Deciphering the Role of the rs2651899, rs10166942, and rs11172113 Polymorphisms in Migraine: A Meta-Analysis.

The genetic basis of migraine is rather complex. The rs2651899 in the PR/SET domain 16 (PRDM16) gene, the rs10166942 near the transient receptor potential cation channel subfamily M member 8 (TRPM8) gene, and the rs11172113 in the LDL receptor-related protein 1 (LRP1) gene, have been associated with migraine in a genome-wide association study (GWAS). However, data from subsequent studies examining the role of these variants and their relationship with migraine remain inconclusive. The aim of the present study was to meta-analyze the published data assessing the role of these polymorphisms in migraine, migraine with aura (MA), and migraine without aura (MO). We performed a search in the PubMed, Scopus, Web of Science, and Public Health Genomics and Precision Health Knowledge Base (v7.7) databases. In total, eight, six, and six studies were included in the quantitative analysis, for the rs2651899, rs10166942, and rs11172113, respectively. Cochran's Q and I2 tests were used to calculate the heterogeneity. The random effects (RE) model was applied when high heterogeneity was observed; otherwise, the fixed effects (FE) model was applied. The odds ratios (ORs) and the respective 95% confidence intervals (CIs) were calculated to estimate the effect of each variant on migraine. Funnel plots were created to graphically assess publication bias. A significant association was revealed for the CC genotype of the rs2651899, with the overall migraine group (RE model OR: 1.32; 95% CI: 1.02−1.73; p-value = 0.04) and the MA subgroup (FE model OR: 1.40; 95% CI: 1.12−1.74; p-value = 0.003). The rs10166942 CT genotype was associated with increased migraine risk (FE model OR: 1.36; 95% CI: 1.18−1.57; p-value < 0.0001) and increased MO risk (FE model OR: 1.41; 95% CI: 1.17−1.69; p-value = 0.0003). No association was detected for the rs11172113. The rs2651899 and the rs10166942 have an effect on migraine. Larger studies are needed to dissect the role of these variants in migraine.

Back to basics in COVID-19: Antigens and antibodies-Completing the puzzle.

The outbreak of the coronavirus disease 2019 (COVID-19) has gathered 1 year of scientific/clinical information. This informational asset should be thoroughly and wisely used in the coming year colliding in a global task force to control this infection. Epidemiology of this infection shows that the available estimates of SARS-CoV-2 infection prevalence largely depended on the availability of molecular testing and the extent of tested population. Within molecular diagnosis, the viability and infectiousness of the virus in the tested samples should be further investigated. Moreover, SARS-CoV-2 has a genetic normal evolution that is a dynamic process. The immune system participates to the counterattack of the viral infection by pathogen elimination, cellular homoeostasis, tissue repair and generation of memory cells that would be reactivated upon a second encounter with the same virus. In all these stages, we still have knowledge to be gathered regarding antibody persistence, protective effects and immunological memory. Moreover, information regarding the intense pro-inflammatory action in severe cases still lacks and this is important in stratifying patients for difficult to treat cases. Without being exhaustive, the review will cover these important issues to be acknowledged to further advance in the battle against the current pandemia.

Circulating miR-146a and miR-134 in predicting drug-resistant epilepsy in patients with focal impaired awareness seizures.

OBJECTIVE: Epilepsy is one of the most prevalent neurologic disorders, causing serious psychological problems and reducing quality of life. Although 20 different antiepileptic drugs (AEDs) have been approved by the US Food and Drug Administration (FDA), 30% of patients have drug-resistant epilepsy (DRE). Considering the role of miR-146a and miR-134 in neuroinflammation and dendritic functionality, respectively, the aim of this study was the clinical evaluation of circulating miR-146a and miR-134 as novel noninvasive molecular markers for the prognosis of refractory epilepsy. METHODS: The study included 162 patients with focal impaired awareness seizures. Total RNA was extracted from serum samples spiked with synthetic cel-miR-39-3p for normalization purposes. First-strand complementary DNA (cDNA) synthesis was performed using microRNA-specific stem-loop primers, and hsa-miR-134/146a levels were quantified by quantitative polymerase chain reaction (qPCR). DRE was used as clinical end point event. Internal validation was performed by bootstrap analysis, and decision curve analysis was used to evaluate the clinical benefit on disease prognosis. RESULTS: The circulating levels of both miR-134 and miR-146a were elevated in patients with drug-resistant seizures. The receiver-operating characteristic (ROC) curve and logistic regression analysis demonstrated that patients with increased circulating miR-134/146a levels are at significantly higher risk for developing DRE, independently of temporal lobe sclerosis, epilepsy duration, familial history, age at first seizure, age, body mass index (BMI), smoking behavior, and gender. Finally, decision curve analysis highlighted that the evaluation of circulating miR-134/146a led to superior clinical benefit for DRE prognosis and patients' risk stratification. SIGNIFICANCE: Elevated serum miR-134/146a levels are associated with a higher risk for AED-resistant epilepsy and could constitute novel noninvasive molecular markers to improve disease early prognosis and support precision medicine.

Contribution of MTHFR gene variants in lupus related subclinical atherosclerosis.

OBJECTIVE: Elevated concentrations of homocysteine have been previously identified as an independent risk factor for subclinical atherosclerosis in patients with systemic lupus erythematosus (SLE). Given that heightened homocysteine levels are known to be strongly influenced by genetic factors, in the current study we investigated the contribution of high homocysteine levels as well as of functional polymorphisms of the gene encoding for the enzyme 5, 10- methylenetetrahydrofolate reductase (MTHFR) to atherosclerotic disease characterizing SLE patients. METHODS: Peripheral DNA samples from 150 SLE patients, 214 rheumatoid arthritis (RA) patients and 561 age/sex matched apparently healthy volunteers (HC) were genotyped by PCR-based assays for the detection of the MTHFR gene polymorphisms (c. 677C > T and c. 1298A > C). All SLE patients and 30 age sex matched RA patients underwent assessment for subclinical atherosclerosis [ultrasound measurement of intima-media thickness scores (IMT) and detection of carotid and/or femoral (C/F) plaque] and complete clinical and laboratory evaluation including serum homocysteine levels. Data were analyzed using univariate and multivariate models (SPSS 21.0). RESULTS: Hyperhomocysteinemia was detected in 26.0% of SLE patients compared to 6.7% of age/sex matched RA controls (p = 0.02). Higher serum B12 levels and decreased frequency of the MTHFR 677TT variant in RA patients could potentially account for the observed differences between the groups. In SLE patients, both hyperhomocysteinemia and MTHFR 677TT genotype were identified as independent contributors for plaque formation, following adjustment for traditional cardiovascular risk factors and disease related features, including age, sex, BMI, cholesterol and triglyceride levels, presence of arterial hypertension, smoking (pack/years), disease duration and total steroid dose [OR 95% (CI): 5.8 (1.0-35.8) and 5.2 (1.1-24.0), respectively]. MTHFR 677TT genotype, but not hyperhomocysteinemia was also found to confer increased risk for arterial wall thickening, after the above confounders were taken into account [OR (95%) CI: 4.9 (1.2-20.6)]. CONCLUSIONS: Hyperhomocysteinemia and MTHFR 677TT genetic variant emerged as independent risk factors for subclinical atherosclerosis in SLE patients, implying genetic influences as potential contributors to the increased burden of atherosclerotic disease characterizing SLE.

The role of glutamine supplementation in thoracic and upper aerodigestive malignancies.

In cancer patients, marked glutamine (gln) depletion develops over time. Host tissues (epithelial cells and lymphocytes) that depend upon adequate stores of gln for optimal functioning can be negatively influenced. In addition, radiation and/or chemotherapy cause normal tissues damage that might be enhanced by this depletion effect. The present review evaluates in vivo clinical data about the potential beneficial role of gln administration in the prevention of host tissue toxicity, in a patient group with thoracic and upper aerodigestive malignancies (T&UAM) during cancer treatment. Publications were identified in a systematic review of MEDLINE Database from the last 2 decades (1994-2014) using key search terms and through manual searches. Overall, 13 clinical studies (9 oral/4 parenteral) evaluated the safety and tolerance of gln supply, showing a beneficial effect in the grade, duration of mucositis and esophagitis, decreased gut permeability, and weight loss. Only 1 Phase 1 clinical trial had negative results because the chemo-radiotherapy combined treatment was not feasible. The use of oral gln may especially have an important role in the prevention of acute radiation toxicities, the weight loss and the need for analgesics in patients with T&UAM, especially if the treatment plan includes combined modality therapy with chemo-radiation.

Topical calcineurin and mammalian target of rapamycin inhibitors in inflammatory dermatoses: Current challenges and nanotechnology­based prospects (Review).

Topical therapy remains a critical component in the management of immune­mediated inflammatory dermatoses such as psoriasis and atopic dermatitis. In this field, macrolactam immunomodulators, including calcineurin and mammalian target of rapamycin inhibitors, can offer steroid­free therapeutic alternatives. Despite their potential for skin­selective treatment compared with topical corticosteroids, the physicochemical properties of these compounds, such as high lipophilicity and large molecular size, do not meet the criteria for efficient penetration into the skin, especially with conventional topical vehicles. Thus, more sophisticated approaches are needed to address the pharmacokinetic limitations of traditional formulations. In this regard, interest has increasingly focused on nanoparticulate systems to optimize penetration kinetics and enhance the efficacy and safety of topical calcineurin and mTOR inhibitors in inflamed skin. Several types of nanovectors have been explored as topical carriers to deliver tacrolimus in both psoriatic and atopic skin, while preclinical data on nanocarrier­based delivery of topical sirolimus in inflamed skin are also emerging. Given the promising preliminary outcomes and the complexities of drug delivery across inflamed skin, further research is required to translate these nanotherapeutics into clinical settings for inflammatory skin diseases. The present review outlined the dermatokinetic profiles of topical calcineurin and mTOR inhibitors, particularly tacrolimus, pimecrolimus and sirolimus, focusing on their penetration kinetics in psoriatic and atopic skin. It also summarizes the potential anti­inflammatory benefits of topical sirolimus and explores novel preclinical studies investigating dermally applied nanovehicles to evaluate and optimize the skin delivery, efficacy and safety of these 'hard­to­formulate' macromolecules in the context of psoriasis and atopic dermatitis.

A Machine Learning-Based Web Tool for the Severity Prediction of COVID-19.

Predictive tools provide a unique opportunity to explain the observed differences in outcome between patients of the COVID-19 pandemic. The aim of this study was to associate individual demographic and clinical characteristics with disease severity in COVID-19 patients and to highlight the importance of machine learning (ML) in disease prognosis. The study enrolled 344 unvaccinated patients with confirmed SARS-CoV-2 infection. Data collected by integrating questionnaires and medical records were imported into various classification machine learning algorithms, and the algorithm and the hyperparameters with the greatest predictive ability were selected for use in a disease outcome prediction web tool. Of 111 independent features, age, sex, hypertension, obesity, and cancer comorbidity were found to be associated with severe COVID-19. Our prognostic tool can contribute to a successful therapeutic approach via personalized treatment. Although at the present time vaccination is not considered mandatory, this algorithm could encourage vulnerable groups to be vaccinated.

miRNA-Based Technologies in Cancer Therapy.

The discovery of therapeutic miRNAs is one of the most exciting challenges for pharmaceutical companies. Since the first miRNA was discovered in 1993, our knowledge of miRNA biology has grown considerably. Many studies have demonstrated that miRNA expression is dysregulated in many diseases, making them appealing tools for novel therapeutic approaches. This review aims to discuss miRNA biogenesis and function, as well as highlight strategies for delivering miRNA agents, presenting viral, non-viral, and exosomic delivery as therapeutic approaches for different cancer types. We also consider the therapeutic role of microRNA-mediated drug repurposing in cancer therapy.

Genetic Variability in Vitamin D Receptor and Migraine Susceptibility: A Southeastern European Case-Control Study.

Migraine is a common primary headache disorder with both environmental and genetic inputs. Cumulative evidence indicates an association between vitamin D and headache. Unravelling the precise role of vitamin D and its receptor in the pathophysiology of migraine can eventually contribute to more efficient prevention and management of this headache disorder. The aim of the study was to investigate the relation of the three most studied VDR variants, i.e., FokI (rs2228570), TaqI (rs731236) and BsmI (rs1544410), with migraine susceptibility and distinct clinical phenotypes in a Southeastern European case-control population residing in Greece. DNA was extracted from 191 unrelated patients diagnosed with migraine and 265 headache-free controls and genotyped using real-time PCR (LightSNiP assays) followed by melting curve analysis. Genotype frequency distribution analysis of the TaqI and BsmI variants showed a statistically significant difference between migraine cases and controls. In addition, subgroup analyses revealed a significant association between all three studied VDR variants, particularly with a migraine without aura subtype. Therefore, the current study provides supporting evidence for a possible association of VDR variants with migraines, particularly migraine without aura susceptibility in Southeastern Europeans residing in Greece, further reinforcing the emerging role of vitamin D and its receptor in migraines.

Psoriasis immunometabolism: progress on metabolic biomarkers and targeted therapy.

Psoriasis is a common inflammatory disease that affects mainly the skin. However, the moderate to severe forms have been associated with several comorbidities, such as psoriatic arthritis, Crohn's disease, metabolic syndrome and cardiovascular disease. Keratinocytes and T helper cells are the dominant cell types involved in psoriasis development via a complex crosstalk between epithelial cells, peripheral immune cells and immune cells residing in the skin. Immunometabolism has emerged as a potent mechanism elucidating the aetiopathogenesis of psoriasis, offering novel specific targets to diagnose and treat psoriasis early. The present article discusses the metabolic reprogramming of activated T cells, tissue-resident memory T cells and keratinocytes in psoriatic skin, presenting associated metabolic biomarkers and therapeutic targets. In psoriatic phenotype, keratinocytes and activated T cells are glycolysis dependent and are characterized by disruptions in the TCA cycle, the amino acid metabolism and the fatty acid metabolism. Upregulation of the mammalian target of rapamycin (mTOR) results in hyperproliferation and cytokine secretion by immune cells and keratinocytes. Metabolic reprogramming through the inhibition of affected metabolic pathways and the dietary restoration of metabolic imbalances may thus present a potent therapeutic opportunity to achieve long-term management of psoriasis and improved quality of life with minimum adverse effects.

Advancing athletic assessment by integrating conventional methods with cutting-edge biomedical technologies for comprehensive performance, wellness, and longevity insights.

In modern athlete assessment, the integration of conventional biochemical and ergophysiologic monitoring with innovative methods like telomere analysis, genotyping/phenotypic profiling, and metabolomics has the potential to offer a comprehensive understanding of athletes' performance and potential longevity. Telomeres provide insights into cellular functioning, aging, and adaptation and elucidate the effects of training on cellular health. Genotype/phenotype analysis explores genetic variations associated with athletic performance, injury predisposition, and recovery needs, enabling personalization of training plans and interventions. Metabolomics especially focusing on low-molecular weight metabolites, reveal metabolic pathways and responses to exercise. Biochemical tests assess key biomarkers related to energy metabolism, inflammation, and recovery. Essential elements depict the micronutrient status of the individual, which is critical for optimal performance. Echocardiography provides detailed monitoring of cardiac structure and function, while burnout testing evaluates psychological stress, fatigue, and readiness for optimal performance. By integrating this scientific testing battery, a multidimensional understanding of athlete health status can be achieved, leading to personalized interventions in training, nutrition, supplementation, injury prevention, and mental wellness support. This scientifically rigorous approach hereby presented holds significant potential for improving athletic performance and longevity through evidence-based, individualized interventions, contributing to advances in the field of sports performance optimization.

Vitamin D Supplementation and Genetic Polymorphisms Impact on Weight Loss Diet Outcomes in Caucasians: A Randomized Double-Blind Placebo-Controlled Clinical Study.

Vitamin D deficiency or insufficiency is common in obese people, with some studies suggesting that low vitamin D level might be an independent predictor of obesity. Thus, the purpose of the present randomized, double-blind, placebo-controlled study was to investigate the effect of oral spray vitamin D3 3000 IU supplementation along with personalized weight-loss diet on obesity markers in overweight and obese Caucasians with vitamin d deficiency or insufficiency. The impact of vitamin D receptor (VDR) and adrenergic receptors (ADRs) genetic variants on vitamin D levels and weight loss diet outcomes was also investigated. After signing informed consent, a total of 125 eligible volunteers were randomly assigned into vitamin D (vitamin D3 3000 IU/d oral spray supplementation, n = 76) or placebo (xylitol, water, mint, n = 49) group following a weight loss program (600 calories less than the total energy expenditure of each volunteer) for 3 months. Fat mass, BMI, REE and 25(OH)D serum level were monitored on baseline and each month. DNA samples were extracted from buccal swabs and genotyped for the rs2228570 (VDR), rs1544410 (VDR), rs731236 (VDR), rs1800544 (ADRA2A), rs1801252 (ADRB1), rs1042713 (ADRB2), and rs4994 (ADRB3) polymorphisms. Statistical analysis was performed using SPSS package (v.23). Between group comparisons revealed significant improvement in serum 25(OH)D level and greater reduction in weight, BMI and fat percentage in the vitamin D group compared to placebo group (p < 0.05). In the vitamin D group, carriers of the rs2228570 T allele tended to have greater vitamin D level improvement compared with the homozygous C allele (p = 0.067). Furthermore, heterozygous (CT) for the rs731236 tended to have lesser weight loss (p = 0.068) and for the rs1042713, a lower decline in fat percentage was observed for homozygous AA carriers compared to the heterozygous (p = 0.051). In the control group, differences in weight loss (p = 0.055) and BMI (p = 0.045) were observed between rs1544410 AA and GG homozygous. In conclusion, vitamin D oral spray supplementation seems to improve vitamin D status and decrease obesity markers during a weight-loss intervention in overweight/obese Caucasians with vitamin D deficiency or insufficiency. Also, the results of the present study indicate that VDR and ADRs genetic polymorphisms seem to influence vitamin D supplementation response and obesity markers.

Variability in oxidative stress-related genes (SOD2, CAT, GPX1, GSTP1, NOS3, NFE2L2, and UCP2) and susceptibility to migraine clinical phenotypes and features.

Introduction: Migraine is a complex disorder with genetic and environmental inputs. Cumulative evidence implicates oxidative stress (OS) in migraine pathophysiology while genetic variability may influence an individuals' oxidative/antioxidant capacity. Aim of the current study was to investigate the impact of eight common OS-related genetic variants [rs4880 (SOD2), rs1001179 (CAT), rs1050450 (GPX1), rs1695 (GSTP1), rs1138272 (GSTP1), rs1799983 (NOS3), rs6721961 (NFE2L2), rs660339 (UCP2)] in migraine susceptibility and clinical features in a South-eastern European Caucasian population. Methods: Genomic DNA samples from 221 unrelated migraineurs and 265 headache-free controls were genotyped for the selected genetic variants using real-time PCR (melting curve analysis). Results: Although allelic and genotypic frequency distribution analysis did not support an association between migraine susceptibility and the examined variants in the overall population, subgroup analysis indicated significant correlation between NOS3 rs1799983 and migraine susceptibility in males. Furthermore, significant associations of CAT rs1001179 and GPX1 rs1050450 with disease age-at-onset and migraine attack duration, respectively, were revealed. Lastly, variability in the CAT, GSTP1 and UCP2 genes were associated with sleep/weather changes, alcohol consumption and physical exercise, respectively, as migraine triggers. Discussion: Hence, the current findings possibly indicate an association of OS-related genetic variants with migraine susceptibility and clinical features, further supporting the involvement of OS and genetic susceptibility in migraine.

Use of oral glutamine in radiation-induced adverse effects in patients with thoracic and upper aerodigestive malignancies: Results of a prospective observational study.

Cancer growth in host tissues features glutamine (gln) depletion over time, decreasing epithelial cells' optimal functioning. In addition, radiotherapy (RT) and/or chemotherapy (CT) cause damage to normal tissues, probably enhanced by this depletion. The present study prospectively examined the effect of gln supplementation on 72 patients with thoracic and upper aerodigestive malignancies (T&UAM) treated with sequential or concurrent RT-CT or RT alone. All patients received prophylactic gln powder 15 g bid for the full duration of treatment. The severity of acute radiation toxicities was graded according to the RT Oncology Group/European Organization for Research and Treatment of Cancer criteria. Primary endpoints were the incidence of grade >2 toxicities, weight loss and requirement for analgesics, and the secondary endpoint was the association of the length of irradiated esophagus from treatment planning with the use of opioids. The incidence of adverse effects was as follows: Grade >2 stomatitis, 25.0%; esophagitis, 60.5%; dysphagia, 54.2%; pain, 25.4%; mycosis, 40.8%. Stomatitis grade >2 was more frequent in patients with head and neck tumors (P<0.001) and in those with prior surgery (P<0.001). Esophagitis (P=0.020) and dysphagia (P=0.008) grade >2 were more frequent in patients with concurrent RT-CT. Regarding analgesics, 9.9% of patients received no pain treatment, 56.3% received simple analgesic therapy and 33.8% opioids. Patients on opioid therapy had a greater mean length of irradiated esophagus (P=0.024) or length >12 cm (P=0.018). In 54.2% of patients, weight loss was observed, particularly with concurrent RT-CT (P=0.007). Thus, the use of oral gln may have an important role in reducing acute radiation toxicities and weight loss, and in lowering the requirement for analgesics in patients with T&UAM. Further randomized trials are required to identify the appropriate gln dose, duration of treatment and precise radiation dosimetric parameters in this group of patients. The present clinical trial was retrospectively registered in the ClinicalTrials.gov Protocol Registration and Results System (registration no. NCT05054517/22-09-2021).

Contributing factors common to COVID­19 and gastrointestinal cancer.

The devastating complications of coronavirus disease 2019 (COVID­19) result from the dysfunctional immune response of an individual following the initial severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) infection. Multiple toxic stressors and behaviors contribute to underlying immune system dysfunction. SARS­CoV­2 exploits the dysfunctional immune system to trigger a chain of events, ultimately leading to COVID­19. The authors have previously identified a number of contributing factors (CFs) common to myriad chronic diseases. Based on these observations, it was hypothesized that there may be a significant overlap between CFs associated with COVID­19 and gastrointestinal cancer (GIC). Thus, in the present study, a streamlined dot­product approach was used initially to identify potential CFs that affect COVID­19 and GIC directly (i.e., the simultaneous occurrence of CFs and disease in the same article). The nascent character of the COVID­19 core literature (~1­year­old) did not allow sufficient time for the direct effects of numerous CFs on COVID­19 to emerge from laboratory experiments and epidemiological studies. Therefore, a literature­related discovery approach was used to augment the COVID­19 core literature­based 'direct impact' CFs with discovery­based 'indirect impact' CFs [CFs were identified in the non­COVID­19 biomedical literature that had the same biomarker impact pattern (e.g., hyperinflammation, hypercoagulation, hypoxia, etc.) as was shown in the COVID­19 literature]. Approximately 2,250 candidate direct impact CFs in common between GIC and COVID­19 were identified, albeit some being variants of the same concept. As commonality proof of concept, 75 potential CFs that appeared promising were selected, and 63 overlapping COVID­19/GIC potential/candidate CFs were validated with biological plausibility. In total, 42 of the 63 were overlapping direct impact COVID­19/GIC CFs, and the remaining 21 were candidate GIC CFs that overlapped with indirect impact COVID­19 CFs. On the whole, the present study demonstrates that COVID­19 and GIC share a number of common risk/CFs, including behaviors and toxic exposures, that impair immune function. A key component of immune system health is the removal of those factors that contribute to immune system dysfunction in the first place. This requires a paradigm shift from traditional Western medicine, which often focuses on treatment, rather than prevention.

Evidence That HFE H63D Variant Is a Potential Disease Modifier in Cluster Headache.

Cluster headache (CH) is a primary headache disorder with a complex genetic background. Several studies indicate a potential link between iron homeostasis and the pathophysiology of primary headaches. The HFE gene encodes for a protein involved in iron metabolism, while genetic variants in HFE have been associated with hereditary hemochromatosis (HH), an iron overload disorder. The objective of the current study was to examine the association of the more common HFE H63D variant, with the susceptibility to develop CH and diverse clinical phenotypes in a population of Southeastern European Caucasian (SEC) origin. Genomic DNA samples from 128 CH patients and 294 neurologically healthy controls were genotyped for the HFE rs1799945 (H63D) variant. H63D genotypic and allelic frequency distribution did not differ significantly between patients and controls (p > 0.05). Subgroup analysis revealed a significantly more frequent occurrence of the variant G allele in chronic compared to episodic CH patients, indicative for a possible correlation of the HFE gene with the susceptibility for disease chronification. Although homozygosity for the less prevalent H63D variant G allele was minimal in the CH cohort, the results of the present study are in accordance with previous studies in CH and migraine patients, suggesting that HFE H63D variant modifies the disease clinical characteristics. Hence, despite the absence of a per se association with CH susceptibility in the current SEC cohort, variability in HFE gene may be potentially regarded as a disease modifier genetic factor in CH.

VDR Gene Polymorphisms and Cluster Headache Susceptibility: Case-Control Study in a Southeastern European Caucasian Population.

Cluster headache (CH) is a severe primary headache disorder with a genetic component, as indicated by family and twin studies. Diurnal and seasonal rhythmicity are key features of the disease and might be related to vitamin D, as low vitamin D levels have been observed in patients with cluster headache. In addition, the vitamin D receptor (VDR) occurs in brain areas and particularly in the hypothalamus. The aim of the present case-control study was to investigate the association of cluster headache susceptibility and clinical phenotypes with the VDR gene polymorphisms FokI, BsmI and TaqI in a Southeastern European Caucasian population. DNA was extracted from 131 unrelated CH patients and 282 non-headache controls and genotyped using real-time PCR (melting curve analysis). Linkage disequilibrium (LD) analysis confirmed that BsmI and TaqI, both located in the 3'UTR of the VDR gene, are in strong LD. Genotype and allele frequency distribution analysis of the VDR FokI, BsmI, and TaqI polymorphisms showed no statistically significant difference between cases and controls, whereas haplotype analysis indicated that the TAC haplotype might be associated with decreased cluster headache susceptibility. Intra-patient analysis according to diverse clinical phenotypes showed an association of the BsmI GG and TaqI TT genotypes with more frequent occurrence of CH attacks in this cohort. Therefore, a possible association was observed between VDR gene polymorphisms BsmI and TaqI or a linked locus and susceptibility for cluster headache development and altered clinical phenotypes in the Southeastern European Caucasian study population. Further large-scale replication studies are needed to validate these findings.

Association of vitamin D receptor gene TaqI polymorphism with Alzheimer's disease in a Southeastern European Caucasian population.

The role of vitamin D in Alzheimer's Disease (AD) has been studied over the past years. The results from numerous studies have indicated that the molecular pathways involved in the development of AD are closely related to the molecular pathways of the mechanisms of action of vitamin D. However, only a limited number of studies have described the key role of vitamin D receptor (VDR) in the regulation of the functions of vitamin D and the potential effect of single nucleotide polymorphisms (SNPs) of the VDR gene. Thus, the aim of the present study was to investigate the VDR TaqI polymorphism in relation to AD in a Southeastern European Caucasian (SEC) cohort. Further, the present study aimed to compare the results obtained with those of other AD populations. For this purpose, blood samples from 90 confirmed patients with AD [median age, 74 years; median mini-mental state examination (MMSE) score of 21; median frontal assessment battery (FAB) score of 10] and 103 healthy controls (median age, 57 years) were analyzed to determine the genotypes of TaqI (rs731236) using quantitative PCR. The frequencies (%) of the TaqI TT, TC and CC genotypes in the controls/patients were 34/48.9, 47.6/41.1 and 18.4/10.0, respectively. Statistically significant differences were observed for the TaqI C allele [odds ratio (OR). 0.54; 95% confidence interval (CI), 0.30-0.96; P=0.035], the TaqI TT genotype (OR, 1.86; 95% CI, 1.04-3.32; P=0.035) and the TaqI CC genotype (OR, 0.119; 95% CI, 0.014-0.995; P=0.032,) in relation to the MMSE score <21 in the patient's group. The TaqI TT allele was found to increase the risk of developing AD by 1.86-fold in the SEC population, while the TaqI C allele may act protectively, with a 46% lower risk of developing the disease. Patients with the TaqI CC genotype were found to have an 88% less likelihood of developing severe cognitive impairment based on the MMSE score. On the whole, the present study did not confirm the results of previous studies on the VDR TaqI C allele in patients with AD.

Association of vitamin D receptor gene haplotypes with late-onset Alzheimer's disease in a Southeastern European Caucasian population.

Vitamin D receptor (VDR) gene single nucleotide polymorphisms (SNPs) have been investigated over the past years with the aim of identifying any association with the development of Alzheimer's disease (AD). However, information regarding the potential association of VDR SNP haplotypes with AD is limited. The aim of the present study was to provide additional knowledge on the effects of VDR haplotypes on the development of late-onset AD in a cohort of Southeastern European Caucasians (SECs). The study sample included 78 patients with late-onset AD and 103 healthy subjects as the control group. VDR SNPs that were analyzed were TaqI (rs731236), BsmI (rs1544410) and FokI (rs2228570). The CAC (TaqI, BsmI and FokI) haplotype was found to be associated with a 53% lower risk of developing the disease (OR, 0.47; 95% CI, 0.23-0.96; P=0.04) and the TAC (TaqI, BsmI and FokI) haplotype was associated with an ~6-fold greater risk of developing AD (OR, 6.19; 95% CI, 1.91-20.13; P=0.0028). Female subjects carrying the TAC haplotype had a ~9-fold greater risk of developing AD in comparison to female control subjects (OR, 9.27; 95% CI, 1.86-46.28; P<0.05). The TaqI and BsmI polymorphisms were in high linkage disequilibrium (D'=0.9717, r=0.8467) and produced a haplotype with a statistically significant different frequency between the control and AD group. The TA (TaqI and BsmI) haplotype was associated with an ~8-fold greater risk of developing AD (OR, 8.27; 95% CI, 2.70-25.28; P<0.05). Female TA carriers had an ~14-fold greater risk of developing the disease in comparison to female control subjects (OR, 13.93; 95% CI, 2.95-65.87; P<0.05). On the whole, the present study demonstrates that in the SEC population, TAC and TA are risk haplotypes for AD, while the CAC haplotype may act protectively. SEC women carrying the TAC or TA haplotype are at a greater risk of developing AD, thus suggesting that women are markedly affected by the poor utilization of vitamin D induced by the VDR haplotype.

Endothelial Function in Postmenopausal Women: The Possible Role of Heat Shock Protein 60 and Serum Androgens.

Background: Heat shock protein 60 (HSP60), a potentially homeostatic antigen, is involved in physiological and non-physiological conditions. Experimental data support the role of HSP60 in placental and mitochondrial steroidogenesis. Furthermore, HSP60 is translocated into the endothelial-cell plasma membrane and the extracellular space under stress conditions, promoting the atherosclerotic process. Therefore, we investigated the association between HSP60 and endothelial function in postmenopausal women, considering the possible atherogenic effect of androgenic hormones. Methods: This study included 123 healthy postmenopausal women. Exclusion criteria were treated hypertension or dyslipidaemia, menopause hormone therapy during the last 6 months, and previously diagnosed peripheral vascular disease or cardiovascular disease. Fasting venous blood samples were obtained for biochemical and hormonal assessment and evaluation of HSP60. Sonographic assessment of flow-mediated dilation (FMD) occurred immediately after that in one session. Results: Univariate analysis showed that women with FMD values below median 5.12% had lower logHSP60 values (low vs. high FMD, HSP60 values: 2.01 ± 1.16 ng/ml vs. 3.22 ± 1.17 ng/ml, p-value = 0.031). Multivariable analysis showed that logHSP60 was associated with FMD (b-coefficient = 0.171, p-value = 0.046), adjusting for traditional cardiovascular risk factors (TRFs) and insulin levels. Further adjustment for testosterone and DHEAS rendered the result non-significant. In the multivariable analysis, FMD was associated with insulin (b-coefficient = -0.166, p-value = 0.034), testosterone (b-coefficient = -0.165, p-value = 0.034), DHEAS (b-coefficient = -0.187, p-value = 0.017), adjusting for TRFs. Discussion: The results of this study indicate that the association between androgens and endothelial function is possibly mediated by HSP60 molecules, in women with low insulin resistance and androgenicity. Further prospective studies are needed to explore the significance of our findings.