Interleukin-9 serves as a key link between systemic inflammation and angiogenesis in psoriasis.

BACKGROUND: Psoriasis is a T helper cell-mediated chronic immune-mediated inflammatory disease affecting mainly the skin, although systemic pathological effects are also observed. Cytokine-mediated interaction between T lymphocytes and keratinocytes lead to excessive proliferation of keratinocytes, which in turn leads to formation of a proinflammatory milieu and finally to psoriatic plaque formation. AIM: To measure interleukin (IL)-9, IL-17 and vascular endothelial growth factor (VEGF) levels in patients with psoriasis compared with controls, and to evaluate the effect of methotrexate (MTX) monotherapy on the aforesaid cytokine levels in psoriasis. METHODS: This cohort study included 54 patients with psoriasis and 54 age- and sex-matched healthy controls (HCs). IL-9, IL-17 and VEGF levels were measured by using commercially available ELISA kits. Patients with psoriasis who were on MTX monotherapy were followed up for a period of 3 months. RESULTS: Patients with psoriasis had increased levels of IL-9, IL-17 and VEGF at baseline, compared with the HC group. After 3 months of MTX monotherapy, Psoriasis Area Severity Index (PASI), Dermatology Life Quality Index (DLQI) and levels of cytokines (IL-9, IL-17 and VEGF) were significantly decreased compared with baseline. PASI and DLQI at baseline also showed a positive correlation with IL-9, IL-17 and VEGF. CONCLUSION: Our results suggest the existence of a proinflammatory milieu in psoriasis, with increased levels of IL-9, IL-17 and the proangiogenic growth factor VEGF, showing an increasing trend with increasing disease severity and impaired quality of life (QoL). MTX treatment helps to reduce levels of IL-9, IL-17 and VEGF, thereby limiting disease progression and improving QoL in psoriasis.

Effect of methotrexate monotherapy on T-cell subsets in the peripheral circulation in psoriasis.

BACKGROUND: Psoriasis is a T-helper (Th)1/Th17-mediated chronic inflammatory disease. There is an increased population of Th cells in skin lesions and peripheral circulation of patients with psoriasis. Systemic methotrexate (MTX) is an effective treatment for moderate to severe psoriasis; however, its effect on different T-cell subsets is not yet clear. AIM: To study the effect of MTX monotherapy on the psoriatic T-cell profile in the peripheral circulation of patients with psoriasis. METHODS: This was a follow-up study involving 50 patients with moderate to severe psoriasis treated with systemic MTX for 12 weeks. Blood samples (5 mL) were collected from participants, from which PBMCs were isolated, and T-cell phenotyping was performed by flow cytometry. RESULTS: Following 12 weeks of MTX treatment, there was an increase in the percentages of Th2/Treg cells, and a relative decrease in the percentages of Th1/Th17 cells, along with a significant reduction in the median Psoriasis Area and Severity Index (PASI). CONCLUSION: MTX helps in the restoration of the immune balance by decreasing the numbers of Th1 and Th17 cells and increasing the numbers of Th2 and Treg cells, thus resulting in a significant reduction in disease severity. MTX converts a proinflammatory T-cell phenotype to a protective anti-inflammatory phenotype, thus significantly suppressing the inflammation in psoriasis.

Tear Fluid Protein Changes in Dry Eye Syndrome Associated with Rheumatoid Arthritis: A Proteomic Approach.

PURPOSE: Sjögren syndrome (SS) secondary to rheumatoid arthritis (RA) affects lacrimal and salivary glands, and therefore dry eye syndrome (DES) is more prevalent in patients with RA. This study used a proteomic approach to identify potential biomarkers in tear of DES secondary to RA (DES-RA). METHODS: Tear specimens were collected with Schirmer strips from patients with DES with RA, patients with other types of dry eye (namely, primary Sjögrens and non-Sjögrens [NSS]), and age-matched controls. Tear proteins were subjected to 2D-differential gel electrophoresis (2D-DIGE), and the differentially expressed proteins were identified using nano ESI-LC-MS/MS analysis. RESULTS: Among the differentially regulated proteins of DES-RA that were identified, lactotransferrin isoform 1 precursor was found to be d own-regulated in 100% cases and SHC transforming 1 isoform in 63% of the cases, while proteins such as ribonuclease p protein subunit 20, protocadherin, and heterogeneous nuclear ribonucleoprotein Q isoform 6 were down-regulated in over 80% of the cases. Proteins such as Ecto-ADP ribosyltransferase 5 precursor, Rho-related GTP-binding protein, and RhoJ precursor were up-regulated in 80% of the cases. CONCLUSION: Functional annotation revealed that these proteins have roles in regulation, antimicrobial activity, immune, metabolic, and cellular processes. The study observed characteristic marker proteins differentially expressed in DES-RA that are previously unreported. Further validation is needed.

Serum bilirubin: a simple routine surrogate marker of the progression of chronic kidney disease.

BACKGROUND: Studies suggest that Chronic Kidney Disease (CKD) is a global burden health associated with significant comorbid conditions. Few biochemical parameters have gained significance in predicting the disease progression. The present work aimed to study the association of the simple biochemical parameter of serum bilirubin level with the estimated glomerular filtration rate (eGFR), and to assess their association with the co-morbid conditions in CKD. METHODS: We recruited 188 patients with CKD who attended a Nephrology out-patient department. eGFR values were calculated based on the serum creatinine levels using CKD-EPI formula. Various biochemical parameters including glucose, creatinine, uric acid, total and direct bilirubin were assayed in all study subjects. Study subjects were categorized into subgroups based on their eGFR values and their diabetic status and the parameters were compared among the different subgroups. RESULTS: We observed a significantly decreased serum bilirubin levels (p < 0.001) in patients with lower eGFR values, compared to those with higher eGFR levels. There was a significant positive correlation between the eGFR levels and the total bilirubin levels (r = 0.92). We also observed a significant positive correlation between the eGFR levels and the direct bilirubin levels (r = 0.76). On multivariate linear regression analysis, we found that total and direct bilirubin independently predict eGFR, after adjusting for potential confounders (p < 0.001). CONCLUSIONS: Our results suggest that there is significant hypobilirubinemia in CKD, especially with increasing severity and co-existing diabetes mellitus. This finding has importance in the clinical setting, as assay of simple routine biochemical parameters such as serum bilirubin may help in predicting the early progression of CKD and more so in diabetic CKD.

Elevated fibrinogen and lowered homocysteine-vitamin determinants and their association with left atrial thrombus in patients with rheumatic mitral stenosis.

Mitral stenosis (MS) causes stagnation of blood flow, leading to thrombus formation in the left atrium (LA), which may lead to systemic thrombo-embolic complications and stroke. We compared the alterations in echocardiographic and procoagulant parameters in patients with severe rheumatic MS with and without LA thrombus. The study was a cross-sectional study of patients with rheumatic MS, being evaluated for percutaneous mitral commisurotomy. Group 1 patients comprised of patients with rheumatic MS with LA thrombus (n=35) and Group 2 patients had rheumatic MS without LA thrombus (n = 45). Platelet aggregability, fibrinogen, homocysteine, vitamin B12 and folate; mitral valve area (MVA), mean mitral gradient and pulmonary artery pressure (PAP) were assessed in all study subjects. Significant increase in fibrinogen, homocysteine and platelet aggregation and fall in homocysteine-associated determinants were seen in Group 1, as compared with Group 2. Raised fibrinogen, lowered homocysteine-vitamin determinants and lowered mitral valve area were associated independently, with presence of LA thrombus in rheumatic MS. In this study, fibrinogen, vitamin B12 and folate were independently associated with the occurrence of thrombus in patients with rheumatic MS. Hence, our results suggest that increase in procoagulant mechanisms contribute to increased risk of thrombosis in the left atrium in patients with rheumatic MS.

25-hydroxy vitamin D and ischaemia-modified albumin levels in psoriasis and their association with disease severity.

Psoriasis is a T-helper-1 (Th1)/Th17-mediated chronic inflammatory skin disease, characterised by hyperproliferation of keratinocytes. Psoriasis and cardiovascular disease share similar pathogenic mechanisms such as vascular endothelial cell dysfunction, oxidative stress and metabolic syndrome. 25-hydroxy vitamin D is an immune-regulatory hormone, with the ability to reduce cellular proliferation in psoriasis. Ischaemia-modified albumin (IMA) is a marker of oxidative stress. This study examined 25-hydroxy vitamin D, IMA and high-sensitivity C-reactive protein (hs-CRP) levels in patients with psoriasis, in comparison with healthy controls and their possible association with disease severity. A total of 43 cases of psoriasis and 43 controls were included in this cross-sectional study, and severity grading was performed according to psoriasis area severity index (PASI) scoring. Serum 25-hydroxy vitamin D, IMA and hs-CRP were evaluated in all study subjects. In psoriasis, 25-hydroxy vitamin D showed a significant decline, while hs-CRP and IMA levels were significantly elevated, as compared with controls. Serum 25-hydroxy vitamin D showed a significant negative correlation with PASI score. hs-CRP and IMA showed a significant positive correlation with PASI score. Significant negative correlation was observed between 25-hydroxy vitamin D and hs-CRP; 25-hydroxy vitamin D and IMA levels in psoriasis. The results indicate that psoriasis is associated with significantly lowered 25-hydroxy vitamin D levels, along with increased systemic inflammation and oxidative stress, especially in severe disease. Thus, vitamin D supplementation might reduce systemic inflammation and oxidative stress and help in delaying the pathogenesis of co-morbidities associated with psoriasis.

Pentraxin-3 and nitric oxide as indicators of disease severity in alcoholic cirrhosis.

Recent studies have indicated that pentraxin-3 can be used as a marker to assess the severity of hepatic fibrosis in non-alcoholic steatohepatitis. The present study was designed to assess pentraxin-3, nitric oxide and tumour necrosis factor-α (TNFα) in alcoholic cirrhosis and their association with disease severity. We enrolled 47 alcoholic cirrhosis cases and 32 controls. Serum pentraxin-3, nitric oxide (NO) and TNFα levels were estimated in both groups. Serum pentraxin-3, NO and TNFα were significantly increased in alcoholic cirrhosis patients compared to controls. Pentraxin-3 had a significant positive correlation with TNFα (r=0.303, P=0.039), Child-Pugh score (r=0.394, P=0.006) and MELD score (r=0.291, P=0.047) in alcoholic cirrhosis cases. Also we found positive association between NO with Child-Pugh score (r=0.391, P=0.007) and MELD score (r=0.311, P=0.033) in these cases. Linear regression analysis shows significant association of pentraxin-3 and NO (ß=0.375, r2=0.141, P=0.009). We conclude that elevated pentraxin-3 and NO levels are associated with severity of alcoholic cirrhosis.

TNFAIP3 and TNIP1 polymorphisms confer psoriasis risk in South Indian Tamils.

Psoriasis is a chronic inflammatory skin disease with genetic and environmental factors having an important role in its aetiology. Several genome-wide association studies have reported the association of the genes of the TNFα signalling, tumour necrosis factor alpha-induced protein 3 (TNFAIP3), TNFAIP3-interacting protein 1 (TNIP1) with psoriasis in Western and Chinese populations. The aim of this study is to demonstrate whether the TNFAIP3 and TNIP1 genes contribute to the risk of psoriasis in the ethnically distinct South Indian population. 360 psoriatic subjects and 360 healthy controls were recruited in this case control study. TNFAIP3 (rs610604) and TNIP1 (rs17728338) polymorphisms were typed by using TaqMan 5 allele discrimination assay. The results demonstrated that the SNPs rs610604 and rs17728338 of the TNFAIP3 and TNIP1 genes, respectively, were associated with psoriasis in our population at both allelic and genotypic levels. Thus, our results suggest that TNFAIP3 (rs610604) and TNIP1 (rs17728338) polymorphisms confer increased risk of psoriasis and may play a vital role in its pathogenesis in our ethnic South Indian Tamils.

Effect of treatment with methotrexate and coal tar on adipokine levels and indices of insulin resistance and sensitivity in patients with psoriasis vulgaris.

BACKGROUND AND OBJECTIVES: Recent studies have implicated adipokines in the pathogenesis of the immune-mediated inflammatory disease, psoriasis and its associated comorbidities. Hence, we undertook to study adipokine levels and indices of insulin resistance and sensitivity in patients with psoriasis vulgaris, in comparison with controls and their association with disease severity and response to therapy. METHODS: Sixty cases of psoriasis vulgaris and 60 age- and gender-matched healthy controls were included in this study. Severity grading according to psoriasis area severity index scoring was done in all psoriatics. Serum levels of adipokines [leptin, adiponectin, resistin and interleukin-6 (IL-6)] and insulin were estimated in all psoriatics at baseline and at 12 weeks on follow-up and in controls. RESULTS: Baseline levels of the inflammatory adipokines (leptin, resistin and IL-6) and insulin resistance indices were significantly higher in psoriatics, as compared to controls, while that of the anti-inflammatory adipokine, adiponectin and insulin sensitivity indices were significantly lower in psoriatics, as compared with controls. Baseline inflammatory adipokines, serum insulin level and insulin resistance indices demonstrated a significant positive correlation with the severity of psoriasis, while the anti-inflammatory adipokine, adiponectin and insulin sensitivity indices demonstrated a significant negative correlation with the disease severity. After 12 weeks of therapy (both topical and systemic), there was a significant reduction in the levels of inflammatory adipokines and a significant increase in the levels of anti-inflammatory adipokine-adiponectin. However, a significant decrease in insulin levels and insulin resistance indices were observed only with systemic therapy with methotrexate. CONCLUSION: The present results implicate that adipokines are significantly associated with pathogenesis of psoriasis and hence adequate and early control of psoriasis may contribute to the decreased development of metabolic syndrome, including the risk of cardiovascular disease.

Elevated levels of serum sialic acid and high-sensitivity C-reactive protein: markers of systemic inflammation in patients with chronic heart failure.

Heart failure (HF) is a common, debilitating disorder in which the heart is unable to pump an adequate blood supply to the tissues. Although it has been shown that inflammation occurs in HF, inflammatory markers have yet to be defined. Inflammatory markers such as high-sensitivity C-reactive protein (hs-CRP), cytokines and serum sialic acid (SA) have been suggested as cardiovascular risk biomarkers. This study aims to assess the serum levels of inflammatory markers such as sialic acid and hs-CRP in chronic heart failure (CHF). Forty-eight patients with CHF and 30 healthy controls were recruited. Total sialic acid (TSA) and lipid-associated sialic acid (LASA), and the inflammatory marker hs-CRP, were assayed in all study subjects. N-terminal pro-brain natriuretic peptide (NT-proBNP) was assayed in the patient group only. Serum mean TSA and LASA were significantly higher in CHF patients when compared to healthy controls (P < 0.01). Mean hs-CRP levels in CHF patients showed a significant elevation compared with healthy controls (P < 0.01). There was a significant positive correlation between TSA and hs-CRP. Thus, TSA and hs-CRP would appear to be stable markers of systemic inflammation in chronic heart failure.

D-Dimer assay as a non invasive test for the diagnosis of left atrial Thrombi in Indian patients with Rheumatic MS.

BACKGROUND: Systemic embolism is a serious and sometime fatal complication of rheumatic MS. OBJECTIVE: We assessed the predictive power of D-Dimer level to predict occurrence of left atrial (LA) thrombi in patients with rheumatic mitral stenosis (MS). METHODS: D-dimer levels were analyzed for 24 patients with rheumatic MS with LA clot and 22 patients with rheumatic MS with no LA clot undergoing transeosophageal echocardiography. A level more than 4 µg/ml was taken as elevated to predict the presence of LA clot in the study groups. RESULTS: For a cut-off value of 4 µg/ml, sensitivity was 66.67 % and specificity 100 % for prediction of LA clot and AUC 0.710. A cut-off value of less than 1 µg/ml, sensitivity was 91.67 % and 87. 5 % negative predictive value for ruling out presence of LA clot and AUC 0.721. CONCLUSION: A higher value of D-dimer can predict the possible presence of a LA clot and very low value can predict absence of clot in patients with rheumatic MS.

Two dimensional electrophoretic analysis of human tears: collection method in dry eye syndrome.

Tear proteomics, by 2-DE, can give a fingerprint of the protein profile, which is well suited in clinical proteomics for biomarker identification and in diagnostics. The mode of tear collection can influence the representation of the proteins in the tear and therefore it is important to use the appropriate method. In this study, capillary and Schirmer mode of tear collection was done in the healthy controls and the Schirmer method was validated in dry eye syndrome conditions. 2-D PAGE of normal and dry eye tear was performed using pH 3-10 linear IPG strips followed by 13% SDS-PAGE. The spot intensity was analyzed by the PD quest software. The two methods were compared using Bland-Altman statistical tool. The 2-D map of capillary and Schirmer tear showed 147 ± 8 spots and 145 ± 7 spots respectively. Both the collection methods were in agreement with each other and were comparable. Dry eye tear protein showed differential expression of proteins as observed in 25-35 kDa region. One of the significantly reduced protein was identified as proline-rich 4 protein. Schirmer method of tear collection is reliable in patients with dry eye, which can display the differential protein expression and help in biomarker identification.

Inflammation and dyslipidaemia: a possible interplay between established risk factors in North Indian males with coronary artery disease.

OBJECTIVES: Coronary artery disease (CAD) is a leading cause of morbidity and mortality in the developed world and is rapidly assuming epidemic proportions in developing countries, including India. This has led to extensive research to determine the risk factors and the pathways that may predispose to the elevated risk of this disease. Important among them include lipoproteins, homocysteine, lipoprotein (a), pro-inflammatory cytokines and others. The following study was undertaken to determine a possible inter-relationship between inflammation and dyslipidaemia, which are important risk factors for CAD in the atherosclerosis-prone North Indian male population. METHODS: The study groups comprised 150 clinically assessed North Indian male patients with acute myocardial infarction (AMI), diagnosed on electrocardiographic and biochemical criteria, and 150 healthy controls. Apolipoprotein-AI (Apo-AI), apolipoprotein-B (Apo-B) and C-reactive protein (CRP) levels were estimated using kits based on the immunoturbidimetric assay from Randox, UK. Tumour necrosis factor-alpha (TNF-alpha) and lipoprotein (a) were assayed using commercially available ELISA kits from Diaclone Research, Belgium and Innogenetics, Belgium, respectively. RESULTS: The patients with AMI showed highly significant elevations in the levels of total serum cholesterol, triglycerides, LDL cholesterol, Apo-B and a significant decline in HDL cholesterol, compared with healthy controls. Significantly elevated serum levels of inflammatory markers, TNF-alpha and CRP were seen in patients with AMI, compared to the control subjects. A significantly positive correlation of TNF-alpha was observed with lipoprotein (a) in patients with CAD. CONCLUSION: The data clearly underlines a possible interplay between inflammation and dyslipidaemia in the pathogenesis of CAD in the Indian context. This insight into the aetiopathogenesis of CAD will prove highly beneficial for devising better preventive measures and pharmacological interventions for CAD.

Inherited metabolic disorders involving the eye: a clinico-biochemical perspective.

The diagnosis of inborn errors of metabolism is challenging for most physicians. Improvements in medical technology and greater knowledge of the human genome are resulting in significant changes in the diagnosis, classification, and treatment of inherited metabolic disorders (IMDs). Many known inborn errors of metabolism will be recognised earlier or treated differently because of these changes. It is important that physicians recognise the clinical signs of IMDs and know when to propose advanced laboratory testing or referral to a higher centre for better patient management. Ocular manifestations occur in various metabolic disorders. Although there is an extensive understanding of many inborn errors of metabolism at the biochemical, molecular, and metabolic levels, little is known about their pathogenesis. In particular, how systemic metabolic disease contributes to ocular defects remains to be elucidated in IMDs. The occurrence of eye abnormalities could be due to direct toxic mechanisms of abnormal metabolic products or accumulation of normal metabolites by errors of synthetic pathways or by deficient energy metabolism. A detailed ophthalmological assessment is essential. Definitive diagnosis and management of patients with IMDs is ideally carried out by a combination of specialists, including an ophthalmologist, paediatrician, biochemist, and medical geneticist. Recent advances in the diagnosis and treatment of IMDs have substantially improved the prognosis for many of these conditions.

Inflammation: its role and interplay in the development of cancer, with special focus on gynecological malignancies.

The relationship between inflammation and cancer is intriguing. Mechanisms contributing to the pathobiology of carcinogenesis are multiple and complex. Many aspects still elude researchers and are subjects of intense speculation and debate, for example, the triggering factor for malignant transformation in inflammation. A comprehensive literature search was conducted from the Web sites of the National Library of Medicine and Pubmed Central, the US National Library of Medicine's digital archive of life sciences literature. The data were accessed from books and journals that published recent articles in this field. Several recent studies have identified nuclear factor-kappa B as a key modulator in driving inflammation to cancers. An inflammatory microenvironment inhabiting various inflammatory cells and a network of signaling molecules is essential for the malignant progression of transformed cells. This is attributed to the mutagenic predisposition of persistent infection-fighting agents at sites of chronic inflammation. The appreciation of the role of inflammation in carcinogenesis provides a mechanistic framework to understand clinical benefits of newer therapeutic strategies An in-depth knowledge about various pathogenic mechanisms involved in cancer will help clinicians in better management of the disease.

Antioxidant status in advanced cervical cancer patients undergoing neoadjuvant chemoradiation.

Cervical cancer is the most common cancer in Indian women. The aim of this study is to assess the alterations in the circulating lipid peroxide, antioxidant components and activities of defence enzymes in advanced cervical cancer patients, and to monitor the variations in their levels before and after neoadjuvant chemoradiation. Sixty patients with advanced cancer of the cervix (FIGO IIIa-IVb) are included in the study, along with 60 healthy controls. Blood samples are collected before the start of therapy (S1), two weeks after the second course of chemotherapy (S2) and two weeks after completion of tele/brachyradiation (S3). Single blood samples are taken from controls. Lipid peroxides, conjugated dienes, reduced glutathione (GSH), catalase (CAT) and glutathione-S-transferase (GST) are estimated using standard methods. Glutathione peroxidase (GPx) and superoxide dismutase (SOD) are assayed using commercially available kits. The pretreatment levels of plasma lipid peroxide were significantly elevated in cancer patients, while significantly lowered levels of GSH, GPx, GST, SOD and CAT were observed when compared to controls. After chemotherapy, the levels of lipid peroxidation showed a significant decline (P < 0.05), which became highly significant after chemoradiation (P < 0.01). Levels of GSH, GPx, SOD, GST and CAT showed a mild increase after chemotherapy. After chemoradiation, levels reverted to normal or near normal (P < 0.01). Low levels of antioxidants in the circulation of patients with cervical cancer may be due to their increased utilisation to scavenge lipid peroxidation as well as their sequestration by tumour cells. The observed increase in antioxidant concentration after therapy might be due to the death of tumour cells or the arrest of tumour growth by chemotherapeutic agents. The normalisation of these parameters may provide information about the efficacy of neoadjuvant chemoradiation. A larger patient cohort with a longer follow-up period for therapeutic response studies may yield more significant data.

Cytokine profile in Indian women with cervical intraepithelial neoplasia and cancer cervix.

Cervical cancer develops from the preneoplastic cervical intraepithelial neoplasia (CIN). Host factors are critical in regulating tumor growth and cytokines, which modulate immunologic control may be of particular importance. The objective of this study was to assess the production of cytokines by peripheral blood mononuclear cells (PBMCs) in Indian women with cancer cervix and CIN. Sixty patients with cancer cervix (including all FIGO stage I-IV), 35 patients with CIN, and 30 healthy controls were enrolled in this study. The human papillomavirus (HPV) 16 and 18 status was determined in all the study groups. The PBMC culture supernatant was collected for cytokine estimations by enzyme-linked immunosorbent assay (interleukin-2 [IL-2], interferon-gamma [IFN-gamma], interleukin-4 [IL-4], and interleukin-10 [IL-10]). IL-2 levels showed a significant decline in high-grade CIN and cancer patients, whereas IFN-gamma levels were decreased only in patients with advanced cancer cervix. An increase in the levels of IL-4 and IL-10 was found in all cancer cervix and CIN grade III patients, as compared to those with early CIN grades and healthy controls. The cytokine ratios decreased significantly (P < 0.001 for all the ratios), when cervical cancer patients were compared with controls and CIN cases. The type 2 and type 1 cytokine levels were significantly correlated (P < 0.000) with HPV status. We conclude that a pronounced shift from type 1 to type 2 cytokine production is associated with more severe disease. These data reinforce the need for detailed analysis of immune dysregulation in CIN and cancer cervix patients.