Study Proposal: Causative Mutations in Optic Neuropathy

Study Proposal: Causative Mutations in Optic Neuropathy Optic neuropathy refers to degeneration of optic nerve. It is often described as optic atrophy that means loss of few or most of optic nerve fibers [1]. It can be symmetric or bilateral based on toxic or nutritional ( vitamin B12 or folate deficiency) insults and genetic defects [4]. In genetically inherited optic atrophies, retinal ganglion cells and optic nerve fiber layer are damaged. This damage can be focal (affects macular beam of optic nerve) or generalized [6]. The axons of retinal ganglion cells arise from retina and from optic nerve. The optic nerve enter cortex via optic disc where input signal is processed into vision. The retinal ganglion cells or nerve cells of inner retina form 1.2 million nerve fibers [1]. The key features of optic neuropathy results from death of these nerve cells or neurons. Autosomal recessive optic atrophies (ROAs) indicate loss of nerve fibers that form optic disc, optic nerve, optic chiasm and optic tracts [net bookmark]. The only key feature of isolated ROAs is optic nerve degeneration. To date defects in genes coding for mitochondrial proteins leads to isolated ROAs [4]. The genetically inherited atrophies can be familial that follows Mendelian pattern of inheritance (X-linked recessive, autosomal recessive and autosomal dominant) or non Mendelian (mitochondrial) [2]. In autosomal recessive Mendelian pattern of inheritance, two copies of mutant allele in affected person and one copy of mutant allele in carrier are present. When two carriers mate, there is an equal chance (25%) of being affected and unaffected. There is a 50% chance of being heterozygous (unaffected carrier). But in autosomal dominant pattern of inheritance, affected individuals have one mutant copy of allele so every individual has 50% chance of being affected or being normal. In the pure congenital autosomal recessive optic atrophy, symptoms like visual impairment appear very early and are present at birth or appear in first year of life. Affected individuals are severely impaired visually leading to visual disability or complete blindness. It is never associated with neurological disorders. It can be diagnosed very early, usually before the age of 4 years. Fundus examination reveals optic disc pallor temporally or bilaterally. A cupping may develop with age [3]. Affected individuals suffer from central scotoma, photophobia and also have red green color confusion [6]. Family history is critical for diagnosis [Hereditaryà ¿opticà ¿neuropathies: from clinical signs to diagnosis]. Clinical diagnosis involves fundoscopy, visual field testing, fluorescein angiography, optical coherence tomography scan of the retinal nerve fiber layers, color vision analysis and standard electroretinogram. Damage from optic nerve atrophy cannot be reversed [4].To clinically distinguishes it from LHON flourscene angiography was done which fails to show any peripapillary microvascular changes, beside this retinal activity is also normal confirmed by electroretinogram. Pathology of arOA is confirmed by testing visual evoked potential which was totally absent in affected individuals. Central or cecocentral faults are diagnosed through visual field testing. Lesion in the fovea or papillomacular bundle leads to cental scotoma which ultimately affects the central fixation. Thinning of retinal nerve fiber layer is diagnosed through optical coherence tomography scan [3, 4, clinical diagnosis]. Papillomacular bundle leads to the extension of cecocentral sctoma towards blind spot. There is no effective treatment for optic atrophy because degeneration of nerve fibers is irreversible process. Although further damage can be prevented by early diagnosis and by treating underlying causes of the disorder [ net bookmark]. As environmental factor play their role in every aspect of life likewise in this disorder alcohol consumption and smoking should be strictly prohibited [Hereditaryopticneuropathies: from clinical signs to diagnosis]. Genetic counseling and proper awareness of people is very important to prevent such genetic disorders without any effective treatment. New therapies are being formulated by designing animal models or by clinical trial on affected humans these therapies mainly focuses in preventing oxidative stress. Animal models have been designed for testing the various treatments in case of Leber hereditary optic neuropathy [Treatment of hereditaryopticneuropathies]. arOA is divided into syndromic and non-syndromic form, syndromic arOA involve multiple organs other than eye which are effected just like wolfram syndrome [6, net bookmarks]. While in non-syndromic optic nerve is affected only and it also shows familial transmission more than one members of same family can also be affected [Hereditaryopticneuropathies: from clinical signs to diagnosis]. OPA 6 and 7 are the two loci which are characterized till now, mutation in any one of two leads to arOA. Disease causing gene has been localized at chromosome 8q21–q22 (Zmax of 3.41 at h ¼0 for D8S270). D8S1794 and D8S1702 markers present on OPA6 in a 12Mb interval [6]. OPA7 containing 40 known genes, only one gene TMEM126A screened as a causative agent of non-syndromic arOA [4, 7]. TMEM126A is homozygous nonsense mutation characterized as first known mutation in case of isolated arOA, this gene transcribed into mitochondrial transmembrane protein. TMEM126A helps in early nucleation of mitochondrial complexes that is why it is also termed as mitochondria-localized mRNA (MLR) protein. It play important role in function of retinal ganglion cells by arranging protein complexes essential for the proper functioning of RGCs. It is hypothesized that TMEM126A may accelerate the rate at which protein complex assemble, which otherwise occurs slowly that ultimately affect high energy demanding RGCs. While in other tissues the effect of this mutation may be substituted by some other protein of TMEM family [4, 7]. TMEM126A transcribe single ubiquitous transcript of 770bp that contain total five exons four coding and one non-coding exon. TMEM126A present on chromosome 11 and its span is 8.5 kb. Testis, fetal retinal pigmentary epithelium (RPE), fetal retina, brain (whole), cerebellum, fetal brain and skeletal muscle are the sites where strong expression of TMEM126A has been observed. Substantial amount of specific mRNA in the ganglion cell layer, optic nerve head, the outer ellipsoide length of photoreceptor inner segments, and the outer plexiform layer is detected by the process of insitu hybridization in mouse i.e. 8 month old. In the photoreceptor outer segments and outer nuclear layer (ONL) no labeling is noticed. Mitochondria specific Alpha subunit of the ATP synthase is Immunolocalized on retinal sections of the same mouse which resulted into the same pattern of expression. So it is confirmed that TMEM126A transcribe mitochondrial localized m RNA. Linkage analysis is the process helps in finding mutation or gene resulted into arOA. Potential functionality of genes with their chromosomal location is associated through this statistical method. During chromosomal recombination markers present closely or on the same area on chromosome will remain attached together are transmitted as such in offspring’s this idea is exploited in linkage analysis. If in an individual disease gene is transmitted along with some specific markers it means disease causing gene is present close to these markers. Those disorders that follow Mendelian inheritance pattern can easily be analyzed through this process [5]. This study will be the first step which further helps in identifying the causative gene responsible for arOA in Pakistani population and also help in designing therapeutic tools for the benefit of affected persons. By conducting these type of studies we can also aware our population about such type of rare disorders.

Ozymandias and Death the Leveller Essay

â€Å"Death is a leveller†, this statement implies that death makes everyone equal or ‘level’. In the poems, â€Å"Ozymandias† by Percy Bysshe Shelley and â€Å"Death the Leveller† by James Shirley, they each portray this in similar ways. Each refer to this statement by using the notion of a powerful figure, who would seem to be ‘invincible’, forgotten through time, hence forth, making them equal to people who would have achieved very little within their lifetime. In â€Å"Ozymandias†, Percy Bysshe Shelley relates a description of a mysterious land laid to waste. The speaker recalls having met a traveller â€Å"from an antique land,† who told him a story about the ruins of a statue in the desert of his native country. At the very beginning of the poem, Shelley creates a remote landscape, unknown by many therefore distancing the narration. The title â€Å"Ozymandias† refers to the great Egyptian King Rameses II. This unfamiliar name gives the impression to the reader that it will about someone anonymous though during his life, he would have been very influential on the world around him. â€Å"Half sunk, a shattered visage lies† denotes the face of the statue damaged and worn throughout time, metaphorically, like his power lost though time. Shelley then describes the face of the statue more, † whose frown and wrinkled lip, and sneer of cold command† implies that throughout this rein over Egypt, he was a forceful and merciless ruler and wanted to be known for that and sculptor himself, also makes show it is understood. â€Å"Which yet survive, stamped on these lifeless things† explains to the reader that even though part of the statue has survived the abuse from nature, it still means nothing as it stands in a desolate landscape undiscovered by many. This links back to his reputation’s destruction over time. However, Shelley adds â€Å"The hand that mocked them and the heart that fed† implying that even though he may have shunned those less powerful than him, in his heart, he did want them to survive in this ruling. â€Å"My name is Ozymandias, king of kings:  Look on my works, ye Mighty, and despair!†Ã‚  In this quotation, Shelley emphasises greatly the irony of this message scribed into his statue. Within Ozymandias’ time, this statue would have represented the fear he caused to his people and the power he possessed over them. Yet now, it lies crumbled and forgotten in the middle of a desert inhabited by no one with his city in ruins around him. Shelley expresses how even the mighty have no power of death and how they are forgotten. The following line says â€Å"Nothing besides remains†, as if Shelley mocks his once mighty power with a simple yet painfully truthful statement, showing that it is inevitable that nothing will make him remembered again. â€Å"Round the decay of that colossal wreck, boundless and bare  The lone and level sands stretch far away.†Ã‚  Shelley mentions the sand as level and stretching far away. Sand is related to hourglasses, used to measure time. He also says the sand is ‘level’ meaning that you could far around you and see nothing but the isolated environment around you. This links in with time making everything equal and making eventually forgotten, and how each piece of sand is indefinable from the other. Alliteration is used to create an effective rhythm within the last lines of the stanza. It creates a feeling of total certainty that this is how this statue, like Ozymandias’ reputation, will stand until it is worn away to become another grain of sand. This poem was written in the age when Napoleon Bonaparte was at his height of power, but Shelley believed this would eventually been his fate. ‘Death the Leveller’ was written by James Shirley the time when King Charles was reined over England. In that time period, many people did not wish to have a king; therefore, King Charles was eventually beheaded. The purpose of the poem was a warning to the King, showing that he had no escape from death, even with his courage a huge army. Shirley begins â€Å"The glories of our blood and state are shadows, not substantial things† denotes that how no matter how important your blood is or how powerful you are in life, death will make you as meaningful as a shadow, forgotten and neglected. Shirley then states how there is â€Å"no armour against fate† meaning that death is something you cannot escape, regardless of who you are within life. Shirley also makes death human like by saying it lays its â€Å"icy hand on kings†

Battle of Dien Bien Phu in the First Indochina War

The Battle of Dien Bien Phu was fought from March 13 to May 7, 1954, and was the decisive engagement of the First Indochina War (1946-1954), the precursor to the Vietnam War. In 1954, French forces in French Indochina sought to cut the Viet Minhs supply lines to Laos. To accomplish this, a large fortified base was constructed at Dien Bien Phu in northwest Vietnam. It was hoped that the presence of the base would draw the Viet Minh into a pitched battle where superior French firepower could destroy its army. Poorly sited in the low ground of the valley, the base was soon besieged by Viet Minh forces which used artillery and infantry assaults to grind down the enemy while also deploying a large number of anti-aircraft guns to prevent the French from resupplying or evacuating. In nearly two months of fighting, the entire French garrison was either killed or captured. The victory effectively ended the First Indochina War and led to the 1954 Geneva Accords which split the country into North and South Vietnam. Background With the First Indochina War going poorly for the French, Premier Rene Mayer dispatched General Henri Navarre to take command in May 1953. Arriving in Hanoi, Navarre found that no long-term plan existed for defeating the Viet Minh and that French forces simply reacted to the enemys moves. Believing that he was also tasked with defending neighboring Laos, Navarre sought an effective method for interdicting Viet Minh supply lines through the region. Working with Colonel Louis Berteil, the hedgehog concept was developed which called for French troops to establish fortified camps near Viet Minh supply routes. Supplied by air, the hedgehogs would allow French troops to block the Viet Minhs supplies, compelling them to fall back. The concept was largely based on the French success at the Battle of Na San in late 1952. General Vo Nguyen Giap. Photograph Source: Public Domain Holding the high ground around a fortified camp at Na San, French forces had repeatedly beaten back assaults by General Vo Nguyen Giaps Viet Minh troops. Navarre believed that the approach used at Na San could be enlarged to force the Viet Minh to commit to a large, pitched battle where superior French firepower could destroy Giaps army. Building the Base In June 1953, Major General Renà © Cogny first proposed the idea of creating a mooring point at Dien Bien Phu in northwest Vietnam. While Cogny had envisioned a lightly defended airbase, Navarre seized on the location for trying the hedgehog approach. Though his subordinates protested, pointing out that unlike Na San they would not hold the high ground around the camp, Navarre persisted and planning moved forward. On November 20, 1953, Operation Castor commenced and 9,000 French troops were dropped into the Dien Bien Phu area over the next three days. Colonel Christian de Castries. US Army With Colonel Christian de Castries in command, they quickly overcame local Viet Minh opposition and began building a series of eight fortified strong points. Given female names, de Castries headquarters was located in the center of four fortifications known as Huguette, Dominique, Claudine, and Eliane. To the north, northwest, and northeast were works dubbed Gabrielle, Anne-Marie, and Beatrice, while four miles to the south, Isabelle guarded the bases reserve airstrip. Over the coming weeks, de Castries garrison increased to 10,800 men supported by artillery and ten M24 Chaffee light tanks. Battle of Dien Bien Phu Conflict: First Indochina War (1946-1954)Dates: March 13-May 7, 1954Armies and Commanders:FrenchBrigadier General Christian de CastriesColonel Pierre LanglaisMajor General Rene Cogny10,800 men (March 13)Viet MinhVo Nguyen Giap48,000 men (March 13)Casualties:French: 2,293 killed, 5,195 wounded, and 10,998 capturedViet Minh: approx. 23,000 Under Siege Moving to attack the French, Giap dispatched troops against the fortified camp at Lai Chau, forcing the garrison to flee towards Dien Bien Phu. En route, the Viet Minh effectively destroyed the 2,100-man column and only 185 reached the new base on December 22. Seeing an opportunity at Dien Bien Phu, Giap moved approximately 50,000 men into the hills around the French position, as well as the bulk of his heavy artillery and anti-aircraft guns. The preponderance of Viet Minh guns came as a surprise to the French who did not believe that Giap possessed a large artillery arm. Though Viet Minh shells began falling on the French position on January 31, 1954, Giap did not open the battle in earnest until 5:00 PM on March 13. Utilizing a new moon, Viet Minh forces launched a massive assault on Beatrice behind a heavy barrage of artillery fire. French M24 Chaffee light tanks firing during the Battle of Dien Bien Phu, 1954. US Army Extensively trained for the operation, Viet Minh troops quickly overcame French opposition and secured the works. A French counterattack the next morning was easily defeated. The next day, artillery fire disabled the French airstrip forcing supplies to be dropped by parachute. That evening, Giap sent two regiments from the 308th Division against Gabrielle. Battling Algerian troops, they fought through the night. Hoping to relieve the beleaguered garrison, de Castries launched a counterattack north, but with little success. By 8:00 AM on March 15, the Algerians were forced to retreat. Two days later, Anne-Maries was easily taken when the Viet Minh were able to convince the Tai (a Vietnamese ethnic minority loyal to the French) soldiers manning it to defect. Though the next two weeks saw a lull in fighting, the French command structure was in tatters. The End Nears Despairing over the early defeats, de Castries secluded himself in his bunker and Colonel Pierre Langlais effectively took command of the garrison. During this time, Giap tightened his lines around the four central French fortifications. On March 30, after cutting off Isabelle, Giap began a series of assaults on the eastern bastions of Dominique and Eliane. Achieving a foothold in Dominique, the Viet Minhs advance was stopped by concentrated French artillery fire. Fighting raged in Dominique and Eliane through April 5, with the French desperately defending and counterattacking. Pausing, Giap shifted to trench warfare and attempted to isolate each French position. Over the next several days, fighting continued with heavy losses on both sides. With his mens morale sinking, Giap was forced to call for reinforcements from Laos. While the battle raged on the eastern side, Viet Minh forces succeeded in penetrating Huguette and by April 22 had captured 90% of the air strip. This made resupply, which had been difficult due to heavy anti-aircraft fire, next to impossible. Between May 1 and May 7, Giap renewed his assault and succeeded in overrunning the defenders. Fighting to the end, the last French resistance ended by nightfall on May 7. French prisoners of war are marched out of Dien Bien Phu, 1954. Public Domain Aftermath A disaster for the French, losses at Dien Bien Phu numbered 2,293 killed, 5,195 wounded, and 10,998 captured. Viet Minh casualties are estimated at around 23,000. The defeat at Dien Bien Phu marked the end of the First Indochina War and spurred peace negotiations which were ongoing in Geneva. The resulting 1954 Geneva Accords partitioned the country at the 17th Parallel and created a communist state in the north and a democratic state in the south. The resulting conflict between these two regimes ultimately grew into the Vietnam War.