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Molecular Genetic Elucidation of Inherited Retinal Diseases

Thesis Info

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Author

Khan, Muhammad Imran

Supervisor

Raheel Qamar

Program

PhD

Institute

COMSATS University Islamabad

City

Islamabad

Province

Islamabad.

Country

Pakistan

Thesis Completing Year

2012

Thesis Completion Status

Completed

Subject

Natural Sciences

Language

English

Link

http://prr.hec.gov.pk/jspui/handle/123456789/1492

Added

2021-02-17 19:49:13

Modified

2024-03-24 20:25:49

ARI ID

1676726705925

Similar


Molecular Genetic Elucidation of Inherited Retinal Diseases Inherited retinal dystrophies are characterized by gradual loss of vision due to underlying degeneration of light sensitive photoreceptors or the surrounding retinal pigment epithelium. Clinical subtype of RD called Retinitis pigmentosa involves progressive degeneration of Rod photoreceptor cells earlier in life than the cones cells, and represents one of the most common forms. As rod cells are sensitive to dim light the patients first experience night vision problems but might eventually end up with complete blindness as the degeneration prevails. Of the inherited forms of RP the autosomal recessive inheritance pattern is most common and accounts for more than 50% of cases. RP is genetically heterogeneous, where arRP is at the extreme as mutations in about 40 genes are known to cause same phenotype. Despite large number of genes associated with arRP these genes only explain about 60% of the cases and hence the further research is warranted to find out the missing pieces. In three families, missense mutations were identified in TULP1, which include p.(Thr380Ala), p.(Arg482Gln), and p.(Lys489Arg). In three arRP families protein- truncating mutations were identified in ABCA4 p.(Gln2220*), AIPL1 p.(Trp278*) and CERKL p.(Arg283*). In three families novel missense mutations were identified in different genes, which include CNGA1 (p.(Gly433Asp), EYS (p.(Asp2767Tyr) and PDE6A (p.(Arg544Trp). A novel splice site mutation (c.2493-2A>G; p.(?), was identified in CNGB1 in a family with arRP. In five other unrelated arRP families, previously reported mutations were identified, which include two families with a missense mutation p.(Glu150Lys) in RHO, two families with mutations p.(Arg44Gln) and p.(Ser121Leufs*6) in RPE65, and one family with a mutation p.(Thr745Met) in CRB1. In an X-linked RP family the causative mutation p.(Glu809Glyfs*25) was identified in RPGR. A splice site mutation c.488-1G>A; p.(?) in IQCB1 was identified in a family with syndromic RP. Two families with fundus albipunctatus were identified to have a frameshift p.(Val305Hisfs*29) and a missense p.(Met253Arg) mutation in RDH5 gene. xiiIn an arRP family Exome next generation sequencing (NGS) helped to identify a plausible pathogenic variant c.3269G>A; p.(Arg1090Gln) in SNRNP200, a gene previously found to be mutated in autosomal dominant RP (adRP). We hypothesize that the mutation identified in the Pakistani arRP family represents a hypomorphic variant but further experiments are warranted to prove the causality of the mutation. An overlapping homozygous region was identified that was shared between all the affected individuals of two arRP families. The region encompasses CLRN1, a gene previously found to be mutated in Usher syndrome type III. Two novel missense mutations p.(Pro31Leu) and p.(Leu154Trp) were identified, which were proven to be pathogenic. Hence a novel genotype-phenotype correlation was established for CLRN1. Taking together, sequence variants were identified in 32 of 41 (78%) families of our Pakistani RD cohort, which very likely explains the retinal phenotypes. In addition, we were able to identify nine potential novel arRP loci, which are likely to harbor novel retinal disease gene.
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طفیل ہوشیار پوری

طفیل ہوشیار پوری(۱۹۱۴ء۔۱۹۹۳ء) کا اصل نام محمد طفیل اور شہرت طفیل ہوشیار پوری کے نام سے ہوئی۔ طفیل ضلع ہوشیارپورکی تحصیل گڑھ شنکر کے ایک گاؤں بینے والی میں پیدا ہوئے۔ ۱۹۳۴ء میں ہوشیار پور سے ہجرت کر کے سیالکوٹ میں مستقل سکونت اختیار کر لی ۔یہاں انھوں نے اپنے بڑے بھائی کے ساتھ مل کر منیمی(حساب کتاب) سکول قائم کیا۔ اس سکول میں سیالکوٹ کے ممتاز تاجر ان کے شاگرد رہے ہیں۔(۶۰۷)

۱۹۴۳ء میں طفیل آل انڈیا ریڈیو سے منسلک ہو گئے۔ ۱۹۵۴ء میں ان کا ناطہ فلمی دنیا سے جڑ گیا ۔ اور آپ فلموں کے لیے گیت لکھنے لگے۔یہ گیت اردو اور پنجابی زبان میں ہیں۔۱۹۵۴ء میں ہی انھوں نے لاہور سے ایک ادبی اور علمی رسالے کا اجرا کیا جس کا نام ’’محفل‘‘ تھا۔ آپ ہفت روزہ رسالہ ’’صاف گو‘‘ کے مدیر اعلیٰ بھی رہے ہیں۔(۶۰۸)

حُب وطن پر مشتمل نظموں اور جنگی ترانوں پر مشتمل ’’میرے محبوب وطن‘‘ طفیل کا پہلا شعری مجموعہ کلام ہے۔ جوجنوری ۱۹۶۶ء میں شائع ہوا۔مولانا ابو الا علیٰ مودودی نے حرفِ اول لکھا۔ جسٹس ایس۔اے رحمان نے ’’پیشِ لفظ‘‘ سید عابد علی عابد نے ’’دیباچہ‘‘ اور سید نذیرنیازی نے ’’مقدمہ ‘‘ اور طفیل نے’’میں خود کہوں تو‘‘ کے عنوان سے اپنی قومی نظموں کا پس منظر بیان کیا ہے۔ جامِ مہتاب طفیل کا دوسرا شعری مجموعہ ہے۔ جو رباعیات و قطعات پر مشتمل ہے ۔یہ مجموعہ ۱۹۷۵ء میں شائع ہوا۔ حرفِ آغاز جسٹس ایس ۔اے رحمان نے لکھا۔’’تعارف و تقریظ‘‘ مولانا حامد علی خان نے لکھا۔ عرضِ حال کے عنوان سے طفیل نے اس کتاب میں اپنی شاعری پر روشنی ڈالی ہے۔ ڈاکٹر سید عبداﷲ نے ’’شعلہ جام پر ایک نظر‘‘ کے عنوان سے مضمون قلم بند کیا ہے۔ ڈاکٹر عبادت بریلوی نے مقدمہ لکھا ہے۔ جب کہ شاعر لکھنوی نے ’’شعلہ جام سے طفیل ہوشیار...

Epiphyseal Fusion of Iliac Crests in Male and Female Adolescents: An Age Estimation Criterion

Background: Determination of age depends upon physical examination, dental assessment, and skeletal evaluation. The radiological examination of bone for appearance and fusion of ossification centers helps in the assessment of skeletal maturity as the process occurs in a particular sequence which is almost constant for that particular bone. Objectives: The objective of this study was to determine the age of fusion of iliac crest by radiological examination of subjects of age bracket 17-25 years coming to Shalamar Hospital Lahore Methods: In this cross-sectional study, radiological examinations (Digital X-Rays) were performed to evaluate the fusion of Iliac Crest in 200 subjects of both genders of 17 – 25 years. Data analysis was done using SPSS Version 23. Conclusions were drawn and compared with available results of previous work done in this field. Results: Out of 200 subjects, there were 132 males (66 %) and 68 females (34%). The mean ± SD age of both genders was 20.41± 2.55. There were 93 cases (70.45%) of complete fusion among males, showing 100 % union in the age groups of 21-25 years, while 40 cases (58.83%) of complete union among females were observed during 20-25 year of age groups. The mean ± SD age of complete union for males was 20.67± 2.61 years and for females 19.90 ± 2.38 years, with a significant p value of <0.05. Similarly, a statistically significant difference was observed among people of different socio-economic statuses. No difference was observed among different ethnic groups. Conclusions: The fusion of the iliac crest is not affected by ethnicity. Factors like diet and nutrition directly affect bone growth and hence bone age. More studies should be conducted across the country to formulate a standard in setting up a uniform criterion for assessing the age of adolescents

Studies on Medicinal Herbs Used for Depression, Epilepsy and Schizophrenia Available in Local Market

The aim of present study was to identify the various pharmacognostic and pharmacological properties of herbal plants by employing different analytical techniques, which are used traditionally for the cure of ailments. Powder drug of rhizomes of A. calamus produced different color and solubility when treated with different solvents. Phytochemical screening of A. calamus was positive for the presence of Alkaloids, Terpinoids, Anthraquinones, Saponins, Carbohydrates, Glycosides, Coumarins Tannins and phenolic compounds, Flavonoids, Triterpenoids and steroids and Phalbotannins. Infra-Red Spectroscopy of A. calamus displayed the presence of alcohols, phenols, alkanes, α, β-unsaturated aldehydes, ketone, nitro compounds, aliphatic amines, carboxylic acids and alkyl halide groups. Crude methanolic extract of A. calamus showed significant inhibition in number of writhes. Significant decrease in number of writhes in acetic acid induced writhing at the dose of 500mg/kg was observed. For this experiment we had used (Albino) mices and methanolic extract of roots and rhizomes was used at 100, 300 and 500mg / kg doses. Whereas 0.5ml of normal saline was used for control group and Aspirin 300mg / kg was used as standard drug. Crude methanolic extract of A. calamus at the dose of 500mg / kg showed 31.2+ 1.689 writhes, whereas Aspirin showed 29.6+ 0.601 writhes. A. calamus crude methanolic extract showed significant results in formalin test, decrease in number of licking and time spent on licking and biting in both phases at the dose of 500 mg/kg was observed in formalin test. For this experiment we had used (Albino) mices and crude methanolic extract of roots and rhizomes was used at 300 and 500mg/kg doses. Whereas 0.5ml of normal saline was used for control group and Aspirin 300mg/kg was used as standard drug. During first half of the experiment at the dose of 500mg/kg, number of licking and biting were 22.0± 1.051 and time spent on licking was 37.2± 0.665 seconds and in second half number of licking and biting were 21.8±1.07 and time spent on licking and biting was 50.0± 1.584. Aspirin at the dose 300mg/kg in first half number of licking and biting were 20.8± 0.972 and time spent on licking and biting was 33.6± 1.032 and in second half number of licking and biting were 18.4± 0.874 and time spent on licking and biting was 30.0± 0.448. From the above results it is revealed that crude methanolic extract of A. calamus at 500mg /kg dose has excellent analgesic and anti inflammatory properties. Gross behavior profile of A. calamus was observed for the emotional stress which showed anti depressant behavior after oral administration of extract of different strengths. Exploratory activities of A. calamus showed anti depressant effect as results shows significant decrease in open field, cage crossing and rearing tests. A. calamus showed sedative effect as decrease in Head dip test, light and dark test and traction test. For exploratory activities we had used Albino mice, crude methanolic extract of roots and rhizomes were used at 100, 300 and 500mg / kg doses as test dose. Diazepam, 2mg/kg is used as standard drug while 0.5ml normal saline was used for control group. Following results were obtained when 100mg / kg dose of A. calamus is given, open field (194.00+ 0.707), cage crossing (32.2 + 0.734), rearing (29.2+ 0.86) head dip (35.80+ 2.537), traction (13.6+ 0.509), in light and dark test the result was (2.20+ 0.05) in light, while (7.40 + 0.05) in dark. At a dose of 300mg / kg dose of A. calamus shows these results, in open field (156.0+ 1.581), cage crossing (25.6+ 3.613), rearing (26.2+ 1.356) head dip (31.2+ 0.86), traction (10.6+ 0.509), in light and dark test the result was (2.06+ 0.11) in light, while (7.54+ 0.11) in dark. At a dose of 500mg / kg dose of A. calamus shows these results, in open field (121.6+ 0.812), cage crossing (21.8+ 0.461), rearing (17.8+ 0.374) head dip (27.0+ 0.707), traction (8.2+ 0.374), in light and dark test the result was (1.50+ 0.08) in light, while (8.10+ 0.08) in dark. Diazepam (2mg/kg), showed these results in open field (99.0+ 5.531), cage crossing (8.2+ 0.374), rearing (10.2+ 0.583) head dip (17.6+ 0.748), traction (15.2+ 0.663), in light and dark test the result was (1.10+ 0.09) in light, while (8.50+ 0.09) in dark compartment. In forced swimming test animals showed decrease in immobility time. For this activity crude methanolic extract of root and rhizomes at doses of 100, 300 and 500mg/kg were used as test dose, whereas 0.5ml normal saline is used for control group while Diazepam 2mg/kg was used as standard drug. At the end of experiment following results were obtained, at test dose of 100, 300 and 500mg /kg mobility time was 4.20+ 0.02, 4.50+ 0.06 and 5.20+ 0.13 respectively. At same test dose immobility time was 1.40+ 0.02, 1.10+ 0.06 and 0.40+ 0.13 respectively. Standard drug (diazepam) at the dose of 2mg/kg gives 1.10+ 0.05 mobility time and immobility time was 4.50+ 0.05. Decrease in immobility time shows the anti depressant effects. In Sodium pentothal induced sleeping time activity, Albino rats were used as testing animals. Crude methanolic extract of A. calamus was used in a dose of 300 and 500mg /kg as test dose, 0.5ml normal saline is used for control group while Diazepam 1mg /kg was used as standard drug. At 300 and 500mg /kg dose the onset of sleep was 5.128± 1.127 and 4.4± 0.1 and duration of sleep was 67.0± 0.709 and 83.8± 0.665 respectively. When diazepam is used the onset of sleep was 2.48± 0.116 and duration of sleep was 95.8± 0.862. Decrease in onset of sleeping time and an increase in sleeping time shows anxiolytic action of the extract. Powder drug of whole plant of A. absinthium produced different color and solubility when treated with different solvents. Phytochemical screening of A. absinthium was positive for the presence of Terpinoids, Anthraquinones, Saponins, Carbohydrates, Glycosides, Tannins and phenolic compounds, Flavonoids, Triterpenoids and steroids and Phalbotannins. Infra-Red Spectroscopy of A. absinthium exhibited the presence of alkyl group, methyl group, alcohol, ether, ester, carboxylic acid, anhydrides, imines and deoxyribose groups. Crude methanolic extract of A. absinthium showed dose dependant inhibition in number of writhes. Significant decrease in number of writhes in acetic acid induced writhing at the dose of 500mg/kg was observed. For this experiment we had used (Albino) mices and crude methanolic extract of whole plant was used at 100, 300 and 500mg/kg doses. Whereas 0.5ml of normal saline was used for control group and Aspirin 300mg/kg was used as standard drug. Crude methanolic extract of A. absinthium at the dose of 500mg/kg showed 34.2+ 1.466 writhes, whereas Aspirin showed 26.0+ 0.951 writhes. A. absinthium crude methanolic extract showed significant results in formalin test, decrease in number of licking and time spent on licking and biting in both phases at the dose of 500mg/kg was observed in formalin test. For this experiment we had used (Albino) mice and crude methanolic extract of whole plant was used at 300 and 500mg/kg doses. Whereas 0.5ml of normal saline was used for control group and Aspirin 300mg/kg was used as standard drug. During first half of the experiment at the dose of 500mg/kg, number of licking and biting were 26.2± 1.125 and time spent on licking was 36.2± 0.802 seconds and in second half number of licking and biting were 20.6± 0.982 and time spent on licking and biting was 30.4± 1.032. Aspirin at the dose 300mg/kg in first half number of licking and biting were 21.8± 0.972 and time spent on licking and biting was 30.8± 1.244 and in second half number of licking and biting were 17.2± 0.862 and time spent on licking and biting was 31.0± 1.707. From the above results it is revealed that crude methanolic extract of A. absinthium at 500mg /kg dose has excellent analgesic and anti inflammatory properties. Gross behavior profile of A. absinthium was observed for the emotional stress which showed anti depressant behavior after oral administration of extract of different strengths. Exploratory activities of A. absinthium showed anti depressant effect as results shows significant increase in open field and cage crossing. A. absinthium showed sedative effect as decrease in Head dip test, rearing, light and dark test and traction test. Decrease in immobility time shows the anti depressant effects. Decrease in onset of sleeping time and an increase in sleeping time shows anxiolytic action of the extract. For exploratory activities we had used Albino mice, crude methanolic extract of whole plant was used at 100, 300 and 500mg/kg doses as test dose. Diazepam, 2mg/kg is used as standard drug while 0.5ml normal saline was used for control group. Following results were obtained when 100mg/kg dose of A. absinthium is given, open field (176.6+ 1.077), cage crossing (33.2+ 1.24), rearing (25.8+ 0.8) head dip (36.2+ 0.374), traction (13.2+ 0.663), in light and dark test the result was (2.30+ 0.05) in light, while (7.30+ 0.05) in dark. At a dose of 300mg/kg dose of A. absinthium shows these results, in open field (192.2+ 1.029), cage crossing (31.6+ 0.509), rearing (21.6+ 0.509) head dip (31.6+ 0.678), traction (10.4+ 0.509), in light and dark test the result was (2.14+ 0.10) in light, while (7.46+ 0.10) in dark. At a dose of 500mg/kg dose of A. absinthium shows these results, in open field (123.0+ 0.707), cage crossing (20.6+ 0.509), rearing (18.4+ 1.02) head dip (28.8+ 1.714), traction (8.6+ 0.044), in light and dark test the result was (2.00 +0.07) in light, while (8.00+ 0.07) in dark. Diazepam (2mg /kg), showed these results in open field (94.6+ 3.414), cage crossing (9.6 + 0.244), rearing (9.2+ 0.86) head dip (17.8+ 0.663), traction (10.6+ 0.509), in light and dark test the result was (1.20+ 0.06) in light, while (8.40+ 0.06) in dark compartment. In forced swimming test animals showed decrease in immobility time. For this activity crude methanolic extract of whole plant at doses of 100, 300 and 500mg/kg were used as test dose, whereas 0.5ml normal saline is used for control group while Diazepam 2mg/kg was used as standard drug. At the end of experiment following results were obtained, at test dose of 100, 300 and 500mg/kg mobility time was 3.50+ 0.02, 4.10+ 0.06 and 4.30+ 0.13 respectively. At same test dose immobility time was 2.10+ 0.02, 1.50+ 0.06 and 1.30+ 0.1 respectively. Standard drug (diazepam) at the dose of 2mg/kg gives 1.26+ 0.04 mobility time and immobility time was 4.34+ 0.04. Decrease in immobility time shows the anti depressant effects. In Sodium pentothal induced sleeping time activity, Albino rats were used as testing animals. Crude methanolic extract of A. absinthium was used in a dose of 300 and 500mg/ kg as test dose, 0.5ml normal saline is used for control group while Diazepam 1mg /kg was used as standard drug. At 300 and 500mg/kg dose the onset of sleep was 7.054± 0.019 and 4.76± 0.051 and duration of sleep was 74.2± 1.16 and 93.6± 1.032 respectively. When diazepam is used the onset of sleep was 3.42± 0.058 and duration of sleep was 116.6± 3.394. Decrease in onset of sleeping time and an increase in sleeping time shows anxiolytic action of the extract. Powder drug of roots of B. himalaica produced different color and solubility when treated with different solvents. Phytochemical screening of B. himalaica was positive for the presence of terpenoids, anthraquinones, triterpenoids and steroids, saponins, glycosides, tannins and phenolic compounds, flavonoids and phlobatannins. Infra-Red Spectroscopy of B. himalaica confirmed the presence of amines, alkanes, α, β- unsaturated aldehydes, ketone, nitro compounds, alkenes, aromatics and alkyl halide groups. Crude methanolic extract of B. himalaica showed significant decrease in number of writhes. This result was significant at the dose of 500mg/kg. For this experiment we had used (Albino) mice and crude methanolic extract of roots at 100, 300 and 500mg/kg doses. Whereas 0.5ml of normal saline was used for control group and Aspirin 300mg/kg was used as standard drug. Crude methanolic extract of B. himalaica at the dose of 500mg/kg showed 34.06+ 1.584 writhes, whereas Aspirin showed 24.2+ 0.375 writhes. Crude methanolic extract of B. himalaica showed decrease in number of licking and time spent on licking and biting in both phases at the dose of 500 mg/kg. This reflects the anti nociceptive effects of B. himalaica. Crude methanolic extract of B. himalaica showed significant results in formalin test, decrease in number of licking and time spent on licking and biting in both phases at the dose of 500mg/kg was observed in formalin test. For this experiment we had used (Albino) mice and crude methanolic extract of whole plant was used at 300 and 500mg/kg doses. Whereas 0.5ml of normal saline was used for control group and Aspirin 300mg/kg was used as standard drug. During first half of the experiment at the dose of 500mg/kg, number of licking and biting were 26.2± 0.375 and time spent on licking was 36.0± 0.709 seconds and in second half number of licking and biting were 21.4± 0.68 and time spent on licking and biting was 31.8± 0.802. Aspirin at the dose 300mg/kg in first half number of licking and biting were 19.8± 0.736 and time spent on licking and biting was 27.4± 0.75and in second half number of licking and biting were 18.6± 1.211 and time spent on licking and biting was 29.2± 1.719. From the above results it is revealed that crude methanolic extract of B. himalaica at 500mg/kg dose has excellent analgesic and anti inflammatory properties. Gross behavior profile of B. himalaica was observed to evaluate the aggressive or isolated behavior in mice, a positive attitude was observed among mice upon administration of crude extract at 300 & 500mg/kg doses. Exploratory activities of B. himalaica showed anti depressant effect as results shows significant decrease in open field, cage crossing and rearing tests. B. himalaica showed sedative effect as decrease in Head dip test, light and dark test, traction time test. Decrease in immobility time shows the anti depressant effects. For exploratory activities we had used Albino mice, crude methanolic extract of whole plant was used at 100, 300 and 500mg/kg doses as test dose. Diazepam, 2mg/kg is used as standard drug while 0.5ml normal saline was used for control group. Following results were obtained when 100mg/kg dose of B. himalaica is given, open field (171.2+ 0.583), cage crossing (29.2+ 0.86), rearing (26.0+ 3.178) head dip (35.0+ 1.923), traction (13.2+ 0.374), in light and dark test the result was (2.39+ 0.1) in light, while (7.21+ 0.01) in dark. At a dose of 300mg/kg dose of B. himalaica shows these results, in open field (152.2+ 0.86), cage crossing (25.4+ 0.509), rearing (22.0 + 0.316) head dip (30.6+ 0.509), traction (10.2+ 0.374), in light and dark test the result was (2.23 + 0.15) in light, while (7.37+ 0.15) in dark. At a dose of 500mg/kg of B. himalaica shows these results, in open field (109.0+ 0.707), cage crossing (20.8+ 0.583), rearing (17.0+ 0.316) head dip (26.4+ 0.678), traction (8.0+ 0.447), in light and dark test the result was (2.10+ 0.07) in light, while (7.50+ 0.1) in dark. Diazepam (2mg/kg), showed these results in open field (95.6+ 1.363), cage crossing (10.4+ 0.927), rearing (8.8+ 0.374) head dip (16.4+ 0.509), traction (7.8+ 0.509), in light and dark test the result was (1.05+ 0.08) in light, while (8.55+ 0.08) in dark compartment. Decrease in immobility time shows the anti depressant effects. Decrease in onset of sleeping time and an increase in sleeping time shows anxiolytic action of the extract. In Sodium pentothal induced sleeping time activity, Albino rats were used as testing animals. Crude methanolic extract of B. himalaica was used in a dose of 300 and 500mg/kg as test dose, 0.5ml normal saline is used for control group while Diazepam 1mg /kg was used as standard drug. At 300 and 500mg/kg dose the onset of sleep was 7.96± 0.103 & 6.1± 0.054 and duration of sleep was 73.0± 1.002 and 96.0± 0.709 respectively. When diazepam is used the onset of sleep was 4.32+ 0.086 and duration of sleep was 111.0+ 2.633. In Sodium pentothal sleep inducing time activity, decrease in onset of sleeping time and an increase in sleeping time shows anxiolytic action of the extract." xml:lang="en_US