Differential Combination of Cytokine and Interferon- γ +874 T/A Polymorphisms Determines Disease Severity in Pulmonary Tuberculosis

BACKGROUND: Mycobacterium tuberculosis infects nearly 1/3 of the world population and this reservoir forms the largest pool from which new cases arise. Among the cytokines, IFN-γ is a key determinant in protection against tuberculosis. Single nucleotide polymorphisms (SNPs) in IFN-γ gene (+874 T/A) which determine TT high ((hi)), AA low ((lo)) and TA intermediate ((int)) responder phenotypes have shown variable associations with tuberculosis disease outcome in different ethnic populations. The objective of the current study was to analyze IFN-γ gene combinations with other IFN-γ regulating cytokine genes (IL-10, TNF -α, IL-6) to see the effect of gene- combinations on disease severity outcome in pulmonary tuberculosis. METHODS AND FINDINGS: Study groups comprised of pulmonary TB patients stratified according to lung tissue involvement into mild (Pmd = 74) or advance (Pad = 23) lung disease and compared with healthy controls (TBNA = 166). Genotype analysis was carried out using amplification refractory mutation system-PCR (ARMS-PCR). IFN-γ gene (+874 T/A) functional SNP combinations in TNFα (-308 G/A), IL-10 (-1082 A/G) and IL-6 (-174 G/C) were analyzed. Single gene analysis (Pearson χ²) showed a dominant association of IFN-γ TT (hi) genotype (p = 0.001) and T allele (p = 0.001) with mild disease. IFN-γ(lo) -IL-10(lo) genotype combination was associated with advanced disease (p = 0.002). IFN-γ(hi) -IL-6(hi) combination was associated with mild disease (p = 0.0005) while IFN-γ(lo) -IL-6(int) was associated with protection against both forms of pulmonary disease (p = 0.002). CONCLUSION: Our results show that a limited number of IFN-γ gene combinations with other cytokine functional SNPs determine the outcome of disease severity in tuberculosis

Differential combination of cytokine and interferon- gamma +874 T/A polymorphisms determines disease severity in pulmonary tuberculosis.

Background:Mycobacterium tuberculosis infects nearly 1/3 of the world population and this reservoir forms the largest pool from which new cases arise. Among the cytokines, IFN-gamma is a key determinant in protection against tuberculosis. Single nucleotide polymorphisms (SNPs) in IFN-gamma gene (+874 T/A) which determine TT high ((hi)), AA low ((lo)) and TA intermediate ((int)) responder phenotypes have shown variable associations with tuberculosis disease outcome in different ethnic populations. The objective of the current study was to analyze IFN-gamma gene combinations with other IFN-gamma regulating cytokine genes (IL-10, TNF -alpha, IL-6) to see the effect of gene- combinations on disease severity outcome in pulmonary tuberculosis. Methods andFindings:Study groups comprised of pulmonary TB Patients stratified according to lung tissue involvement into mild (Pmd = 74) or advance (Pad = 23) lung disease and compared with healthy controls (TBNA = 166). Genotype analysis was carried out using amplification refractory mutation system-PCR (ARMS-PCR). IFN-gamma gene (+874 T/A) functional SNP combinations in TNFalpha (-308 G/A), IL-10 (-1082 A/G) and IL-6 (-174 G/C) were analyzed. Single gene analysis (Pearson chi) showed a dominant association of IFN-gamma TT (hi) genotype (p = 0.001) and T allele (p = 0.001) with mild disease. IFN-gamma(lo) -IL-10(lo) genotype combination was associated with advanced disease (p = 0.002). IFN-gamma(hi) -IL-6(hi) combination was associated with mild disease (p = 0.0005) while IFN-gamma(lo) -IL-6(int) was associated with protection against both forms of pulmonary disease (p = 0.002).Conclusion:Our results show that a limited number of IFN-gamma gene combinations with other cytokine functional SNPs determine the outcome of disease severity in tuberculosis

Factors Affecting Part-time Students Performance in Pakistan

This research is concerned about part-time student performance within higher educational institutions in Pakistan. Part-time students contain a significant share of the student population. In the perspective of working students as part-time studying, there are some significant factors that should be considered seriously to perform well. This research was examined to find the relationship of soft skills (motivation to learn, stress, time management) among part time-students’ performance in south Punjab of Pakistan. Primary data was collected from a sample of 140 part-time enrolled students. Correlation and regression analysis were tested in this research. The result showed that time management was the most significant factor of student performance. Same as stress has significant but negative correlation with student performance. The study concluded that these soft skills have significant importance with the part-time working student performance

Role of foliar spray of plant growth regulators in improving photosynthetic pigments and metabolites in Plantago ovata (Psyllium) under salt stress – A field appraisal

Salinity is one of the major abiotic factors that limit the growth and productivity of plants. Foliar application of plant growth regulators (PGRs) may help plants ameliorate the negative impacts of salinity. Thus, a field experiment was conducted at the Botanical Garden University of Balochistan, Quetta, to explore the potential role of PGRs, i.e., moringa leaf extract (MLE; 10%), proline (PRO; 1 µM), salicylic acid (SA; 250 µM), and thiourea (TU; 10 mM) in ameliorating the impacts of salinity (120 mM) on Plantago ovata, an important medicinal plant. Salinity hampered plant photosynthetic pigments and metabolites but elevated oxidative parameters. However, foliar application of PGRs enhanced photosynthetic pigments, including Chl b (21.11%), carotenoids (57.87%) except Chl a, activated the defense mechanisms by restoring and enhancing the metabolites, i.e., soluble sugars (49.68%), soluble phenolics (33.34%), and proline (31.47%), significantly under salinity stress. Furthermore, foliar supplementation of PGRs under salt stress led to a decrease of about 43.02% and 43.27% in hydrogen peroxide and malondialdehyde content, respectively. Thus, PGRs can be recommended for improved photosynthetic efficiency and metabolite content that can help to get better yield under salt stress, with the best and most effective treatments being those of PRO and MLE to predominately ameliorate the harsh impacts of salinity

CCL2/MCP-I Genotype-Phenotype Relationship in Latent Tuberculosis Infection

Among the known biomarkers, chemokines, secreted by activated macrophages and T cells, attract groups of immune cells to the site of infection and may determine the clinical outcome. Association studies of CCL-2/MCP-1 -2518 A/G functional SNP linked to high and low phenotypes with tuberculosis disease susceptibility have shown conflicting results in tuberculosis. Some of these differences could be due the variability of latent infection and recent exposure in the control groups. We have therefore carried out a detailed analysis of CCL-2 genotype SNP -2518 (A/G transition) with plasma CCL-2 levels and related these levels to tuberculin skin test positivity in asymptomatic community controls with no known exposure to tuberculosis and in recently exposed household contacts of pulmonary tuberculosis patients. TST positivity was linked to higher concentrations of plasma CCL2 (Mann Whitney U test; p = 0.004) and was more marked when the G allele was present in TST+ asymptomatic controls (A/G; p = 0.01). Recent exposure also had a significant effect on CCL-2 levels and was linked to the G allele (p = 0.007). Therefore association studies for susceptibility or protection from disease should take into consideration the PPD status as well as recent exposure of the controls group used for comparison. Our results also suggest a role for CCL-2 in maintaining the integrity of granuloma in asymptomatic individuals with latent infection in high TB burden settings. Therefore additional studies into the role of CCL-2 in disease reactivation and progression are warranted

Cytokine Gene Polymorphisms across Tuberculosis Clinical Spectrum in Pakistani Patients

BACKGROUND: Pakistan ranks 7(th) globally in terms of tuberculosis (TB) disease burden (incidence 181/100000 pop./yr; prevalence of 329/pop./yr). Reports from different populations show variable associations of TB susceptibility and severity with cytokine gene polymorphisms. Tuberculosis clinical severity is multi-factorial and cytokines play a pivotal role in the modulation of disease severity. We have recently reported that the ratio of two key cytokines (IFNgamma and IL10) show significant correlation with the severity spectrum of tuberculosis. The objective of the current study was to analyze the frequency of cytokine gene polymorphisms linked to high and low responder phenotypes (IFNgamma +874 T(hi)-->A(lo) and IL10 -1082 G(lo)-->A(hi)) in tuberculosis patients. METHODS AND FINDINGS: STUDY GROUPS WERE STRATIFIED ACCORDING TO DISEASE SITE AS WELL AS DISEASE SEVERITY: Pulmonary N = 111 (Minimal, PMN = 19; Moderate, PMD = 63; Advance, PAD = 29); Extra-pulmonary N = 67 (Disseminated DTB = 20, Localized LTB = 47) and compared with healthy controls (TBNA = 188). Genotype analyses were carried out using amplification refractory mutation system-PCR (ARMS-PCR) and stimulated whole blood (WB) culture assay was used for assessing cytokine profiles. Our results suggest that the IFNgamma +874 TT genotype and T allele was overrepresented in PMN (p = 0.01) and PMD (p = 0.02). IFNgamma +874 TT in combination with IL10 GG(lo) genotypes showed the highest association (chi(2) = 6.66, OR = 6.06, 95% CI = 1.31-28.07, p = 0.01). IFNgamma AA(lo) on the other hand in combination with IL10 GG(lo) increased the risk of PAD (OR = 5.26; p = 0.005) and DTB (OR = 3.59; p = 0.045). CONCLUSION: These findings are consistent with the role of IL10 in reducing collateral tissue damage and the protective role of IFNgamma in limiting disease in the lung

Frequency and association of cytokine gene polymorphisms in tuberculosis disease sussceptibility and severity

One third of the world\u27s populations are suspected to be infected with Mycobacterium tuberculosis with an estimation of 8-10 million new cases diagnosed annually. Pakistan is among the 22 high TB burden countries despite a low contribution from HIV. Among the several factors that contribute towards susceptibility to active tuberculosis, evolution of cytokine and chemokine responses are crucial for the disease progression and establishment. Cytokines modulate the activities of target cells and initiate immune response while chemokines are important in the recruitment of immune cells towards the site of infection. Polymorphisms in genes coding for cytokines and their receptors can have a broad effect on killing intracellular mycobacteria which reside and multiply within macrophages. The role of interferon gamma (IFN-y) is to activate macrophages to kill intracellular organisms. Single nucleotide polymorphisms (SNPs) in key cytokine genes may affect the functionality of IFN-y and may result in high and low producer phenotypes. A number of SNPs have been identified in the IFN-y response and regulatory genes that may predispose to mycobacterial disease. However, the relevance of polymorphism within these genes to the common phenotype of TB remains unclear. The frequency distributions of SNPs in different populations have been shown to be highly variable and this may be due to evolutionary pressures in different populations. Therefore, aim of the current study was to investigate functional gene polymorphisms in IFN-y (+874T—*A), its receptor (-273 to -741) and in associated regulatory cytokines and chemokines such as IL-10 (- 1082A—\u3eG), TNF-a (-308G--4A), IL-6 (-174G-0C) and CCL-2 (-2518A-4G) to establish baseline frequencies and to investigate their influence on tuberculosis disease susceptibility and severity in indigenous population. Moreover, chemokine CCL-2, protein levels were also assessed on a subset of samples. When cytokine genotype frequencies were analysed in healthy individuals, Pakistani population seem to have a higher proportion of alleles that are associated with high IFN-y (7), high IL-10 (A), low TIVF-a (G), high IL-6 (G) and low CCL-2 (A) phenotypes as reported from other Asian populations compared to Caucasian, European and African populations and this underlines the importance of a \u27local\u27 reference population when evaluating the clinical relevance of cytokine gene polymorphisms. In relation to TB, the IFN-y T allele was found significantly higher in pulmonary TB (PTB) patients which was restricted to minimal and moderate PTB, increasing the risk by 2-3 fold. This T allele was also found to be linked between first intronic CA11 repeats and moderate PTB while AA was found to be linked between CA13 and disseminated extra-pulmonary TB (DTB). Two novel SNPs in 1FN-y receptor] promoter region at positions -255 (C--+T) and -129 (G—A) were found in association with advance PTB (PAD) and DTB respectively which suggest the link of these SNPs with TB disease severity. The IFN-y response cytokine SNPs were also found in association with differing susceptibility and severity of TB such as IL-10 (-1082) AhIgh with protection from PAD and ETB, TNF-a (-308) Ahigh with susceptibility to ETB and IL-6 CI\u27 allele with protection from PTB. Investigation of CCL-2 genotype-phenotype relation was the next target of this study which showed that CCL-2 GG genotype and higher CCL-2 levels may play a role in TB disease localization but there was no significant relationship between CCL-2 genotypes and phenotypes. In terms of mutiloci interactions, the combination of IFN-y TT high or IFN-y AA1\u27 with IL-6 GGhIgh was the most significant in determining disease severity which is in line with the reported function of IL-6 as part of the Th2 network. These findings suggest that identification of genetic biomarkers which may be predictive of disease progression or severity can provide extremely useful tools for National TB programs for th management of patients with differing disease severity and combinations of key cytokine genotypes would be more meaningful in determining the relationship of polymorphisms with TB disease severity

ترقی پسند تنقید کے دو اہم معمار

It is evident that the Progressive Movement in the Subcontinent started in the objective condition prevailing at that time. In the beginning some men of letters attributed Progressive Criticism to Marxism. But as Dr. Qamar Raees has clarified, it was not a mechanical approach towards criticism. The main emphasis is on social context of literature. In this perspective, two progressive critics, Syed Sibte Hasan and Zoe Ansari can be termed as the important founders of Progressive Criticism in Urdu. Both of them give equal importance to social context of literature as well as the classical and cultural heritage of the society.   </p