Role of the Menstrual Cycle on Performance and Injury Risk: A Survey of Female Professional Rugby Players in the United Kingdom.

BACKGROUND: Female athletic performance and injury risk is impacted by variations in the menstrual cycle (MC), but the understanding of the impacts and mechanisms influenced by the menstrual cycle on exercise performance are not fully delineated. AIMS AND OBJECTIVES: Evaluate associations between the menstrual cycle, perceived performance, and injury risk of elite female rugby players using an online survey. METHODS: An anonymous online questionnaire was completed by 150 elite female rugby players from two English rugby leagues, the Betfred Women's Super League (BWSL) and the Allianz Premier 15s (AP15s). The collected data were analysed thematically. RESULTS: The Chi-square test was used to assess associations between age groups and contraception usage, weight change, and training and playing performance; none of the associations were statistically significant (all p values > 0.05). Thematic analysis of 11,660 words of data revealed four themes: (a) MC impact on training and competition, (b) education and period management plans, (c) openness of conversations and comfort taking time off, and (d) injury risk. The impacted performance areas were physical (83.7%), psychological (85.7%), and nutritional (80.3%); players experienced decreased appetite, nausea, fatigue, strength declines, heighted emotions, and worsened focus. In total, 87.8% of athletes perceived the MC to negatively impact performance, 85.7% of players desired to be educated further to prevent injuries, improve nutrition, and training adaptions, 51.7% of participants perceived risk of injury to be higher during MC, and 86.4% of participants did not feel comfortable taking time off due to the MC, worrying that selection would be affected and about opinions from others. CONCLUSION: A clear negative impact on perceived performance and injury risk was reported by survey participants. The interaction of physical, psychological, and nutritional factors, and a lack of awareness and education emphasise the need for further comprehensive studies and interventions, with measures such as MC monitoring and profiling, education, and training adaptions to develop openness, knowledge, and understanding.

Implications of siRNA Therapy in Bone Health: Silencing Communicates.

The global statistics of bone disorders, skeletal defects, and fractures are frightening. Several therapeutic strategies are being used to fix them; however, RNAi-based siRNA therapy is starting to prove to be a promising approach for the prevention of bone disorders because of its advanced capabilities to deliver siRNA or siRNA drug conjugate to the target tissue. Despite its 'bench-to-bedside' usefulness and approval by food and drug administration for five siRNA-based therapeutic medicines: Patisiran, Vutrisiran, Inclisiran, Lumasiran, and Givosiran, its use for the other diseases still remains to be resolved. By correcting the complications and complexities involved in siRNA delivery for its sustained release, better absorption, and toxicity-free activity, siRNA therapy can be harnessed as an experimental tool for the prevention of complex and undruggable diseases with a personalized medicine approach. The present review summarizes the findings of notable research to address the implications of siRNA in bone health for the restoration of bone mass, recovery of bone loss, and recuperation of bone fractures.

Potential of Nano-Engineered Stem Cells in the Treatment of Multiple Sclerosis: A Comprehensive Review.

Multiple sclerosis (MS) is a chronic and degrading autoimmune disorder mainly targeting the central nervous system, leading to progressive neurodegeneration, demyelination, and axonal damage. Current treatment options for MS are limited in efficacy, generally linked to adverse side effects, and do not offer a cure. Stem cell therapies have emerged as a promising therapeutic strategy for MS, potentially promoting remyelination, exerting immunomodulatory effects and protecting against neurodegeneration. Therefore, this review article focussed on the potential of nano-engineering in stem cells as a therapeutic approach for MS, focusing on the synergistic effects of combining stem cell biology with nanotechnology to stimulate the proliferation of oligodendrocytes (OLs) from neural stem cells and OL precursor cells, by manipulating neural signalling pathways-PDGF, BMP, Wnt, Notch and their essential genes such as Sox, bHLH, Nkx. Here we discuss the pathophysiology of MS, the use of various types of stem cells in MS treatment and their mechanisms of action. In the context of nanotechnology, we present an overview of its applications in the medical and research field and discuss different methods and materials used to nano-engineer stem cells, including surface modification, biomaterials and scaffolds, and nanoparticle-based delivery systems. We further elaborate on nano-engineered stem cell techniques, such as nano script, nano-exosome hybrid, nano-topography and their potentials in MS. The article also highlights enhanced homing, engraftment, and survival of nano-engineered stem cells, targeted and controlled release of therapeutic agents, and immunomodulatory and tissue repair effects with their challenges and limitations. This visual illustration depicts the process of utilizing nano-engineering in stem cells and exosomes for the purpose of delivering more accurate and improved treatments for Multiple Sclerosis (MS). This approach targets specifically the creation of oligodendrocytes, the breakdown of which is the primary pathological factor in MS.

A Molecular Troika of Angiogenesis, Coagulopathy and Endothelial Dysfunction in the Pathology of Avascular Necrosis of Femoral Head: A Comprehensive Review.

Avascular necrosis of the femoral head (ANFH) is a painful disorder characterized by the cessation of blood supply to the femoral head, leading to its death and subsequent joint collapse. Influenced by several risk factors, including corticosteroid use, excessive alcohol intake, hypercholesterolemia, smoking and some inflammatory disorders, along with cancer, its clinical consequences are thrombus formation due to underlying inflammation and endothelial dysfunction, which collaborates with coagulopathy and impaired angiogenesis. Nonetheless, angiogenesis resolves the obstructed free flow of the blood by providing alternative routes. Clinical manifestations of early stage of ANFH mimic cysts or lesions in subchondral bone, vasculitis and transient osteoporosis of the hip, rendering it difficult to diagnose, complex to understand and complicated to cure. To date, the treatment methods for ANFH are controversial as no foolproof curative strategy is available, and these depend upon different severity levels of the ANFH. From an in-depth understanding of the pathological determinants of ANFH, it is clear that impaired angiogenesis, coagulopathy and endothelial dysfunction contribute significantly. The present review has set two aims, firstly to examine the role and relevance of this molecular triad (impaired angiogenesis, coagulopathy and endothelial dysfunction) in ANFH pathology and secondly to propose some putative therapeutic strategies, delineating the fact that, for the better management of ANFH, a combined strategy to curtail this molecular triangle must be composed rather than focusing on individual contributions.

Advances and challenges in thyroid cancer: The interplay of genetic modulators, targeted therapies, and AI-driven approaches.

Thyroid cancer continues to exhibit a rising incidence globally, predominantly affecting women. Despite stable mortality rates, the unique characteristics of thyroid carcinoma warrant a distinct approach. Differentiated thyroid cancer, comprising most cases, is effectively managed through standard treatments such as thyroidectomy and radioiodine therapy. However, rarer variants, including anaplastic thyroid carcinoma, necessitate specialized interventions, often employing targeted therapies. Although these drugs focus on symptom management, they are not curative. This review delves into the fundamental modulators of thyroid cancers, encompassing genetic, epigenetic, and non-coding RNA factors while exploring their intricate interplay and influence. Epigenetic modifications directly affect the expression of causal genes, while long non-coding RNAs impact the function and expression of micro-RNAs, culminating in tumorigenesis. Additionally, this article provides a concise overview of the advantages and disadvantages associated with pharmacological and non-pharmacological therapeutic interventions in thyroid cancer. Furthermore, with technological advancements, integrating modern software and computing into healthcare and medical practices has become increasingly prevalent. Artificial intelligence and machine learning techniques hold the potential to predict treatment outcomes, analyze data, and develop personalized therapeutic approaches catering to patient specificity. In thyroid cancer, cutting-edge machine learning and deep learning technologies analyze factors such as ultrasonography results for tumor textures and biopsy samples from fine needle aspirations, paving the way for a more accurate and effective therapeutic landscape in the near future.

Targeting calcium homeostasis and impaired inter-organelle crosstalk as a potential therapeutic approach in Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, leading to motor symptoms such as tremors, rigidity, and bradykinesia. Current therapeutic strategies for PD are limited and mainly involve symptomatic relief, with no available treatment for the underlying causes of the disease. Therefore, there is a need for new therapeutic approaches that target the underlying pathophysiological mechanisms of PD. Calcium homeostasis is an essential process for maintaining proper cellular function and survival, including neuronal cells. Calcium dysregulation is also observed in various organelles, including the endoplasmic reticulum (ER), mitochondria, and lysosomes, resulting in organelle dysfunction and impaired inter-organelle communication. The ER, as the primary calcium reservoir, is responsible for folding proteins and maintaining calcium homeostasis, and its dysregulation can lead to protein misfolding and neurodegeneration. The crosstalk between ER and mitochondrial calcium signaling is disrupted in PD, leading to neuronal dysfunction and death. In addition, a lethal network of calcium cytotoxicity utilizes mitochondria, ER and lysosome to destroy neurons. This review article focused on the complex role of calcium dysregulation and its role in aggravating functioning of organelles in PD so as to provide new insight into therapeutic strategies for treating this disease. Targeting dysfunctional organelles, such as the ER and mitochondria and lysosomes and whole network of calcium dyshomeostasis can restore proper calcium homeostasis and improve neuronal function. Additionally targeting calcium dyshomeostasis that arises from miscommunication between several organelles can be targeted so that therapeutic effects of calcium are realised in whole cellular territory.

Effect of Acute Walking on Endothelial Function and Postprandial Lipemia in South Asians and White Europeans.

INTRODUCTION: South Asians (SAs) have an elevated risk of cardiovascular disease (CVD) compared with White Europeans (WEs). Postprandial endothelial function (flow-mediated dilatation (FMD%)) in SA women and SA men with central obesity has not been investigated. Research in other populations has highlighted that a 1% higher FMD% is associated with a ~13% lower risk of future CVD events. We investigated whether FMD% and lipemia, two markers for CVD risk, were higher in SAs versus WEs, whether walking improved FMD% and lipemia, and if there were ethnic differences in the response. METHODS: Lean premenopausal women (study 1; 12 SA, 12 WE) and men with central obesity (study 2; 15 SA, 15 WE) completed two 2-d trials. On day 1, participants walked for 60 min at 60% of their peak oxygen uptake or rested. On day 2, participants rested and consumed two high-fat meals over 8 h. Repeated ultrasound assessments of endothelial function and venous blood samples for CVD risk markers were taken. RESULTS: Compared with WEs, SAs had lower postprandial FMD% (study 1, -1.32%; study 2, -0.54%) and higher postprandial triacylglycerol concentrations (study 1, 0.31 mmol·L -1 ·h -1 ; study 2, 0.55 mmol·L -1 ·h -1 ). Walking improved postprandial FMD% (study 1, 1.12%; study 2, 0.94%) and resulted in no significant change or small reductions in postprandial triacylglycerol concentrations (study 1, -0.01 mmol·L -1 ·h -1 ; study 2, -0.25 mmol·L -1 ·h -1 ). Exercise-induced changes in FMD% and triacylglycerol were consistent between ethnic groups. CONCLUSIONS: Walking mitigated the adverse postprandial effect of a high-fat diet on FMD% to a similar extent in SA and WE women and men, even with no/small improvements in triacylglycerol. This study highlights the importance of exercise to clinically improve FMD% in SAs and WEs.

Neutrophil Extracellular Traps and NLRP3 Inflammasome: A Disturbing Duo in Atherosclerosis, Inflammation and Atherothrombosis.

Atherosclerosis is the formation of plaque within arteries due to overt assemblage of fats, cholesterol and fibrous material causing a blockage of the free flow of blood leading to ischemia. It is harshly impinging on health statistics worldwide because of being principal cause of high morbidity and mortality for several diseases including rheumatological, heart and brain disorders. Atherosclerosis is perpetuated by pro-inflammatory and exacerbated by pro-coagulatory mediators. Besides several other pathways, the formation of neutrophil extracellular traps (NETs) and the activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome contribute significantly to the initiation and propagation of atherosclerotic plaque for its worst outcomes. The present review highlights the contribution of these two disturbing processes in atherosclerosis, inflammation and atherothrombosis in their individual as well as collaborative manner.

Impacts of Eccentric Resistance Exercise on DNA Methylation of Candidate Genes for Inflammatory Cytokines in Skeletal Muscle and Leukocytes of Healthy Males.

Physical inactivity and a poor diet increase systemic inflammation, while chronic inflammation can be reduced through exercise and nutritional interventions. The mechanisms underlying the impacts of lifestyle interventions on inflammation remain to be fully explained; however, epigenetic modifications may be critical. The purpose of our study was to investigate the impacts of eccentric resistance exercise and fatty acid supplementation on DNA methylation and mRNA expression of TNF and IL6 in skeletal muscle and leukocytes. Eight non-resistance exercise-trained males completed three bouts of isokinetic eccentric contractions of the knee extensors. The first bout occurred at baseline, the second occurred following a three-week supplementation of either omega-3 polyunsaturated fatty acid or extra virgin olive oil and the final bout occurred after eight-weeks of eccentric resistance training and supplementation. Acute exercise decreased skeletal muscle TNF DNA methylation by 5% (p = 0.031), whereas IL6 DNA methylation increased by 3% (p = 0.01). Leukocyte DNA methylation was unchanged following exercise (p > 0.05); however, three hours post-exercise the TNF DNA methylation decreased by 2% (p = 0.004). In skeletal muscle, increased TNF and IL6 mRNA expression levels were identified immediately post-exercise (p < 0.027); however, the leukocyte mRNA expression was unchanged. Associations between DNA methylation and markers of exercise performance, inflammation and muscle damage were identified (p < 0.05). Acute eccentric resistance exercise is sufficient to induce tissue-specific DNA methylation modifications to TNF and IL6; however, neither eccentric training nor supplementation was sufficient to further modify the DNA methylation.

Genomic diversity and differentiation of Alu insertion polymorphisms in a native British and four South Asian migrant populations.

BACKGROUND: Alu insertions are bi-allelic and primate-specific, this makes them a useful marker for studying genetic variation, migration patterns, forensic analyses, paternity, and evolutionary heritage; however, specific population studies are limited. AIM: The objective of this study is to document the level and extent of genetic variation at 39 different Alu loci in five populations (British, Indian Punjabi, Indian Gujarati, Pakistani, and Bangladeshi) from the East Midlands region of the UK. Genetic data on migrant populations is currently limited. SUBJECTS AND METHODS: DNA samples (n = 543) were analysed for 39 Alu insertion polymorphisms using specific primers and standard protocols. Data were analysed for population and forensic genetic parameters. RESULTS: All studied Alus were polymorphic in the British White population while South Asian migrant populations had a variable number of loci which were monomorphic. Highest heterozygosities and lowest match probabilities were observed in the British sample, while the Bangladeshi sample had the lowest heterozygosity and higher match probability. CONCLUSION: The analysed Alus insertions (TPA25, Ya5NBC123, Ya5NBC182, Ya5NBC241, and Ya5NBC242) are highly polymorphic and variable among migrant populations. These loci could be useful for population genomic and differentiation studies.

Dysregulated autophagy: A key player in the pathophysiology of type 2 diabetes and its complications.

Autophagy is essential in regulating the turnover of macromolecules via removing damaged organelles, misfolded proteins in various tissues, including liver, skeletal muscles, and adipose tissue to maintain the cellular homeostasis. In these tissues, a specific type of autophagy maintains the accumulation of lipid droplets which is directly related to obesity and the development of insulin resistance. It appears to play a protective role in a normal physiological environment by eliminating the invading pathogens, protein aggregates, and damaged organelles and generating energy and new building blocks by recycling the cellular components. Ageing is also a crucial modulator of autophagy process. During stress conditions involving nutrient deficiency, lipids excess, hypoxia etc., autophagy serves as a pro-survival mechanism by recycling the free amino acids to maintain the synthesis of proteins. The dysregulated autophagy has been found in several ageing associated diseases including type 2 diabetes (T2DM), cancer, and neurodegenerative disorders. So, targeting autophagy can be a promising therapeutic strategy against the progression to diabetes related complications. Our article provides a comprehensive outline of understanding of the autophagy process, including its types, mechanisms, regulation, and role in the pathophysiology of T2DM and related complications. We also explored the significance of autophagy in the homeostasis of ß-cells, insulin resistance (IR), clearance of protein aggregates such as islet amyloid polypeptide, and various insulin-sensitive tissues. This will further pave the way for developing novel therapeutic strategies for diabetes-related complications.

Genetic Risk Scores for the Determination of Type 2 Diabetes Mellitus (T2DM) in North India.

BACKGROUND: Globally, type 2 diabetes mellitus (T2DM) is one of the fastest-growing noncommunicable multifactorial and polygenic diseases, which leads to many health complications and significant morbidity and mortality. South Asians have a high genetic predisposition to T2DM, with India being home to one in six diabetics. This study investigates the association of selected genetic polymorphisms with T2DM risk and develops a polygenic risk score (PRS). METHODS: A case-control study recruited fully consented participants from a population of Jat Sikhs in north India. DNA samples were genotyped for a range of polymorphisms and odds ratios were calculated under several genetic association models. Receiver operating characteristic (ROC) curves were produced for combinations of the PRS and clinical parameters. RESULTS: The GSTT1(rs17856199), GSTM1(rs366631), GSTP1(rs1695), KCNQ1(rs2237892), ACE(rs4646994), and TCF7L2(rs12255372; rs7903146; rs7901695) polymorphisms were associated with increased T2DM risk (p ≤ 0.05). No association was observed with IGF2BP2(rs4402960) or PPARG2(rs1801282). The weighted PRS was found to be significantly higher in patients (mean = 15.4, SD = 3.24) than controls (mean = 11.9, SD = 3.06), and t(454) = -12.2 (p < 0.001). The ROC curve analysis found the weighted PRS in combination with clinical variables to be the most effective predictor of T2DM (area under the curve = 0.844, 95%CI = 0.0.808-0.879). CONCLUSIONS: Several polymorphisms were associated with T2DM risk. PRS based on even a limited number of loci improves the prediction of the disease. This may provide a useful method for determining T2DM susceptibility for clinical and public health applications.

A susceptibility putative haplotype within NLRP3 inflammasome gene influences ischaemic stroke risk in the population of Punjab, India.

Despite strong genetic implications of NLRP3 inflammasome, its examination as genetic determinant of ischaemic stroke (IS) remains to be done in Punjab, which has been investigated in this study. In this case control study, 400 subjects (200 IS patients, 200 stroke free controls) were included. Contributions of 5 single nucleotide polymorphisms (SNPs) including a functional SNP within NLRP3 gene (rs10754558, rs4612666, rs2027432, rs3738488 and rs1539019) for the risk of IS were investigated through genetic models after correcting the effect of significant variables. Plasma levels of three pro-inflammatory markers, that is, C-reactive protein (CRP), interleukin-1beta (IL-1ß) and interleukin-18 (IL-18) were measured by enzyme-linked immunosorbent assays (ELISA). Minor alleles of 3 out of 5 SNPs (rs10754558, rs4612666 and rs1539019) exhibited association with IS risk in additive, recessive and multiplicative models. Multivariable regression analysis confirmed that higher levels of systolic blood pressure (ß ± SE: 1.42 ± 0.57, p = .013), CRP (ß ± SE: 1.22 ± 0.41, p = .003), IL-1ß (ß ± SE: 1.78 ± 0.88, p = .043) and IL-18 (ß ± SE: 1.13 ± 0.49, p = .021) were independent risk predictors for IS. Haplotype analysis revealed a susceptibility putative haplotype GTGTA, which approximately doubled the IS risk (OR: 1.98, 95% CI: 1.12-3.78, p = .04) in dominant mode after adjusting the effect with confounding variables. This susceptibility putative haplotype GTGTA was significantly associated with increased concentrations of CRP (ß = 1.21, p = .014) and IL-1ß (ß = 1.53, p = .034) in dose-dependent manner (less in carriers of 1 copy than those who had 2 copies of GTGTA). The present study has revealed a susceptibility putative haplotype GTGTA within NLRP3 gene, carriers of which have double the risk of IS by having increased plasma levels of CRP and IL-1ß in a dose-dependent manner.

Targeting mitochondrial bioenergetics as a promising therapeutic strategy in metabolic and neurodegenerative diseases.

Mitochondria are the organelles that generate energy for the cells and act as biosynthetic and bioenergetic factories, vital for normal cell functioning and human health. Mitochondrial bioenergetics is considered an important measure to assess the pathogenesis of various diseases. Dysfunctional mitochondria affect or cause several conditions involving the most energy-intensive organs, including the brain, muscles, heart, and liver. This dysfunction may be attributed to an alteration in mitochondrial enzymes, increased oxidative stress, impairment of electron transport chain and oxidative phosphorylation, or mutations in mitochondrial DNA that leads to the pathophysiology of various pathological conditions, including neurological and metabolic disorders. The drugs or compounds targeting mitochondria are considered more effective and safer for treating these diseases. In this review, we make an effort to concise the available literature on mitochondrial bioenergetics in various conditions and the therapeutic potential of various drugs/compounds targeting mitochondrial bioenergetics in metabolic and neurodegenerative diseases.

Pilates and telomere dynamics: A 12-month longitudinal study.

Telomeres are dynamic structures that appear to be positively influenced by healthy lifestyle factors such as exercise. Pilates is an increasingly popular exercise modality that is reported to exert beneficial physiological effects in the body, although the cellular mechanisms are poorly understood. The aim of the present study was to investigate the influence of Pilates exercise on telomere length. This longitudinal study followed experienced female Pilates practitioners (n = 11, 50.8 ± 7.5 years) and healthy age- and sex-matched sedentary controls (n = 11, 49.3 ± 6.1 years) over a 12-month period. Leukocyte telomere length was quantified using qPCR. Circulatory inflammatory markers, mRNA gene expression, body composition, physical performance, and mental well-being were also assessed. Telomere length was comparable between Pilates practitioners and controls at baseline (Pre) and 12-months (Post) (p > 0.0125). Pilates practitioners displayed enhanced mRNA gene expression of antioxidant enzymes (SOD2 and GPX1), and lower body fat percentage and visceral fat rating, compared with sedentary controls (p < 0.0125). Over the 12-month longitudinal period, Pilates participants significantly increased dynamic balance (p < 0.05). In conclusion, long-term Pilates participation does not appear to influence telomere length. Nonetheless, Pilates exercise appears to increase antioxidant enzyme gene expression, effectively manage body composition, and improve dynamic balance.

Prevalence and Predictors of Osteoporosis and Osteopenia in Postmenopausal Women of Punjab, India.

The prevalence and predictors of osteoporosis and osteopenia remain to be examined in the postmenopausal women of Punjab, India. The present cross-sectional study screened 1628 postmenopausal women during September 2019 to March 2020. Osteoporosis and osteopenia were confirmed on the basis of T-scores using dual energy X-ray absorptiometry (DXA) at the hip (femoral neck) and lumbar spine regions (L1−L4 vertebrae). The prevalence of osteoporosis and osteopenia was observed to be 30.50% and 44.20%, respectively, in postmenopausal women of Punjab. In univariable and multivariable regression analysis, variables independently influencing the risk of osteoporosis and osteopenia were: higher systolic blood pressure (95%CI: 1.22−3.11 & 1.08−2.49), triglyceride levels (95%CI: 1.21−3.10 & 1.42−2.51), poor sleep quality (95%CI: 1.91−2.47 & 1.76−3.47) and C-reactive protein levels (95%CI: 2.18−3.56 & 1.03−2.18). Years since menopause >10 years was observed to be an independent predictor for the risk of osteopenia but not for osteoporosis. Higher body mass index (>30 kg·m−2) was observed to be a significant protective factor against the risk of osteoporosis (95%CI: 0.26−0.68) and osteopenia (95%CI: 0.19−0.52). The higher prevalence rates of osteoporosis and osteopenia in postmenopausal women of Punjab are alarming, which solicits awareness and earlier testing of those women who are approaching menopause.

Comparison of Telomere Length in Young and Master Endurance Runners and Sprinters.

It is unclear how running modality influences telomere length (TL). This single laboratory visit study compared the TL of master sprinters and endurance runners with their young counterparts. The correlation between leukocyte and buccal cell TL in athletes was also explored. Participants consisted of 11 young controls, 11 young sprinters, 12 young endurance runners, 12 middle-aged controls, 11 master sprinters, and 12 master endurance runners. Blood and buccal samples were collected and randomized for analysis of TL by quantitative polymerase chain reaction. Young endurance runners displayed longer telomeres than master athletes (p < .05); however, these differences were not significant when controlled for covariates (p > .05). A positive correlation existed between leukocyte and buccal cell TL in athletes (r = .567, p < .001). In conclusion, young endurance runners possess longer telomeres than master endurance runners and sprinters, a consequence of lower body mass index and visceral fat.

Multifactorial Landscape Parses to Reveal a Predictive Model for Knee Osteoarthritis.

The present study attempted to investigate whether concerted contributions of significant risk variables, pro-inflammatory markers, and candidate genes translate into a predictive marker for knee osteoarthritis (KOA). The present study comprised 279 confirmed osteoarthritis patients (Kellgren and Lawrence scale >2) and 287 controls. Twenty SNPs within five genes (CRP, COL1A1, IL-6, VDR, and eNOS), four pro-inflammatory markers (interleukin-6 (IL-6), interleuin-1 beta (IL-1ß), tumor necrosis factor alpha (TNF-α), and high sensitivity C-reactive protein (hsCRP)), along with significant risk variables were investigated. A receiver operating characteristic (ROC) curve was used to observe the predictive ability of the model for distinguishing patients with KOA. Multivariable logistic regression analysis revealed that higher body mass index (BMI), triglycerides (TG), poor sleep, IL-6, IL-1ß, and hsCRP were independent predictors for KOA after adjusting for the confounding from other risk variables. Four susceptibility haplotypes for the risk of KOA, AGT, GGGGCT, AGC, and CTAAAT, were observed within CRP, IL-6, VDR, and eNOS genes, which showed their impact in recessive ß(SE): 2.11 (0.76), recessive ß(SE): 2.75 (0.59), dominant ß(SE): 1.89 (0.52), and multiplicative modes ß(SE): 1.89 (0.52), respectively. ROC curve analysis revealed the model comprising higher values of BMI, poor sleep, IL-6, and IL-1ß was predictive of KOA (AUC: 0.80, 95%CI: 0.74-0.86, p< 0.001), and the strength of the predictive ability increased when susceptibility haplotypes AGC and GGGGCT were involved (AUC: 0.90, 95%CI: 0.87-0.95, p< 0.001).This study offers a predictive marker for KOA based on the risk scores of some pertinent genes and their genetic variants along with some pro-inflammatory markers and traditional risk variables.

DNA methylation of tumour necrosis factor (TNF) alpha gene is associated with specific blood fatty acid levels in a gender-specific manner.

BACKGROUND: Fatty acids, specifically polyunsaturated fatty acids (PUFAs) play an important role in inflammation and its resolution, however, their interaction with the epigenome is relatively unexplored. Here we investigate the relationship between circulating blood fatty acids and the DNA methylation of the cytokine encoding gene tumour necrosis factor (TNF, OMIM 191160). METHODS: Using a cross-sectional study approach, we collected blood samples from adults (N=88 (30 males, 58 females); 18-74 years old) for DNA methylation pyrosequencing analysis at four sites in TNF exon 1 and gas-chromatography mass-spectrometry analysis of the fatty acid profile of dried blood spots (DBS). RESULTS: Methylation levels of TNF exon 1 are significantly correlated with specific fatty acids in a gender-specific manner. In the males the PUFAs Docosahexaenoic Acid (DHA) and Arachidonic Acid (AA) were positively associated with TNF methylation, as was the saturated fatty acid (SFA) Stearic Acid; in contrast, mono-unsaturated fatty acids (MUFAs) had a negative association. In the females, omega-6 PUFA γ-Linolenic acid (GLA) was negatively correlated with TNF methylation; Adrenic acid and Eicosadienoic Acid were positively correlated with TNF methylation. CONCLUSION: These results suggest that one way that fatty acids interact with the inflammation is through altered methylation profiles of cytokine genes; thus, providing potential therapeutic targets for nutritional and health interventions.

Genetic Scores of eNOS, ACE and VEGFA Genes Are Predictive of Endothelial Dysfunction Associated Osteoporosis in Postmenopausal Women.

The present study aimed to examine the participation and contribution of endothelial nitric oxide synthase (eNOS), angiotensin converting enzyme (ACE) and vascular endothelial growth factor (VEGFA) genes for the risk of endothelial dysfunction (ED)-associated osteoporosis risk in postmenopausal women of Punjab, India. Women with ED were categorized into women with osteoporosis (n = 346) and women without osteoporosis (n = 330). They were examined for selected SNPs within eNOS, ACE and VEGFA genes. Linear regression analysis revealed a positive association of ED with bone mineral densities (BMDs) at femoral neck (r2 = 0.78, p < 0.001) and lumbar spine (r2 = 0.24, p = 0.001) after Bonferroni correction. Three susceptibility haplotypes were exposed within eNOS (CTAAAT), ACE (ACDG) and VEGFA (GATA) genes. Bearers of CTAAAT (OR 2.43, p = 0.007), ACDG (OR 2.50, p = 0.002) and GATA (OR 2.10, p = 0.009) had substantial impact for osteoporosis after correcting the effects with traditional risk factors (TRD).With uncertainty measure (R2h) and Akaike information criterion (AIC), best fit models showed that CTAAAT manifested in multiplicative mode (ß ± SE: 2.19 ± 0.86, p < 0.001), whereas ACDG (ß ± SE: 1.73 ± 0.54, p = 0.001) and GATA (ß ± SE: 3.07 ± 0.81, p < 0.001) expressed in dominant modes. Area under receiver operating characteristic curve using weighted risk scores (effect estimates) showed substantial strength for model comprising TRD + GATA (AUC = 0.8, p < 0.001) whereas, model comprising TRD + GATA + CTAAAT exhibited excellent ability to predict osteoporosis (AUC = 0.824, p < 0.001).