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.

Takayasu arteritis coexisting with scalp necrosis, alopecia, and sterile osteomyelitis.

A twelve-year-old girl with classical features of Takayasu arteritis presented with scalp ulceration and osteomyelitis. Her computed tomography (CT) of the head revealed an extensive ulcerated lesion over the left high parietal region with lytic destruction of the outer and inner tables of the skull. Because of full-thickness calvarial bone involvement, chronic osteomyelitis, and ulcerated scalp lesion, she underwent debridement of involved bone along with the margin of normal skin. During surgery, underlying dura was found to be not involved, and a transposition flap was done for reconstruction. Histopathology did not reveal any evidence of bacterial infection or granulomas. Sterile osteomyelitis of the skull associated with alopecia and scalp necrosis has not been reported with typical Takayasu disease. Family physicians should be vigilant to keep this as a differential diagnosis in nonhealing osteomyelitis, not responding to antibiotics, or showing any evidence of infection.

MOTHER Study: A Multicenter Observational, Retrospective Study to Determine Coorelation Between Physical CHaracteristics and Ovarian REserve Markers in Sub-feRtile Women.

BACKGROUND: The physical characteristics which are known to affect the ovarian reserve are age, body mass index (BMI), occupational exposures, age at menarche and menstrual cycle length. A correlation between different physical characteristics and the ovarian reserve will help to identify areas which need to be tackled to increase the chances of fertility of women in India. METHODS: In this retrospective, observational study, namely the MOTHER Study, data of women between 18 and 45 years of age, attending the selected fertility centers across different states in India were taken for evaluation. Demographic information along with information on factors potentially related to fertility like age of menarche, menstrual cycle length and occupational factors were collected by review of medical records at screening visit. Most recent AMH assay and antral follicle count (AFC) where the subject has not taken any contraceptives 12 months prior to the test were collected. RESULTS: Age of woman, years of marriage, years of infertility and smoking have shown effect on ovarian reserve testing like AMH and AFC. The other physical characteristics which were evaluated and considered to affect the ovarian reserve like body mass index BMI, occupational exposures, age at menarche and menstrual cycle length have not shown statistically significant correlation. CONCLUSION: Age of woman and years of infertility are inversely proportional to ovarian reserve markers, namely AMH and AFC. Addictions like smoking and alcohol affect ovarian reserve.

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.

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).

Computational and Biological Investigations on Abl1 Tyrosine Kinase: A Review.

Abl1 tyrosine kinase is a validated target for the treatment of chronic myeloid leukemia. It is a form of cancer that is difficult to treat and much research is being done to identify new molecular entities and to tackle drug resistance issues. In recent years, drug resistance of Abl1 tyrosine kinase has become a major healthcare concern. Second and third-generation TKI reported better responses against the resistant forms; still they had no impact on long-term survival prolongation. New compounds derived from natural products and organic small molecule inhibitors can lay the foundation for better clinical therapies in the future. Computational methods, experimental and biological studies can help us understand the mechanism of drug resistance and identify novel molecule inhibitors. ADMET parameters analysis of reported drugs and novel small molecule inhibitors can also provide valuable insights. In this review, available therapies, point mutations, structure-activity relationship and ADMET parameters of reported series of Abl1 tyrosine kinase inhibitors and drugs are summarised. We summarise in detail recent computational and molecular biology studies that focus on designing drug molecules, investigation of natural product compounds and organic new chemical entities. Current ongoing research suggests that selective targeting of Abl1 tyrosine kinase at the molecular level to combat drug resistance in chronic myeloid leukemia is promising.

Promoter polymorphisms in IL-6 gene influence pro-inflammatory cytokines for the risk of osteoarthritis.

BACKGROUND: Interleukin-6 (IL-6) gene regulates IL-6 levels, interplay of which has been found to influence pathophysiology of osteoarthritis (OA). Polymorphism within promoter region of IL-6 gene and its association with plasma levels of pro-inflammatory cytokines; IL-6, interleukin 1-beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α) remained to be investigated in Punjab region of India, where OA is highly prevalent. METHODS: Six single nucleotide polymorphisms (SNPs) in the promoter region of IL-6 gene; rs1800795 (-174G/C), rs1800796 (-572G/C), rs1800797 (-597G/A), rs2069827 (-1363G/T), rs12700386 (-2954G/C) and rs10499563 (-6331G/T) were investigated by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 279 confirmed osteoarthritis patients and 287 controls. Plasma levels of pro-inflammatory cytokines; IL-6, IL-1ß and TNF-α were measured by sandwich Enzyme Linked Immunosorbent Assay (ELISA). RESULTS: Allele frequency spectrum after adjusting the effect of systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), low density lipoprotein (LDL), triglycerides (TG) and body mass index (BMI) revealed that major allele G of rs1800795 and T of rs10499563 were significantly associated with increased risk of OA (P < 0.01) in all the three genetic models; co-dominant (OR 4.08 & 4.12, P < 0.001), recessive (OR 3.00 & 2.51, P < 0.001) and dominant (OR 2.56 & 3.09, P < 0.05). Major allele G of rs1800796 and rs1800797 was observed to enhance OA risk in recessive mode (OR 1.75, P < 0.001 & 1.62, P = 0.01 respectively). Disease risk analysis after adjusting the effect of confounders exposed a susceptibility haplotype GGGGCT, which increased the OA risk by 2.27 times (OR 2.27, 95%CI: 1.26-4.10, P = 0.009) and a protective haplotype CGAGGC which significantly reduced the OA risk (OR 0.47, 95%CI 0.27-0.92, P = 0.031). Both of these haplotypes manifested in the recessive mode of inheritance. Subjects who had one copy of the susceptibility haplotype had lower values of IL-6 (3.6 pg/ml) and IL-1ß levels (3.2 pg/ml) than those who had 2 copies of it (4.4 pg/ml & 4.2 pg/ml respectively). IL-6 and IL-1ß levels were observed to be negatively associated with protective haplotype CGAGGC (P < 0.05). Carriers of 1 copy of this haplotype showed decreased IL-1ß levels than those who had none (1.00 pg/ml vs. 1.3 pg/ml respectively) which further decreased to 0.9 pg/ml in those subjects who carried two copies of protective haplotype. CONCLUSION: The present study discovered susceptibility (GGGGCT) and protective (CGAGGC) haplotypes within promoter region of IL-6 gene which influenced the plasma levels of IL-6 and IL-1ß for the risk of osteoarthritis in the population of Punjab, India.