Clinical Utility of Pro-inflammatory Oligomeric Glycoprotein Tenascin-C in the Diagnosis of Seropositive and Seronegative Rheumatoid Arthritis.

Owing to limited usefulness of Rheumatoid Factor and anti-CCP in rheumatoid arthritis, there is a need to identify a more sensitive and specific biomarker to detect rheumatoid arthritis (RA), particularly seronegative RA cases. Tenascin-C is an extracellular matrix glycoprotein, which has been implicated in the pathophysiology of RA. The objective of our study was to evaluate the diagnostic utility of serum Tenascin-C in seropositive and seronegative rheumatoid arthritis patients. We conducted a cross-sectional case control study. Sixty patients who fulfilled the ACR 2010 criteria for rheumatoid arthritis were included in the study. Thirty patients were found to be positive for RF and/or anti-CCP and 30 were negative for both RF and anti-CCP. Thirty age and gender-matched healthy subjects were taken as controls. Serum Tenascin-C was measured by quantitative sandwich enzyme immunoassay technique. The mean serum concentration of Tenascin-C in controls, seronegative and seropositive cases was 0.66 ng/ml, 20.54 ng/ml and 23.42 ng/ml, respectively. Tenascin-C levels were significantly higher in RA cases compared to controls (p < 0.0001). There was no significant difference in Tenascin-C between seropositive and seronegative cases (p = 0.603). ROC curve analysis showed a sensitivity of 96.6% and specificity of 100% with AUC of 0.98 at 2.21 ng/ml as cut-off value for diagnosing RA. Tenascin-C is elevated in both seronegative and seropositive RA, which indicates that it can be used as a sensitive marker for RA. The addition of Tenascin-C to the existing RF and anti-CCP may help in identifying a large number of patients with RA, particularly seronegative rheumatoid arthritis cases.

Advances in congestive heart failure biomarkers.

Congestive heart failure (CHF) is the leading cause of morbidity and mortality in the elderly worldwide. Although many biomarkers associated with in heart failure, these are generally prognostic and identify patients with moderate and severe disease. Unfortunately, the role of biomarkers in decision making for early and advanced heart failure remains largely unexplored. Previous studies suggest the natriuretic peptides have the potential to improve the diagnosis of heart failure, but they still have significant limitations related to cut-off values. Although some promising cardiac biomarkers have emerged, comprehensive data from large cohort studies is lacking. The utility of multiple biomarkers that reflect various pathophysiologic pathways are increasingly being explored in heart failure risk stratification and to diagnose disease conditions promptly and accurately. MicroRNAs serve as mediators and/or regulators of renin-angiotensin-induced cardiac remodeling by directly targeting enzymes, receptors and signaling molecules. The role of miRNA in HF diagnosis is a promising area of research and further exploration may offer both diagnostic and prognostic applications and phenotype-specific targets. In this review, we provide insight into the classification of different biochemical and molecular markers associated with CHF, examine clinical usefulness in CHF and highlight the most clinically relevant.

Evaluation of Galectin-3 as a Novel Diagnostic Biomarker in Patients with Heart Failure with Preserved Ejection Fraction.

Background Heart failure is a complex cardiovascular disease with a variety of etiologies and heterogeneity. The N-terminal pro-B-type natriuretic peptide (NT-proBNP) value has limited usefulness in diagnosing heart failure with preserved ejection fraction (HFpEF). Aim The aim of the present study is to evaluate serum Galectin-3 as a diagnostic biomarker in patients with HFpEF and to compare Galectin-3 with NT-proBNP levels. Materials and Methods A cross-sectional case-control study including 63 cases of heart failure with ejection fraction ≥50% confirmed by echocardiography. NT-proBNP levels in serum were measured by electrochemiluminescence immunoassay and Galectin-3 levels in serum were measured by using an enzyme-linked-immunosorbent serologic assay kit. Results The median levels of serum Galectin-3 and NT-proBNP in patients were significantly higher than those of controls (26.59 vs. 5.27 and 927 vs. 49.3, p < 0.0001). A positive correlation was observed between serum levels of Galection-3 and NT-ProBNP ( r : 0.21, p = 0.048). At cut-off values of 10.1 ng/mL and 160 pg/mL, serum Galectin-3 has 77.78% sensitivity, 95% specificity with an area under the curve (AUC) of 0.93, and serum NT-proBNP has 71.43% sensitivity, 100% specificity with an AUC of 0.87, respectively, for diagnosing HFpEF. The comparison of receiver operating characteristics curves showed that Galectin-3 has better AUC compared with NT-proBNP in diagnosing HFpEF. Serum Galectin-3 showed a positive correlation with NT-proBNP and lipid parameters. Conclusion Galectin-3 with higher sensitivity and AUC can be used as a valuable biomarker for the diagnosis of HFpEF. Simultaneous testing of both Galectin-3 and NT-proBNP can further improve the detection of patients with HFpEF.

Adaptive Neuro-Fuzzy Inference System-Based Exploration of the Interrelationships of 25-Hydroxyvitamin D, Calcium, Phosphorus with Parathyroid Hormone Production.

The rationale of the current study was to assess the prevalence of 25-hydroxyvitamin D (25-OHD) deficiency and hyperparathyroidism in South Indian population and to explore interrelationships of 25-OHD, Ca, P towards parathyroid hormone (PTH) production using adaptive neuro-fuzzy inference system (ANFIS). A total of 407 subjects (228 men 179 women) with the mean age 56.8 ± 14.1 were tested for these parameters. In view of the skewed distribution of biochemical variables, data segregation was performed in tertiles and this data was trained to generate fuzzy interference system based on subclusters. The optimized model had 358 nodes and followed 44 fuzzy rules for prediction. This ANFIS model demonstrates that the deficiency of 25-OHD and Calcium triggers PTH production. PTH elevation is significant when Phosphorus is in the highest tertile. The associations observed by this model were consistent with the Kendall-Tau correlation matrix, which revealed inverse associations of Ca with P; and Ca with PTH and positive associations of P with PTH, and Ca with 25-OHD. Furthermore, the association statistics of the machine learning algorithm were also consistent, which suggested that depletion of Ca below 8.245 mg/dl was shown to elevate PTH levels greater than 167 pg/ml when P > 4.66. Subnormal depletion in 25-OHD (9.3-16.2 ng/ml) is associated with subnormal elevation in PTH (47-73.6 pg/ml). To conclude, ANFIS and machine learning algorithm are in agreement with each other in stating that 25-OHD deficiency triggers lower calcium levels, lower calcium and higher phosphorus trigger PTH production.

Hepcidin and Ferritin: Important Mediators in Inflammation Associated Anemia in Systemic Lupus Erythematosus Patients.

Systemic Lupus Erythematosus is an autoimmune disease with female preponderance. Anemia is found in 50% of Systemic Lupus Erythematosus patients. This is a cross sectional case control study with 30 female Systemic Lupus Erythematosus patients having inflammation associated anemia (Hemoglobin < 10.0 gm/dl) and 30 age matched controls with the aim to measure serum hepcidin and ferritin levels, correlate and study their role as homeostatic regulators of iron metabolism and utility as markers. Serum transferrin, ferritin, iron, total iron binding capacity, hsCRP, liver enzymes and renal parameters were analyzed by using automated analyser. Hepcidin levels were estimated by Sandwich-ELISA method. There was significant decrease in Iron (p < 0.0001), Iron Binding capacity (p < 0.0001), Transferrin (p < 0.0001) in patients, and a significant increase in inflammatory markers: hs-CRP (p < 0.0001), ESR (p < 0.0001) compared to controls. Significant increase in both Hepcidin (p < 0.0001) and Ferritin (p < 0.0001) was observed in patients with significant positive correlation (r = 0.711) with each other. Additionally, ferritin and hepcidin significantly positively correlated with hs-CRP and ESR (r = 0.526, 0.735); (r = 0.427, 0.742) respectively. Negative correlation with hemoglobin, iron, total iron binding capacity and transferrin with hepcidin (r = - 0.80, - 0.307, - 0.553, - 0.584) and ferritin (r = -0.722, - 0.22, - 0.654, - 0.728) was observed respectively. On ROC analysis both hepcidin and ferritin has sensitivity of 96.7%, specificity of 100% at cut-off values of 110 and 49 respectively. AUC of hepcidin was 0.993 and ferritin was 0.978. We have established a positive linear correlation between Hepcidin and Ferritin levels in disease activity and the changes correlated with the inflammatory state and anemia in patients, making them important mediators and potential markers of inflammation associated anemia.

Application of adaptive neuro-fuzzy inference systems (ANFIS) to delineate estradiol, glutathione and homocysteine interactions.

The rationale of the current study was to elucidate the contributing factors for the gender-based differences in total plasma homocysteine levels. A total of 413 subjects comprising of 293 men and 120 women were enrolled for the study. Chemiluminescence technology for vitamin B12, folate and total plasma homocysteine; ELISA for estradiol and 8-oxo-2-deoxyguanosine; Ellman's method for total glutathione; and PCR-RFLP analysis for the detection of methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism were employed. No statistically significant differences were observed between the men and women in the distribution of age (p = 0.82), vitamin B12 (p = 0.23), folate (p = 0.36) and MTHFR C677T polymorphism (p = 0.35). However, the total plasma homocysteine levels were higher in men compared to women (28.4 ± 17.9 vs. 20.6 ± 13.6 µmol/L, p < 0.0001). In order to explain this gender differences in homocysteine, adaptive neuro-fuzzy inference systems (ANFIS) were developed to understand trivariate interactions among estradiol, glutathione and homocysteine. In the presence of adequate estradiol levels, inverse association was observed between glutathione and homocysteine. This association is lost when estradiol levels were inadequate. Estradiol was found to quench homocysteine mediated oxidative DNA damage. Irrespective of gender, combined deficiency of vitamin B12 and folate showed positive association with hyperhomocysteinemia and vice versa. Homocysteine reduction in response to vitamin status varied according to gender with men responding to folate and women responding to B12. To conclude, gender-differences in homocysteine are attributable estradiol mediated lowering of homocysteine that prevents inactivation of glutathione mediated oxidative defense in women.

Serum Lipid Alterations in Early Rheumatoid Arthritis Patients on Disease Modifying Anti Rheumatoid Therapy.

Dyslipidaemia is a major CVD risk factor in the general population. Current evidence suggests that lipid metabolism is altered in RA due to inflammation, and that use of anti-inflammatory therapy may reverse some of these changes. The objective of our study is to compare the effect of treatment with DMARD on lipid fractions after 6 months of therapy. Forty patients who met the American College of Rheumatology, ACR/EULAR criteria for rheumatoid arthritis, with disease duration of less than 1 year and no prior treatment were included in the study. Thirty healthy volunteers were included as controls. The mean DAS-28 at disease onset was 5.15 ± 1.3. Early Rheumatoid Arthritis (ERA) patients exhibited higher serum levels of total cholesterol (TC) and lowdensity lipoprotein cholesterol (LDL-C) and lower serum high-density lipoprotein cholesterol (HDL-C) levels compared to controls. As a consequence, the atherogenic index of plasma [log (TG/HDL-C)], the atherogenic indices: TC/HDL-C as well as LDLC/HDL-C was significantly higher in ERA patients compared to controls. After 6 months of treatment, there was significant reduction of the DAS 28, HDL-C and Apo A-I improved and Lp(a) decreased significantly. All lipid ratios improved, a phenomenon primarily due to the increase in serum HDL-C levels. These changes were inversely correlated with CRP and ESR. In conclusion, ERA patients are characterized by an atherogenic lipid profile, which improves with DMARD therapy.

Spirulina attenuates cyclosporine-induced nephrotoxicity in rats.

Cyclosporine (CsA) causes a dose-related decrease in renal function in experimental animals and humans. The generation of reactive oxygen species (ROS) has been implicated in CsA-induced nephrotoxicity. It was previously shown that Spirulina, a blue-green algae, with antioxidant properties effectively attenuated the doxorubicin-induced cardiotoxicity in mice and cisplatin-induced nephrotoxicity in rat. The present study investigated the nephroprotective role of Spirulina against CsA-induced nephrotoxicity in rats. Spirulina (500 mg kg(-1) b.w.) was administered orally for 3 days before and 14 days concurrently with CsA (50 mg kg-1 b.w.). Rats treated with CsA showed nephrotoxicity as evidenced from a significant elevation in plasma urea, creatinine, urinary N-acetyl-beta-D-glucosaminidase (beta-NAG) and a decrease in creatinine and lithium clearance. Pretreatment with Spirulina protected the rats from CsA-induced nephrotoxicity. The CsA-induced rise in plasma urea and creatinine and the decrease in creatinine and lithium clearance were attenuated by Spirulina. There was a significant increase in plasma and kidney tissue MDA with CsA. Spirulina prevented the rise in plasma and kidney tissue MDA. Histopathology of the kidney from CsA-treated rats showed severe isometric vacuolization and widening of the interstitium. However, pretreatment with Spirulina prevented such changes, and the kidney morphology was comparable to that of the control. Spirulina treatment did not alter the blood CsA levels. These results suggest that Spirulina has a protective effect against nephrotoxicity induced by CsA. This study further supports the crucial role of the antioxidant nature of Spirulina in protecting against CsA-induced oxidative stress.

Protection against cisplatin-induced nephrotoxicity by Spirulina in rats.

PURPOSE: Cisplatin (CP)-induced nephrotoxicity is associated with the increased generation of reactive oxygen metabolites and lipid peroxidation in kidney, caused by the decreased levels of antioxidants and antioxidant enzymes. The purpose of this study was to evaluate the role of Spirulina, blue-green alga with antioxidant properties, in the protection of cisplatin-induced nephrotoxicity in rat. METHODS: Rats were treated with CP (6 mg/kg bw, single dose, intraperitoneally). Spirulina (1,000 mg/kg) was administered orally for 8 days and CP treatment was given on day 4. Nephrotoxicity was assessed, 6 days after the CP treatment, by measuring plasma urea, creatinine, urinary N-acetyl-(D-glucose-aminidase) (beta-NAG) and histopathology of kidney. RESULTS: Rats treated with CP showed marked nephrotoxicity as evidenced from the significant elevation in plasma urea, creatinine and urinary beta-NAG. Histological assessment revealed marked proximal tubular necrosis and extensive epithelial vacuolization in the kidney of CP-treated rats. Superoxide dismutase, catalase and glutathione peroxidase were decreased and lipid peroxidation was increased in kidney tissue. Pretreatment with Spirulina protected the rats from CP-induced nephrotoxicity. The rise in plasma urea, creatinine, urinary beta-NAG, plasma and kidney tissue MDA and histomorphological changes were significantly attenuated by Spirulina. In vitro studies using human ovarian cancer cells revealed that Spirulina did not interfere with the cytotoxic effects of CP on tumor cells. CONCLUSIONS: In summary, Spirulina significantly protected the CP-induced nephrotoxicity through its antioxidant properties.

Protective effect of Spirulina against doxorubicin-induced cardiotoxicity.

The generation of reactive oxygen species and mitochondrial dysfunction has been implicated in doxorubicin (DOX)-induced cardiotoxicity. The aim of the present study was to determine whether Spirulina, a blue-green algae, could serve as a cardioprotective agent during DOX treatment in a mouse model. Mice were treated with DOX (4 mg/kg bw, intraperitoneally), weekly, for 4 weeks. Spirulina was administered orally for 3 days twice daily, then for 7 weeks along with the four equal injections of DOX. Cardiotoxicity was assessed, at 3 weeks after the end of the DOX-treatment period, by mortality, volume of ascites, liver congestion, oxidative stress and ultrastructural changes of heart tissue. The DOX-treated animals showed higher mortality (53%) and more ascites. Myocardial damage, as assessed by ultrastructural changes, showed loss of myofibrils, cytoplasmic vacuolization and mitochondrial swelling. Myocardial superoxide dismutase and glutathione peroxidase activities were decreased and lipid peroxidation was increased. Pretreatment with Spirulina significantly protected the mice from DOX-induced cardiotoxic effects as evidenced from lower mortality (26%), less ascites, lower levels of lipid peroxidation, normalization of antioxidant enzymes and ultrastructural studies showing minimal damage to the heart. In vitro cytotoxic studies using ovarian cancer cells demonstrated that Spirulina did not compromise the anti-tumor activity of doxorubicin. These results suggest that Spirulina has a protective effect against cardiotoxicity induced by DOX and it may, therefore, improve the therapeutic index of DOX.

Chemotherapy-induced and/or radiation therapy-induced oral mucositis--complicating the treatment of cancer.

The term mucositis is coined to describe the adverse effects of radiation and chemotherapy treatments. Mucositis is one of the most common adverse reactions encountered in radiation therapy for head and neck cancers, as well as in chemotherapy, in particular with drugs affecting DNA synthesis (S-phase-specific agents such as fluorouracil, methotrexate, and cytarabine). Mucositis may limit the patient's ability to tolerate chemotherapy or radiation therapy, and nutritional status is compromised. It may drastically affect cancer treatment as well as the patient's quality of life. The incidence and severity of mucositis will vary from patient to patient. It will also vary from treatment to treatment. It is estimated that there is 40% incidence of mucositis in patients treated with standard chemotherapy and this will not only increase with the number of treatment cycles but also with previous episodes. Similarly, patients who undergo bone marrow transplantation and who receive high doses of chemotherapy have a 76% chance of getting mucositis. Patients receiving radiation, in particular to head and neck cancers, have a 30% to 60% chance. The exact pathophysiology of development is not known, but it is thought to be divided into direct and indirect mucositis. Chemotherapy and/or radiation therapy will interfere with the normal turnover of epithelial, cells leading to mucosal injury; subsequently, it can also occur due to indirect invasion of Gram-negative bacteria and fungal species because most of the cancer drugs will cause changes in blood counts. With the advancement in cytology, a more precise mechanism has been established. With this understanding, we can select and target particular mediators responsible for the mucositis. Risk factors such as age, nutritional status, type of malignancy, and oral care during treatment will play important roles in the development of mucositis. Many treatment options are available to prevent and treat this condition, but none of them can completely prevent or treat mucositis. More and more pathological methods are being developed to understand this condition so that better therapeutic regimens can be selected. Emphasis also should be made in assessing the patient's psychologic condition, particular depressive disorders. This is important because treatment with antidepressants will not only contribute in lifting depression but also reduces pain somatization. Although mucositis is rarely life-threatening, it will interfere with treatment of cancer to a great extent.