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The Role of Genetics and Immune Mechanisms in the Pathogenesis of Diabetic Retinopathy

Thesis Info

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Author

Nadeem Afzal

Program

PhD

Institute

University of Health Sciences

City

Lahore

Province

Punjab

Country

Pakistan

Thesis Completing Year

2012

Thesis Completion Status

Completed

Subject

Applied Sciences

Language

English

Link

http://prr.hec.gov.pk/jspui/bitstream/123456789/2695/1/2641S.pdf

Added

2021-02-17 19:49:13

Modified

2024-03-24 20:25:49

ARI ID

1676727595542

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Diabetes mellitus affects millions of people worldwide especially in Asia, Africa and South America. It can cause many serious complications such as retinopathy and nephropathy. Diabetic retinopathy is a terrible prospect to these patients which is diagnosed with the onset of microaneurysms, haemorrhages and development of cotton wool spots in the retina. Mechanisms underlying pathogenesis of diabetic retinopathy are not completely understood. Integrin α2β1 is a receptor for collagen on platelet cell membrane. Polymorphism in intron 7 of integrin gene produces change in α subunit and this makes retina vulnerable for platelet attachment during chronic hyperglycaemia in diabetes. Earlier studies have established a relationship between variants of α2β1 gene and diabetic retinopathy in Japanese and Caucassions. Derangements of several cytokines and chemokines have been reported in diabetic retinopathy. There are many studies that evaluate the role of IL-6 in the development of ophthalmic complications but they determined the level of IL-6 in the vitreous fluid and majority of them have emphasized the involvement of this cytokine in the development of eye complications. Interleukin 6 increases vascular permeability and neovascularisation and attracts macrophages. A study was performed in Type-I diabetes mellitus to determine its role in diabetic retinopathy whereas some of them have correlated IL-6 with proliferative diabetic retinopathy. In the literature there are a few studies that tried to determine the level of IL-6 in the serum of diabetic retinopathy patients but some of them could not determine its level in the serum while others found its level much less than in the vitreous fluid. The comparatively newly diagnosed subset of T cells known as Th17 cell secretes IL-17 which is a family of six cytokines (IL-17A-E). It is a pro-inflammatory cytokine and mediates inflammation by attracting neutrophils. It has been documented that Th17 cells have major contribution in different human diseases that are related to inflammation and tissue destruction such as rheumatoid arthritis, psoriasis, Crohn’s disease, and multiple sclerosis. Therefore it has also been suggested that IL-17 has got the potential to be used as a treatment option as well. It has been suggested that some early aspects of pathogenesis of diabetic retinopathy could be due to loss of self-tolerance. At the beginning of retinopathy, anti-pericyte and anti-endothelial cell auto-antibodies have been detected in the circulation of diabetic patients. There were increased vitreous concentrations of IL-6 and IL-8 in the patients of diabetic retinopathy while in the serum there were elevated levels of IL-8, TNF-alpha, and soluble IL-2 receptor. T regulatory (Treg) cells: a subset of CD4+ T cells, down regulates the process of autoimmunity. It has been documented that Treg cells are involved in the development of various autoimmune disorders. Two hundred and twelve (212) subjects were divided into three groups i.e. (Group-III) diabetic patients with retinopathy (152), (Group-II) diabetic patients without retinopathy (30) and (Group-I) healthy control without diabetes (30). Blood was drawn after their consent and integrin gene polymorphism was studied by restriction fragment length polymorphism analysis. Concentration of IL-6 and IL-17 was determined by ELISA technique. CD4+CD25+ (T regulatory cells) were enumerated by flow cytometer. There were 77 males and 135 females and their age distribution was from 20 years to 75 years. 109 patients had history of diabetes between 5 and 10 years whereas 73 patients had diabetes for more than 10 years. The percentage of HbA1c was between 5.5% and 15.4%. The mean age of the studied population was 34.66, 49.46, and 50.88 years in Group-I, Group-II and Group-III respectively. There was statistically significant difference of mean age among the three groups. The mean CD4+CD25+ count was 14.53, 14.68, and 16.47 in Group-I, Group-II and Group-III respectively and on comparison of CD4+CD25+ count among the three groups, there was statistically significant difference. The mean of Treg cells was 2.91, 3.07, and 2.88 in Group-I, Group-II and Group-III respectively and there was no statistically significant difference of Treg cells among the three groups,. The mean level of IL-6 was 133.98, 1341.78, and 718.66 in Group-I, Group-II and Group-III respectively and there was statistically significant difference of IL-6 among the three groups. The mean level of IL-17 was 718.05, 415.01, and 375.95 in Group-I, Group-II and Group-III respectively and there was statistically significant difference of IL-17 among the three groups. Mean duration of diabetes was 7.76 and 10.51 years in Group-II and Group-III respectively. There was statistically significant difference of duration of diabetes between these two groups. Mean percentage of HbA1c was 8.54% and 8.83% in Group-II and Group-III respectively and there was no statistically significant difference in percentages of HbA1c between these two groups. There was statistically significant difference in the gender and age of the subjects in all parameters between Group-I and Group-II. There was statistically significant difference in the gender, age, level of IL-6 and the level of IL-17 among the subjects (p<0.05). By comparing Group-II and Group-III, we could find statistically significant difference in the percentage of Treg cells, the level of IL-6 and the duration of diabetes in the studied subjects. Regarding Bgl II polymorphism, 33 (15.6%), 104 (49.05%), and 75 (34.90%) subjects had + +, + -, and - - phenotypes respectively. On comparing Bgl II polymorphism among the three groups, there was no statistically significant difference. By applying logistic regression model between Group-II and Group-III there was statistically significant difference in the percentage of Treg cells and the level of IL-6 in these groups. When the logistic regression model was applied between Group-I and Group-III, significant difference was found in the age of the subjects, the level of CD4+CD25+ cells and the level of IL-6 in these groups. Therefore, it is suggested that age and gender of the subjects, duration of diabetes, levels of IL-6, IL-17, CD4+CD25+ cells and the percentage of Treg cells can contribute towards the development of diabetic retinopathy.
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النتائج

النتائج

1۔ أولاً:

 تعرفنا علی الشاعرۃ العظیمۃ نازک الملائکۃ بالتفصیل منذ ولادتھا إلی وفاتھا، وهي عربية عراقية الأصل من دولة العراق.

2۔ ثانیاً:

 بدایۃ النظم عند نازک الملائکۃ، تعریف الشعر الحر وإلی من تنسب ریادۃ الشعر الحر؟ وقد اتفق النقاد والأدباء بأن نازك الملائكة هي رائدة من روادالشعرالعربي الحر.

3۔ ثالثاً:

 تعتبر نازک الملائکۃ شاعرۃ ممتازہ رائعۃ وھي رائدۃ الشعر العربي الحر والمیزۃ الممتازۃ في شعرھا بأن لدیھا القدرۃ علی تحویل حزنھا إلی مادۃ للتأمل الھاديء والتبصر العمیق والتعجب في الحیاۃ وفي أحوال النفس وأسرارھا ونلاحظ ذلک في قصائدھا، وهي معروفة بأحزانها وأفكارها الرائعة وتعطي تشبيهات دقيقة مطابقة للفطرة.

دعوت کے میدان میں تبلیغی جماعت کے مساعی و مشکلات کا تحقیقی جائزہ

Muhammad (PBUH) was the last Prophet. Almighty Allah sent Him message to preach the people, but the Kufar made His enemies. Instead the situation of opposition and hatred from his enemies how He treated them with patience and love. And how He would be able to establish Islamic states and invites the people of other areas towards Islam. Muhammad (PBUH) was succeeded from the reformers of his ummah and among these reformers were the founder of tableghi jammat, Molana Muhammad Ilyas Kandhalwi. This research paper will compare the difficulties of Muhammad's (PBUH) Da'wah with tableghi Jammat.                       

Investigating Protein Semantic Similarity Measurement and its Correlation With Sequence Similarity

Protein sequence similarity is commonly used to compare proteins, and to search for proteins similar to a query protein. With the growing use of biomedical ontologies, especially Gene Ontology (GO), semantic similarity between ontology terms, proteins and genes is getting attention of researchers. Protein semantic similarity measurement has many applications in bioinformatics, including protein function prediction and protein-protein interactions. Semantic similarity measures were proposed by Resnik, Jiang and Conrath, and Lin. Recent measures include Wang and AIC. The question whether the semantic similarity has a strong correlation with sequence similarity, has been addressed by some authors. It has been reported that such correlation exists, and it has been used for the evaluation of semantic similarity computation methods as well as for protein function prediction. We investigate the correlation between semantic similarity and sequence similarity using graphs, Pearson''s correlation coe cient and example proteins. Wend that there is no strong correlation between the two similarity measures. Pearson''s correlation coef- cient is not su cient to explain the nature of this relationship, if not accompanied by graph analysis. Wend that there are several pairs with low sequence similarity and high semantic similarity, but very few pairs with high sequence similarity and low semantic similarity. Interestingly, the correlation coe cient depends only on the number of common GO terms in proteins under comparison. We propose a novel method SemSim for semantic similarity measurement. It addresses the limitations of existing methods, and computes similarity in two steps. In therst step, SimGIC like approach is used where contribution of common ancestors is divided by contribution of all ancestors. In the second step, we use two new factors: Speci city computed from ontology based information content, and Uniqueness computed from annotation based information content. Thenal result, after applying these two factors, makes clear distinction between the generalized and specialized terms. We conducted experiments on protein pairs having evidence of high similarity, and the ones having evidence of low similarity. Experiments show that SemSim performs better than the previous measures in both cases. When semantic similarity is used for searching proteins from large databases, the speed issue becomes signi cant. To search for proteins similar to a query protein having m annotations, from the database of p proteins, p m n g comparisons would be required. Here n is the average annotations per protein, g is the complexity of GO term similarity computation algorithm, and it is assumed that each term of one protein is compared with each term of the other. We propose a method SimExact that is suitable for high speed searching of semantically similar proteins. Although SimExact works on common terms only, our experiments show that it gives correct results required for protein semantic searching. SimExact can be used as a pre processor, generating candidate list for the existing methods, which proceed for further computation. Such arrangement will gain high speed while retaining the accuracy of the given method. We provide online tool that generates a ranked list of the proteins similar to a query protein, with a response time of less than 8 seconds in our setup. We use SimExact to search for protein pairs having high disparity between semantic similarity and sequence similarity. SimExact makes such searches possible, which would be NP-hard otherwise.