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Background: Vitamin D insufficiency/deficiency is a highly prevalent condition worldwide. At the same time, chronic inflammation is a versatile pathophysiological feature and a common correlate of various disorders, including vitamin D deficiency. Methods: We investigated the possible association of inflammation with 25-hydroxyvitamin D3 (25OHD3) levels and its down-stream pathway by exploring vitamin D-binding protein ( DBP ) and vitamin D receptor ( VDR ) genes for single-nucleotide polymorphisms (SNPs), in healthy non-elderly Bahraini adults. Plasma levels of 25OHD3 were measured by chemiluminescence, and six SNPs, four in the GC gene (rs2282679AC, rs4588CA, rs7041GT, and rs2298849TC) and two in the VDR gene (rs731236TC and rs12721377AG) were genotyped by real-time PCR. The concentrations of five inflammatory biomarkers, IL6, IL8, procalcitonin (PCT), TREM1, and uPAR, were measured by ELISA. Results: The results showed no association between the 25OHD3 level and any of the inflammatory markers' levels. However, three tested SNPs were significantly associated with the concentrations of tested biomarkers except for IL6. The TT mutant genotype of rs2298849TC was associated with lower levels of IL8 and higher levels of PCT and TREM1, the AA mutant genotype of rs2282679AC was associated with decreased levels of IL8 ( p ≤ 0.001) and increased levels of TREM1 ( p = 0.005), and the GG wild genotype of rs12721377AG was associated with increased levels of 25OHD3 ( p = 0.026). Conclusions: Although chronic inflammation is not associated with the vitamin D system in the blood, it is downstream, as revealed by DBP and VDR genotyping. Alternatively, DBP and VDR pursue other functions beyond the vitamin D pathway.

Objectives: Low-grade metabolic inflammation is associated with several chronic metabolic disorders, including obesity. However, no concrete evidence that supports obesity as a direct cause of chronic inflammation. This study aims to identify the association of inflammation with obesity in apparently healthy adults., Methods: In this study, 162 seemingly healthy volunteers, aged between 20 and 40 years, of comparable sex ratio, were recruited and categorized based on their body mass index (BMI) into four obesity scales: normal (N), overweight (OW), obese (OB), and severely obese (SOB). After clinical examination, fasting blood samples were collected from the study subjects for glycemic (fasting blood glucose-FBG, and HbA1c) and lipid (total cholesterol, LDL-C, HDL-C, and triacyl glycerides -TAG) profile analysis. In addition, plasma levels of a panel of diverse inflammatory biomarkers, IL6, IL8, procalcitonin (PCT), TREM1, and uPAR were analyzed by sandwich ELISA., Results: The results showed that LDLC, TAG, FBG, and HbA1c were significantly higher in the obese (OB and SOB) group, compared to the non-obese (N and OW) group, while HDLc was significantly lower. The biomarker levels were not correlated with age or significantly differed between males and females. Importantly, levels of all assessed inflammatory biomarkers were comparable between the obesity classes. Moreover, the assessed biomarkers in subjects with dyslipidemia or dysglycemia were comparable to those with normal profiles. Finally, the biomarker levels were not correlated with the obesity, glycemic, or lipidemic parameters., Conclusions: After correction for age and co-morbidities, our results deny the association of discrete obesity, probably dyslipidemia, and dysglycemia with systemic chronic inflammation. Further studies of local and systemic inflammation in non-elderly, healthy obese subjects are needed.

Background: Sepsis is a major cause of patient death in intensive care units (ICUs). Rapid diagnosis of sepsis assists in optimizing treatments and improves outcomes. Several biomarkers are employed to aid in the diagnosis, prognostication, severity grading, and sub-type discrimination of severe septic infections (SSIs), including current diagnostic parameters, hemostatic measures, and specific organ dysfunction markers. Methods: This study involved 129 critically ill adults categorized into three groups: sepsis (Se = 48), pneumonia (Pn = 48), and Se/Pn (33). Concentrations of five plasma markers (IL-6, IL-8, TREM1, uPAR, and presepsin) were compared with 13 well-established measures of SSI in critically ill patients. These measures were heart rate (HR), white blood count (WBC), C-reactive protein (CRP), procalcitonin (PCT), lactate plasma concentrations, and measures of hemostasis status (platelets count (PLT), fibrinogen, prothrombin time (PT), activated partial thromboplastin time (APTT), international normalization ratio (INR) and D-dimer). Plasma bilirubin and creatinine served as indicators of liver and kidney dysfunction, respectively. Results: Promising roles for these biomarkers were found. The best results were for presepsin, which scored 10/13, followed by IL-6 and IL-8 (each scored 7/13), and the worst were for TREM-1 and uPAR (scored 3/13). Presepsin, IL-6, and IL-8 discriminated between the SSI sub-types, whilst only presepsin correlated with bilirubin and creatinine. uPAR was positive for kidney dysfunction, and TREM-1 was the only indicator of artificial ventilation (AV). Conclusions: Presepsin is an important potential biomarker in SSIs. However, further work is needed to define this marker's diagnostic and prognostic cutoff values.

Objectives: Type 2 diabetes (T2D) is known to be associated with chronic inflammation, but the inflammatory regulators/markers are not exactly defined and the link between them remains undetermined. The objective of this study is to identify these markers by testing traditional (IL6 & IL8) and non-traditional (TREM1 & uPAR) inflammatory markers., Methods: Data and blood samples were obtained from 114 T2D and 74 non-diabetic Kuwaiti subjects attending health facilities in Kuwait. Chemical analyzers were used to measure glycemic and lipid profiles, while ELISA was used to measure plasma levels of insulin and several inflammatory markers., Results: Showed that the IL-6 and TREM1 were significantly higher in T2D compared to non-diabetic controls, and the uPAR level was borderline higher in T2D but significantly correlated with IL-6 levels. Unexpectedly, IL8 was significantly below normal in T2D and IL6/IL8 ratio was significantly higher in T2D patients. Unlike other tested markers, uPAR was in addition strongly correlated with insulin levels and HOMA-IR index., Conclusions: Raised levels of IL6, TREMI, IL6/IL8 ratio, and the strong positive correlation of plasma levels of uPAR with IL-6, insulin, and HOMA-IR index, are reliable spectators of chronic inflammation in T2D patients. The reduced level of IL-8 in T2D was a peculiar observation that needs further explanation. Finally, the consequences and impact of the sustained rise of these inflammatory regulators in diabetic tissues need to be meticulously explored., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Myopathy is the missing slot from the routine clinical checkup for diabetic complications. Similarly, its pathophysiological, metabolic, and molecular bases are insufficiently explored. In this review, the above issues are highlighted with a focus on skeletal muscle atrophy (also described as diabetic sarcopenia), in contrast to the normal histological, physiological, and molecular features of the muscles. Literature search using published data from different online resources was used. Several diabetic myopathy etiological factors are discussed explicitly including; inflammation and immunological responses, with emphasis on TNFα and IL-6 overproduction, oxidative stress, neuropathy and vasculopathy, aging sarcopenia, antidiabetic drugs, and insulin resistance as a denominator. The pathophysiological hallmark of diabetic muscle atrophy is the decreased muscle proteins synthesis and increased degradation. The muscle protein degradation is conveyed by 4 systems; ubiquitin-proteasome, lysosomal autophagy, caspase-3, and calpain systems, and is mostly mediated via the IL6/STAT, TNF&IL6/NFκB, myostatin/Smad2/3, and FOXO1/3 signaling pathways, while the protein synthesis inhibition is mediated via suppression of the IGF1-PI3K-Akt-mTOR, and SC-Gαi2-pathways. Moreover, the satellite cells and multilineage muscle mesenchymal progenitor cells differentiation plays a major role on the fate of the affected muscle cells by taking an adipogenic, fibrogenic, or connective tissue lineage. As a conclusion, in this article, the pathological features of diabetic sarcopenia are reviewed at gross level, while at a molecular level the normal protein turnover, signal transduction, and pathways involved in muscle atrophy are described. Finally, an integrated network describing the molecular partakers in diabetic sarcopenia is presented., (© 2022. Springer-Verlag Italia S.r.l., part of Springer Nature.)

Tendino-myopathy, an unexplored niche, is a non-vascular unstated T2DM complication, which is largely disregarded in clinical practice, thus, we aim to explore it in this review. Literature search using published data from different online resources. Epidemiologically, reported prevalence varies around 10-90%, which is marked variable and unreliable. Clinically, diabetic tendino-myopathy is typified by restriction of movement, pain/tenderness, cramps and decreased functions. Moreover, myopathy is characterized by muscle atrophy, weakness and ischemia, and tendinopathy by deformities and reduced functions/precision. In tendonapthy, the three most affected regions are: the hand (cheiroarthropathy, Dupuytren's contracture, flexor tenosynovitis and carpel tunnel syndrome), shoulder (adhesive capsulitis, rotator cuff tendinopathy and tenosynovitis) and foot (Achilles tendinopathy with the risk of tear/rupture), in addition to diffuse idiopathic skeletal hyperostosis. Pathologically, it is characterized by decreased muscle fiber mass and increased fibrosis, with marked extracellular matrix remodeling and deposition of collagens. The tendon changes include decreased collagen fibril diameter, changed morphology, increased packing and disorganization, with overall thickening, and calcification. Diagnosis is basically clinical and radiological, while diagnostic biomarkers are awaited. Management is done by diabetes control, special nutrition and physiotherapy, while analgesics, steroids and surgery are used in tendinopathy. Several antisarcopenic drugs are in the pipeline. This review aims to bridge clinical practice with research and update routine diabetic checkup by inclusion of tendino-myopathies in the list with an emphasis on management., (© 2022. Springer-Verlag Italia S.r.l., part of Springer Nature.)

Aims: This study aimed to evaluate the effects of Ramadan diurnal intermittent fasting (RDIF; 29-30 days) on cardiometabolic risk factors (CMRF) in healthy adults, and examine the effect of various cofactors on the outcomes using sub-group meta-regression., Data Synthesis: We conducted a systematic review and meta-analysis to measure the effect sizes of changes in CMRF in healthy adult Muslims observing RDIF. Ten scientific databases (EBSCOhost, CINAHL, Cochrane, EMBASE, PubMed/MEDLINE, Scopus, Google Scholar, ProQuest Medical, ScienceDirect, and Web of Science) were searched from the date of inception (1950) to the end of November 2020. The CMRF searched and analyzed were total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), diastolic blood pressure (DBP), and heart rate (HR). We identified 91 studies (4431 adults aged 18-85 years) conducted between 1982 and 2020 in 23 countries distributed over four continents. RDIF-induced effect sizes for CMRF were: TC (no. of studies K = 77, number of subjects N = 3705, Hedge's g = -0.092, 95% confidence interval (CI): -0.168, 0.016); TG (K = 74, N = 3591, Hedge's g = -0.127, 95% CI: -0.203, 0.051); HDL-C (K = 68, N = 3528, Hedge's g = 0.138, 95% CI: 0.051, 0.224); LDL-C (K = 65, N = 3354, Hedge's g = -0.115, 95% CI: -0.197, -0.034); VLDL-C (K = 13, N = 648, Hedge's g = -0.252, 95% CI: -0.431, 0.073), DBP (K = 32, N = 1716, Hedge's g = -0.255, 95% CI: -0.363, 0.147), and HR (K = 12, N = 674, Hedge's g = -0.082, 95% CI: -0.300, 0.136). Meta-regression revealed that the age of fasting people was a significant moderator of changes in both HDL-C (P = 0.02) and VLDL-C (P = 0.01). Male sex was the only significant moderator of changes in LDL-C (P = 0.055). Fasting time duration was the only significant moderator of HDL-C (P = 0.001) at the end of Ramadan., Conclusions: RDIF positively impacts CMRF, which may confer short-term transient protection against cardiovascular disease among healthy people., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Objective: Recent genome-wide association studies and replication analyses have reported the association of variants of the exostosin-2 (EXT2) gene and risk of type 2 diabetes mellitus (T2DM) in some populations, but not in others. This study investigated the associations of EXT2 variants rs1113132, rs3740878 and rs11037909 with T2DM in a Lebanese Arab population., Methods: This case-control study involved 995 T2DM patients and 1076 control subjects. Genotyping was done by the allelic exclusion method., Results: While minor allele frequencies (MAFs) of rs11037909 (P=0.028) and rs3740878 (P=0.048), but not rs1113132 (P=0.841), were higher in patients, this was lost after correcting for multiple testing. Apart from EXT2 rs1113132, which was marginally associated with T2DM in the additive model (P=0.054), but not after adjustment for covariates, none of the tested EXT2 SNPs were associated with T2DM in any of the genetic models tested. However, variable associations of EXT2 variants with T2DM were noted according to BMI status. While the three tested EXT2 variants were not associated with T2DM in obese subjects, rs1113132 and rs11037909, but not rs3740878, were associated with T2DM in non-obese subjects. Meta-analysis revealed a significant association of rs11037909 and a marginal association of rs3740878 with T2DM in the fixed model. Using a common (GTA) haplotype as reference, three-locus (rs1113132/rs11037909/rs3740878) haplotype analysis demonstrated no association between any of the EXT2 haplotypes with T2DM, not even before correcting for multiple testing., Conclusion: This study demonstrated no association of rs1113132, rs3740878 and rs11037909 EXT2 variants with T2DM., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Study Question: Is recurrent spontaneous miscarriage (RSM) associated with changes in vascular endothelial growth factor (VEGF) serum levels, and with polymorphisms in the VEGFA gene?, Summary Answer: Reduced serum VEGF levels, and VEGFA -460T/C (rs833061), 398G/A (rs833068), -583T/C (rs3025020) variants, were associated with RSM., What Is Known Already: Reduced expression of VEGF has been linked with spontaneous miscarriage, likely due to defective fetal and placental angiogenesis. Since VEGF production is in part inherited, VEGFA polymorphisms associated with altered VEGF secretion have been investigated for their association with RSM, often with variable conclusions., Study Design, Size, Duration: A retrospective case-control study, which was conducted between January 2011 and April 15, 2012., Participants/materials, Setting, Methods: Subjects comprised 296 women with RSM (mean age: 31.6 ± 5.4 year), and 305 age-matched (mean age: 31.6 ± 4.9 year) control Arab women, who had attended outpatient obstetrics and gynecology clinics in two teaching hospitals in Bahrain. VEGFA -2578C/A (rs699947), -460T/C (rs833061), -1154G/A (rs15703060), -634G/C (rs2010963), 398G/A (rs833068), 497G/A (rs833070), -583T/C (rs3025020) and 936C/T (rs3025039) genotyping was done by real-time PCR, with defined clusters; VEGF serum levels were measured by ELISA., Main Results and the Role of Chance: Higher minor allele frequency (MAF) and genotype distribution of -460T/C [corrected P (Pc) = 0.003], 398G/A (Pc = 0.016) and -583T/C (Pc < 0.001) single nucleotide polymorphisms (SNPs) were seen in RSM cases than control women. Increased RSM risk was seen with homozygous -460T/C and 398G/A SNPs and with heterozygous -583T/C, which had a stronger effect when homozygous. Serum VEGF levels were significantly reduced in RSM cases compared with control women (P = 0.016), and correlated with -460T/C, 398G/A and -583T/C genotypes. Haploview analysis revealed heterogeneity in linkage disequilibrium between VEGFA variants, and two blocks were identified: Block 1 comprising -2578C/A, -460T/C and -1154G/A, while Block 2 contained -634G/C, 398G/A, 497G/A, -583T/C and 936C/T. Both negatively and positively RSM-associated 3-locus (Block 1) and 5-locus (Block 2) VEGFA haplotypes were identified, after controlling for a number of covariates., Limitations, Reasons for Caution: The study was retrospective and can only demonstrate association and not a cause-effect relationship. Furthermore, it was limited to Bahraini Arabs,thereby necessitating parallel studies on other ethnic groups., Wider Implications of the Findings: Reduced VEGF secretion, and specific VEGFA variants may contribute to the pathogenesis of RSM. However, the association of VEGFA SNPs with RSM appears to be independent of their association with altered VEGF serum levels. The differential association of VEGFA variants with RSM is in line with previous findings on the contribution of ethnicity/racial background to genetic association studies.

Protein Z (PZ) deficiency due to anti-PZ autoantibodies and/or mutations in PZgene was linked with adverse pregnancy outcomes, including idiopathic recurrent miscarriage (IRM). We investigated the association of rs3024718, rs3024719, rs3024731, rs3024778, rs3024772, and rs3024735 (G79A) PZ variants and changes in PZ levels in 287 women with IRM, and 308 control women. Of the 6 single nucleotide polymorphisms (SNPs) analyzed, higher minor allele frequency of rs3024735 (G79A) and rs3024731 were seen in IRM cases than in control women. Significantly higher frequencies of rs3024735/G79A G/A and A/A (P< .001), rs3024719 G/A (P= .009), and rs3024731 A/A (P = .012), but not rs3024718 (P= .12), rs3024778 (P = .76), or rs3024772 (P= .27) genotype carriers were seen between IRM cases versus control women, respectively, and was linked with reduced PZ levels. Six-locus (rs3024718/rs3024719/rs3024778/rs3024731/rs3024735/rs3024772) PZhaplotypes analysis demonstrated increased frequency of GAGAAG and AGGTAG and reduced frequency of AGGTGC haplotypes in IRM cases, thereby conferring disease susceptibility and protective nature to these haplotypes, respectively. These results demonstrate that specific PZSNPs and haplotypes are significantly associated with IRM.

Objective: The association of vascular endothelial growth factor (VEGFA) variants and VEGF secretion with sickle cell disease (SCD) vasoocclusive crisis (VOC) was investigated in 210 VOC patients and 114 pain-free control patients., Methods: VEGFA -2578C/A (rs699947), -460T/C (rs833061), -1154G/A (rs15703060), -634G/C (rs2010963), 398G/A (rs833068), 497G/A (rs833070), -583T/C (rs3025020), and 936C/T (rs3025039) were carried out by real-time PCR., Results: Higher frequency of rs2010963 C-allele, rs833068 A-allele, and rs3025020 C-allele and significant differences in rs2010963, rs833068, and rs3025020 genotype distribution were seen in VOC than steady-state patients. Increased VOC risk was seen with rs2010963 as heterozygous and more as homozygous, and in rs833068 and rs3025020 homozygous carriers. While there were no differences in VEGF levels between VOC and steady-state controls, there was a progressive decline in serum VEGF in rs2010963 and rs833068 heterozygous and homozygous genotypes, but an opposite trend was seen in VOC patients. Haploview analysis revealed high LD between rs699947, rs833061, rs1570360, rs2010963, rs833068, and rs833070, but weak or no LD between rs3025020 and rs3025039 and other SNPs. Six-locus (rs699947/rs833061/rs1570360/rs2010963/rs833068/rs833070) VEGFA haplotype analysis identified haplotype 111111 to be negatively (OR = 0.68) and haplotype 111222 to be positively (OR = 1.89) associated with VOC. rs2010963, rs833068, and rs3025020 were correlated with VOC type, while rs3025020 was correlated with hospitalization, VOC treatment, and duration., Conclusion: Specific VEGFA variants contribute to the pathogenesis of SCD VOC., (© 2012 John Wiley & Sons A/S.)

We investigated the association of protein Z (PZ) promoter (rs3024718, rs3024719, and rs3024731) and intron (rs3024735; G79A) SNPs with sickle cell disease (SCD) vaso-occlusive crisis (VOC). Study subjects included 239 SCD patients with VOC and 138 pain-free SCD control patients. PZ genotyping was done by allelic discrimination (real-time PCR) assays. The minor allele frequency of rs3024718 (P=0.03), rs3024719 (P=0.02), rs3024731 (P<0.001), and rs3024735 (P<0.001) were higher in VOC patients than control SCD patients. Significant differences in the distribution of rs3024731 (P=0.028) and rs3024735 (P=0.045) genotypes were seen between VOC and steady-state SCD patients. This association remained significant after adjusting for gender, HbS, and HbF. Four-locus (rs3024718/rs3024719/rs3024731/rs3024735) PZ haplotypes analysis demonstrated increased frequency of GAAA (P=0.024), AGAA (P=0.011), and GGTG (P=0.002), and reduced frequency of AGTG haplotype (P=0.001) in VOC than in steady-state control patients, thereby conferring disease susceptibility and protective nature to these haplotypes, respectively. Of these, only AGTG (P(c)=0.001) and GGTG (P(c)=0.018) remained significant after applying the Bonferroni correction. In conclusion, specific PZ variants and haplotypes are significantly associated with SCD VOC.

We investigated the association of CDKAL1 (rs7754840 and rs7756992) and CDKN2A/2B (rs10811661) variants with T2DM. Higher MAF of rs7754840 and rs7756992 were seen in patients, and both were associated with T2DM under additive, dominant, and recessive models. CDKAL1 rs7754840 and rs7756992, but not CDKN2A/2B rs10811661, are associated with T2DM in Lebanese., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Objective: To evaluate the association of interleukin-18 (IL-18) promoter single-nucleotide polymorphisms rs1946519 (-656C/A), rs187238 (-137G/C), rs360718 (-119A/C), and rs360717 (-105G/A) and changes in IL-18 serum levels with recurrent spontaneous miscarriage (RSM)., Design: Case-control study., Setting: Outpatient obstetrics and gynecology clinics., Patient(s): Women with confirmed RSM (n = 282), and 283 age- and ethnically matched controls., Intervention(s): None., Main Outcome Measure(s): IL-18 genotyping was accomplished by allelic discrimination assays; serum IL-18 levels were measured by ELISA., Result(s): The minor allele frequencies of rs360717 and rs1946519, but not rs360718 or rs187238, were higher in patients with RSM. Significant differences in the distribution of the rs360717 and rs1946519 genotypes were noted between patients and controls, and both rs360717 and rs1946519 IL-18 single-nucleotide polymorphisms showed significant association with RSM under additive, dominant, and recessive models. Lower serum IL-18 levels were seen between patients and controls and were more pronounced in rs360717 and rs1946519 heterozygous and homozygous genotypes. Four-locus (rs1946519/rs187238/rs360718/rs360717) IL-18 haplotype analysis identified that the AGAA (Pc<.001), CGAA (Pc<.001), and ACAG (Pc=.018) haplotypes were associated with a reduction in IL-18 secretion and with increased RSM risk, after adjustments for body mass index, menarche, and gravida., Conclusion(s): These results demonstrated that reduced IL-18 levels and rs360717 and rs1946519 IL-18 variants are significantly associated with RSM., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Vaso-occlusive crisis (VOC) is a significant cause of morbidity and mortality in sickle cell anemia (SCA) patients; however, its mechanisms are poorly understood. In view of their prothrombotic nature, we hypothesized that SCA-associated VOC may be due to the presence of anti-annexin V antibodies. Anti-annexin V antibodies were measured with ELISA in 177 VOC and 81 steady-state SCA patients. Anti-annexin V IgM and IgG concentrations were significantly higher in VOC patients than in steady-state patients and were associated with elevated VOC risk. After categorizing anti-annexin V antibodies, the adjusted odds ratio increased as the percentile value increased. Monovariate logistic regression analysis demonstrated a positive dose-effect relationship for anti-annexin V IgM with VOC, with increased VOC risk seen with increased antibody titers. Multivariate logistic regression analyses confirmed the association of anti-annexin V IgM, more so than IgG, as an independent VOC risk factor. Anti-annexin V IgG antibodies correlated positively with VOC type and negatively with HbF and age of VOC onset, while anti-annexin V IgM correlated positively with VOC type, duration, frequency, site, pain severity, hospitalization, and medication, and negatively with age of VOC onset and HbS levels. High levels of anti-annexin V IgM antibodies constitute a risk factor for VOC in SCA patients.

Objective: Vascular endothelial growth factor (VEGF) is a pro-angiogenic factor. Variability in VEGF expression, induced by specific VEGFA variants, are involved in angiogenesis-related disorders. This study examined the genotype distribution and functional role (VEGF expression) of rs699947, rs833061, rs1570360, rs2010963, rs833068, rs833070, rs3025020, and rs3025039 VEGFA variants and their haplotypes in 519 healthy Bahraini individuals of both genders., Methods and Results: The distribution of the eight VEGFA polymorphisms screened was in Hardy-Weinberg equilibrium. The minor allele frequencies of rs699947 (0.42), rs833061 (0.32), rs1570360 (0.31), rs2010963 (0.33), rs833068 (0.37), rs833070 (0.42), rs3025020 (0.33), and rs3025039 (0.13) were generally compared to those established for Caucasians. Of the variants tested, rs3025020 was associated with increased VEGF serum levels (p=0.019), while rs3025039 was associated with decreased levels (p=0.038). Linkage analysis identified two VEGFA blocks, the first, spanning 16 kb, was not associated with altered VEGF levels, while the second, spanning 3 kb containing rs3025020 and rs3025039, was linked with higher VEGF expression, of which the (-583)T/(+936)T haplotype (p=0.008) was linked with higher VEGF levels compared to the (-583)C/(+936)C (all wild-type) haplotype., Conclusion: These results support the association of rs30250202 and rs3025039, and specific VEGF haplotypes, with altered VEGF serum levels, although the exact functional mechanisms remain to be elucidated.

The association of vascular endothelial growth factor (VEGF) -583C/T variant with recurrent miscarriage (RSM) was investigated in 173 RSM cases and 248 control women. Increased minor allele and genotype frequencies of -583C/T, and reduced serum VEGF concentrations were associated with increased risk of RSM., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objectives: Insofar as recurrent spontaneous miscarriage (RSM) is linked with dysregulated immunity and inflammatory changes, and given the pro-inflammatory role of interleukin-21 (IL-21), we examined the association between IL-21 polymorphisms and RSM., Methods and Results: IL-21 rs2055979, rs13143866, rs9992580, and rs4833837 were genotyped in 235 cases of RSM and 235 controls. Regression analysis was employed in assessing the contribution of IL-21 variants to the overall RSM risk. Higher minor allele and genotype frequencies of rs2055979 and rs13143866, but not rs9992580 or rs4833837, were seen in RSM patients than in the controls. IL-21 haplotype [rs9992580/rs4833837/rs2055979/rs13143866] analysis revealed a lower frequency of the TGCG haplotype, and a higher frequency of the GGCG and GAAA haplotypes in patients, thus conferring protection from or a susceptibility to RSM by these haplotypes respectively. Regression analysis confirmed the association of TGCG [OR (95%CI)=0.09 (0.05-0.16)], and GGCG [OR (95%CI)=2.52 (1.34-4.54)] and GAAA [OR (95%CI)=4.02 (2.20-7.70)] haplotypes, after adjusting for age and BMI., Conclusions: Our findings indicate that IL-21 is a novel susceptibility gene for RSM.

Problem:  Protein Z (PZ) system is an anticoagulant pathway involved in the physiologic regulation of coagulation, and PZ deficiency reportedly enhances prothrombophilic mechanisms, including those implicated with idiopathic recurrent miscarriage (RSM). We investigate plasma anti-PZ IgM and IgG levels in RSM women and in multiparous control women., Methods: Anti-PZ IgM and IgG levels were measured in 265 RSM women and 283 age-matched control women by ELISA., Results: Elevated anti-PZ IgG (P < 0.001) and IgM (p < 0.001) titers were seen in patients. The areas under the curves for ROC curve for anti-PZ IgM (0.898 ± 0.044) and IgG (0.898 ± 0.042) demonstrated no variation in diagnostic capacity. Multivariate analysis confirmed the association of elevated anti-PZ IgM [adjusted odds ratio, aOR (95% CI) = 6.46 (2.44-17.11)] and IgG [aOR (95% CI) = 7.44 (2.54-21.79)] as independent predictors of RSM after adjusting for confounding covariates and demonstrated a clear gradation of increasing RSM risk associated with increased antibody titers., Conclusion: The presence of anti-PZ IgM and IgG antibodies are risk factors for RSM., (© 2010 John Wiley & Sons A/S.)

Anti-annexin V antibodies have been identified as risk factors for recurrent spontaneous miscarriage (RSM) in some, but not all previous studies. We investigated the association between anti-annexin IgM and IgG in RSM cases and control women. Blood samples from 244 women with idiopathic RSM, and 283 multi-parous control women were tested for anti-annexin V antibodies by ELISA. A significant elevation in anti-annexin V IgM and IgG was seen in the RSM cases. An increased prevalence of elevated anti-annexin V IgM and to a lesser extent anti-annexin V IgG was seen in RSM patients. Receiver operating characteristic analysis indicated that the area under the curve for anti-annexin V IgM was 0.916, and for anti-annexin V IgG was 0.725. A systematic shift in anti-annexin V IgM and IgG distributions toward higher values occurred in RSM women, which was confirmed by percentile analysis. For each of the anti-annexin V isotypes, the adjusted odds ratio increased as the percentile value increased; the strongest risk was for anti-annexin V IgM, in which the 99th percentile (P99) was associated with a 165-fold higher risk than P50, and for anti-annexin V IgG where P99 was associated with a 38-fold higher risk than P50. In addition, a higher prevalence of elevated anti-annexin V IgM and anti-annexin V IgG was seen in RSM cases than in control women. We conclude that anti-annexin V IgM and IgG antibody positivity are independent risk factors for RSM., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Absence of the palmaris longus muscle has been well documented in several populations at a prevalence rate ranging between 2.2 and 63.9% which varies according to race, sex, and side of the body. There is little documentation of the prevalence of absence of this muscle from populations in the Arabian Gulf region. We examined 1,043 subjects, 3-85 years old, from the Kingdom of Bahrain for the presence or absence of the palmaris longus muscle using the conventional test for the presence of this muscle. Statistical analyses investigated the association of muscle absence with sex, hand dominance, and laterality. The palmaris longus muscle was absent in 36.8% of subjects. Bilateral absence (19%) was more common than unilateral absence (17.9%) with preponderance in female subjects. The muscle was absent more often on the left side than the right (P = 0.003). In the right upper limbs the muscle was absent in female subjects more than male subjects (P = 0.031). This study reaffirms that there is population variation in the frequency of absence of the palmaris longus muscle. The tendon of the palmaris longus bifurcated at the wrist in 7.1% of subjects, with male subjects showing this feature more frequently than female subjects in the right hand (P = 0.037) and the left hand (P = 0.030). This has not been reported before. The clinical significance of our findings is discussed.