Total and HMW-adiponectin were measured by ELISA. RESULTS: Compared to controls, women with PCOS had significantly reduced plasma HMW-adiponectin, and HMWR, more so than total adiponectin. Logistic regression analysis revealed that HMW-adiponectin and HMWR, more than total adiponectin, were negatively associated with PCOS. ROC area-under-the-curve for predicting PCOS were larger for HMW-adiponectin (0.679 ± 0.037), and HMWR (0.653 ± 0.039), than total adiponectin (0.537 ± 0.041). Regression analysis confirmed the association of low HMW-adiponectin and HMWR with PCOS. HMW-adiponectin and HMWR inversely correlated with age, BMI, hirsutism, insulin, HOMA-IR, and positively correlated with serum LDL-cholesterol. Total adiponectin was negatively correlated with waist-hip ratio and serum LH levels. CONCLUSIONS: Reduction in adiponectin plasma levels is an independent risk factor for PCOS. Changes in HMW-adiponectin serum levels and HMW/total adiponectin ratio are better markers for the presence of PCOS, when compared with total adiponectin.

Lebecetin, a potent antiplatelet C-type lectin from Macrovipera lebetina venom.

A novel C-type lectin protein (CLP), lebecetin, was purified to homogeneity from the venom of Macrovipera lebetina by gel filtration on a Sephadex G75 column and ion exchange chromatography on Mono S column. Lebecetin is a basic protein with a pHi=9.9 and migrates in SDS-PAGE as a single band or two distinct bands under nonreducing and reducing conditions, respectively. These results are further confirmed by MALDI-TOF mass spectrometry that indicates a molecular mass of 29779 Da for native lebecetin and molecular masses of 15015 and 16296 Da for alpha and beta subunits, respectively. The N-terminal amino acid sequences of lebecetin subunits show a high degree of similarity with those of C-type lectin-like proteins. In addition, functional studies showed that lebecetin has a potent inhibitory effect on platelet aggregation induced by thrombin in a concentration-dependent manner. In contrast, no inhibitory effect is observed when platelets are exposed to thromboxane A2 (TxA2) mimetic (U46619) or arachidonic acid. Moreover, there was no effect either on blood coagulation or A, B and O washed human erythrocytes agglutination. Furthermore, flow cytometric analysis revealed that fluoro-isothiocyanate (FITC)-labelled lebecetin bound to human formalin fixed platelets in a saturable and concentration manner and this binding was specifically prevented by anti-glycoprotein Ib (GPIb) mAb. These observations suggest that lebecetin is a C-type lectin-like protein that selectively binds to platelet GPIb.

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

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.