Level of VEGF in Chronic Nephropathy Models

Level of VEGF in Chronic Nephropathy Models The number of patients with chronic kidney disease (CKD) progressing to end-stage renal disease (ESRD) and requiring renal replacement therapy are increasing worldwide. In India, the age-adjusted incidence rate of ESRD is estimated to be 229 per million population (pmp), and >100,000 new patients enter renal replacement programs annually (1). Diabetic nephropathy (DN) is the most common cause of ESRD development among other disorders predisposing to ESRD. The costs of DN are significantly higher than those from other diabetic complications because the patients are subjected to haemodialysis programs and renal transplant when failure occurs. Thus, the burden of DN on public health is enormous (2). The current therapy for patients with renal injury includes glycemic control by antidiabetic medications. Blockage of renin angiotensin system (RAS) is the most commonly practiced way of controlling blood pressure in DN. However, angiotensin-converting enzyme inhibitors and angiotensin recep tor blockers moderately slow the rate of progression but do not arrest or reverse the progression of disease. Moreover, RAS blockade is usually initiated only after DN manifests itself clinically with persistent proteinuria in both type 1 and type 2 diabetes. But despite knowledge of the devastating effects of these complications and the involved costs to patients, to date, there is still no method that is sufficiently sensitive and accurate for subclinical diagnoses of diabetic nephropathy. The pathomechanisms leading to these changes are not yet clearly understood and therefore, therapeutic approaches for relief of this disease are scarce or do not permit a favorable pharmacological intervention. Angiogenesis the development of new blood vessels from pre-existing ones is involved in physiological events and in pathological disorders including cancer, proliferative retinopathy, rheumatoid arthritis, psoriasis, and neointimal formation. Angiogenesis is controlled by the balance between proangiogenic and anti-angiogenic factors. Experimental studies have demonstrated the involvement of an imbalance of angiogenesis-related factors in the progression of CKD and the potential therapeutic effects of modulating these factors have been identified (3, 4). Vascular endothelial growth factor (VEGF)-A, a potent pro-angiogenic factor, is involved in the development of the kidney, and also plays an important role in maintaining the glomerular capillary structure and in the repair process following injuries of glomerular endothelial cells and peritubular capillaries (5-7). It is constitutively expressed in podocytes, proximal tubular cells and medullary thick ascending limb cells in the ju xtamedullary region of the normal kidney. Evidence is emerging that VEGF plays a critical role in maintaining renal homeostasis (8, 9). Altered (increased or decreased) expression of VEGF leads to glomerular dysfunction and proteinuria (3, 10-15). It has been demonstrated that VEGF administration has a beneficial effect in both acute and chronic nondiabetic renal disease. In the remnant kidney model and cyclosporine nephropathy, decreased VEGF expression was observed. These observations were correlated with renal dysfunction and capillary loss. VEGF administration was found to reverse the renal dysfunction in these models (4, 16, 17). In contrast, both circulating and local VEGF levels are high in diabetes. In diabetic nephropathy , the increases in the number of glomerular capillaries and in the glomerular levels of VEGF-A and its receptor VEGFR-2 are observed (3, 18). The role of abnormal angiogenesis induced by VEGF has been implicated in diabetic retinopathy and diabetic nephrop athy associated with progression of disease and the excessive VEGF has been shown to have a role in mediating glomerular hypertrophy (3). The precise mechanism is unclear for contradictory status of VEGF-A in diabetic and non diabetic kidney disease. So, in the present study we decided to investigate the level of VEGF in two different chronic nephropathy models; one was diabetes induced chronic nephropathy and the other was non diabetic nephropathy. VEGF and NO interaction has been explained as one of the regulating mechanism in causing paradoxical effects of VEGF by Takahiko Nakagawa et al.; 2007. The author explained the dark side and the bright side of VEGF effects. VEGF normally stimulates endothelial nitric oxide (NO) release and acts in coordination with elevated NO levels as a trophic factor for vascular endothelium. The increased NO derived from the endothelial cell acts as an inhibitory factor that prevents excess endothelial cell proliferation, vascular smooth muscle cell proliferation, and macrophage infiltration. Normally, an elevation in VEGF expression should result in elevated endothelial NO levels, since VEGF increases both endothelial NOS (eNOS) expression and NO release from endothelial cells. However, in diabetes, despite high levels of VEGF, endothelial NO levels are low. The authors have summarized several mechanisms to explain the low endothelial NO bioavailability. First, glucose can scavenge NO. Second, t here is an impairment of eNOS activation. A third mechanism could be oxidative stress, which quenches NO to form peroxynitrite. Fourth, the formation of advanced glycation products in diabetes may also result in the consumption of endothelial NO. Fifth, both asymmetric dimethyl arginine and uric acid are commonly elevated in diabetes and can reduce endothelial NO bioavailability. Finally, NO may bind to glycosylated deoxyhemoglobin. Thus in diabetic settings high levels of VEGF, in absence of NO; lead to excessive endothelial cell proliferation, stimulation of macrophage chemotaxis, and vascular smooth muscle cell activation resulting in vascular injury (19, 20). Based on these observations we decided to investigate level of NO, in addition to VEGF; in two different chronic nephropathy models. The therapeutic effects of anti-VEGF-A strategies and anti-angiogenic factors in diabetic nephropathy have been reported (21). The beneficial effects of administration of VEGF in non diabetic CKD have been reported (17). The contrasting effects of VEGF in non-diabetic and diabetic kidney disease prompted us to review factors modulating VEGF expression in CKD. Hypoxia and certain cytokines are major regulators of VEGF expression (22-29). Physiological adaptation to hypoxia is an area of intense investigation. Adenosine is a critical mediator during ischemia and hypoxia and contributes to diseases as diverse as inflammation and carcinogenesis (30). Inhibition of adenosine kinase and the dephosphorylation of ATP and AMP by surface apyrases (e.g., CD39) and ecto-5’ nucleotidase (CD73), respectively, represent the major pathways of extracellular adenosine liberation during oxygen supply imbalances. Once liberated in the extracellular space, adenosine is either recycled (e.g., throu gh dipyridamole-sensitive carriers) or interacts with cell surface Adenosine Receptors (ARs). Presently, four subtypes of G protein-coupled ARs exist, designated A1, A2A, A2B, and A3. They are classified according to utilization of pertussis toxin sensitive pathways (A1 and A3) or adenylate cyclase (A2A and A2B). The A2BAR have been recently much investigated for their role on renal functions. A2BAR have been reported to inhibit PDGF induced growth of mesangial cells ,they also protect the kidney from ischemia (31, 32). A2BAR have also been reported to inhibit inflammation, so it is remained to be determined which type of A2AR are involved in inflammation associated with diabetic nephropathy. A2B receptors have a lower affinity compared with other subtypes and require higher concentrations of adenosine for their stimulation and such high levels can be reached during hypoxia, ischemia, inflammation, and injury. A2BAR regulate various pathological processes, including mast cell activation, vasodilatation, inhibition of cardiac fibroblast and vascular smooth muscle growth, stimulation of endothelial cell (EC) growth, and angiogenesis (8,9,10,11,12). The functional aspects of ARs responses may be determined by surface expression profiles. Microarray analyses of cDNA derived from endothelial cells subjected to various periods of hypoxia revealed significant changes in the ARs profile, wherein the prominent phenotypic change favored A2BAR expression, with concomitant down regulation of A1AR and A3AR(2). As chronic state of nephropathy also involve hypoxic intra renal environment (33), we decided to find the expression of A2BAR in two different models of chronic nephropathy. The most potent stimuli for VEGF production is hypoxia as stated above. The evidence of line also suggests the hyperglycemic state of diabetes to be hypoxic. Particularly, it has been demonstrated that in a mouse podocytes cell line the expression of VEGF increases under exposition to high D-glucose concentrations. At present however, it is not clear how glomerular VEGF production is unregulated in response to diabetes or high glucose concentration (13). Ex vivo exposure of rat kidney glomeruli to adenosine leads to an increase in VEGF content. Activation of A2BAR subtypes augments expression and releases VEGF beyond basal levels in rat glomeruli. Additionally, the status of VEGF and NO axis in non diabetic nephropathy is not well investigated. Based on these observations we decided to investigate the effects of A2BAR modulators on VEGF and NO in chronic diabetic nephropathy. Reconstitution of endothelial NO synthesis and/or its availability in glomeruli of diabetic nephropathy anima l models via the A2BAR modulation, remains an interesting matter. We thus hypothesize that differential expression of VEGF in diabetic and non-diabetic kidney diseases is mediated by A2BAR. The expression of A2B receptor is disease specific. Cyclosporine A (CsA) is a potent immunosuppressive agent with definite efficacy to prevent organ allograft rejection. However, CsA causes significant nephrotoxicity that might contribute to long-term kidney graft loss (34). Acute CsA nephrotoxicity is characterized by renal vasoconstriction, which is dose-related and reversible with dose reduction. In contrast, chronic CsA nephrotoxicity may be progressive and irreversible, the histological lesion of which includes tubular atrophy, afferent arteriolar hyalinosis. We resolved to investigate the mechanisms of cyclosporine induced nephropathy as non diabetic chronic nephropathy model in present study. A line of evidence has demonstrated reduction in vascular endothelial growth factor (VEGF) and nitric oxide (NO) in CsA nephropathy(35, 36). VEGF is an endothelial cell mitogen that increases angiogenesis and vascular permeability. Endogenous VEGF has a relevant role in the renal tubular defense against CsA toxicity. Blockade of the VEGF by ÃŽ ±-VEGF results in intensification of the tubular injury the CsA nephropathy(37). The occurrence of both in-vivo and in-vitro effects of VEGF blockade provides evidence of a direct protective effect of VEGF on the tubular cell. Numerous studies have reported a important role of NO in regulation of the effects of VEGF on angiogenesis, vascular permeability, and blood pressure regulation (38, 39). A2BAR have been known to mediate NO release in various pathological settings (40, 41). In the late phase of CsA nephropathy, nitric oxide synthase activation is reduced (42). However, it is necessary to determine whether or not A2BAR agonist induces VEGF in chronic CsA nephropathy. Previous in vitro studies using vascular smooth muscle cells as well as macrophages suggest administration of A2BAR agonists results in increased VEGF expression, potentially stimulating angiogenesis. Accordingly, it was hypothesized that A2BAR agonists induce expression of key angiogenic factors such as VEGF in CsA induced chronic nephropathy. Such an increase in renal VEGF expression by A2BAR activators may initiate the angiogenic response at the site of renal injury. Hence present study was designed to investigate the effects of A2BAR modulators on VEGF expression and NO levels in kidneys of chronic CsA induced nephropathy.

Gone with the Wind Essay

â€Å"Gone with the Wind† is an adaptation of an historical romance. The film, set in Civil War-era southern United States, tends to be highly sentimental. Paradoxically, the circumstances in which it is set are often harrowing and serve to highlight the bravery required to survive during that time. The â€Å"frothiness† of the plot is in stark contrast to the utter seriousness of its context. The film opens in the antebellum South, on a Georgia plantation where the heroine entertains two gentlemen callers. The talk is of imminent war, a theme which guests carry through the subsequent picnic. Talk then turns to action and the men depart to enlist in the Confederate Army. Confidence and jubilation quickly become disappointment which gives way to horror as the realities of war intrude upon the genteel tableau. Under assault, the Southerners struggle to keep their society together in the face of poverty, filth, and chaos. We see the major historical points of the period, especially Sherman’s march through Georgia and the burning of Atlanta, a scorched earth policy. The women are the main characters in the film. In the effects of war and its aftermath we see destitution, famine, terror, desperation. The wounded are legion and supplies dwindle and disappear. The war ends and the soldiers come home to regroup. Carpetbaggers descend and begin an uneasy alliance with enterprising individuals, notably Scarlett. She casts aside honor to regain prosperity, marrying for money and using her combination of feminine wiles and shrewdness to rise above abject poverty. Finally she marries Rhett, a selfish opportunist like her. At the end he realizes that she will never love him and leaves Scarlett with that which has sustained her; an abiding love for Tara. This narrative is history seen from the women’s perspective. They are alternately brave, childish, and childlike, treading on the line between what they are and what they must be. They do it for the men of the South, themselves, and for the South itself. The depiction of the war and the events surrounding it is largely consistent with the historical record. The factual portions of the film are in part accurate. For instance, at a benefit supporting the war, the ladies are asked to relinquish their jewelry. Such a depiction is consistent with the account in â€Å"The American Civil War† by Peter J. Parish and it highlights one of the sacrifices women made during this time. George A. Trenholm, who replaced Secretary of the Confederate Treasury Memminger, asked for these concessions as the finances of the South became particularly desperate. This detail concerns one of the points at which â€Å"Gone With the Wind† succeeds as history. â€Å"†¦wealthy female slaveholders escaped significant disruption in their lives at the outset of the war, for they had money to maintain their antebellum lifestyle and the slaves to maintain plantation production. † (Frank 514) Thus the sheltered experience depicted in the film is wholly consistent with rich women’s lives until the last stages of the period. In opposition, several events as depicted in â€Å"Gone with the Wind† are inaccurate. At the end and after the war, black people did not leap to the aid of their former masters as the film asserts. The character Mammy would have sought paid employment rather than stay on a ruined plantation. In reality, the vast majority of the planters used violence to subjugate their â€Å"property. † In one scene, the character Ashley Wilkes chides Scarlett for treating the convict workers in her lumber mill cruelly in supposed contrast with their treatment of the slaves. It is true that in the darkest days for the South they did choose to prevail upon the Negroes to fight for their own oppression. â€Å"There was no greater irony in all the efforts of the Confederacy to find adequate means to match its ambitious goals than the proposal to arm Negroes. † (Parish 561) But the slaves did not fight for the South as much for a newfound and cherished liberty, greater than they had ever known. And once they had tasted that liberty, they did not willingly acquiesce in the imposition of a terrible, unjust burden. The importance of the Civil War and its aftermath can hardly be overstated. The struggle has been the only armed conflict fought on our territory. It consumed nearly 500,000 lives, the largest wartime death toll in American history. It also was a first step in remedying the shame of slavery which Americans had perpetrated in a country which largely had been the realization of a vision of freedom and equality. They fought with not only the political reality of the South’s secession of 1861, but with the region’s separate psychology. â€Å"By 1860 the South was a state of mind as well as a place on the map. A definition of ‘Southernness’ was and is at least as much a task for the psychologist as for the geographer. † (Parish 303) This enduring mindset notwithstanding, had the South won, not only would the crime of slavery have been continued, it is doubtful that the U. S. would have grown into the superpower it is today. The war determined that an integral part of the union would remain. The significance of the war for the world at large in the mid-nineteenth century â€Å"†¦belongs in part to the realm of might-have-beens; its long-term consequences derived less from what did happen from what did not. † (Parish 381) Among the events that very well might have happened were interference from foreign governments, international recognition of the Confederacy, and the widening of this internecine war into a general conflagration abroad. Such luck for the union was due to the relative isolation the U. S. has enjoyed throughout its history. Americans fought their war amid constant threats from abroad. â€Å"There was nothing inevitable about the fact that it remained a domestic†¦affair. It remained a purely American affair through a combination of good fortune and great skill on the part of those who wished to keep it so, gross errors on the part of those who did not, and canny calculations of national and self-interest on the part of those who might have been caught in its toils. † (Parish 381) Although some continue to fight this war in their minds, they benefit from over 200 years of federal association and its attendant largess. As I stated earlier, with regard to the historical accuracy of the film as document, it is a women’s narrative. Though there was no Scarlett O’Hara per se, the things we see her experience and perpetrate on others is consistent with the accounts of those who actually lived in that time and place. The threat of starvation was indeed present in all households in the later stages. â€Å"Domestic production and ingenuity staved off a state of crisis for slaveholding women for a while, but, by the end of the war starvation and material deprivation shook even the most affluent households. † (Frank 515) When Scarlett was forced to hide her wagon under a bridge with three highly vulnerable people in it while Northern soldiers passed overhead, she was surviving a circumstance familiar to many Southern women. â€Å"†¦many faced the hazards of living in the path of the Union army. Those who resided near the battlefront risked having their property commandeered, stolen, or destroyed by Northern soldiers. (Frank 515) Such dangers were in addition to the threat, both potential and realized, of bodily violation. Scarlett valiantly, not to say desperately, defends herself and her loved ones against a looting Union soldier when she shoots him in the face. It is an act not uncommon to those willing and able to defend themselves. The depiction of slave and ex-slave loyalty is highly romanticized to say the least. â€Å"Gone with the Wind† depicts Negroes as possessing a childlike innocence. They seem to be a rich vein of merriment instead of the human beings upon which the horrors of bondage had been visited. Nowhere do we see slavery’s pain and degradation. The black characters in the film are even more a caricature than even the heroine is at times. The film’s tendency toward opaque sentiment at first glance is a terrible injustice to a period quite painful to the American psyche be it black or white, Northern or Southern. Certainly the film is nowhere near the caliber of slave narratives, Ken Burns’ â€Å"the Civil War†, or â€Å"Uncle Tom’s Cabin. † However, it is important as hitherto all-too-often neglected genre of women’s history. Seldom in mainstream culture is the women’s perspective represented so faithfully. And equally seldom is it given the attention and resources devoted to this film. It is simply not taken seriously enough and shunted off into women’s studies classes rather than included in the mainstream of scholarship. Valuable though they are, the women’s studies classes or gender studies courses tend to attract the favor of those predisposed to appreciate them. â€Å"Gone With the Wind†, for a long while a staple of popular culture, has reached a much wider audience. In many ways this movie is indeed an historical romance, ladies’ fiction. However it is also a significant historical document. Many more people have learned about the Civil War from the women’s point of view by means of viewing this film than from any other source. This fact, in addition to its inclusion of important data, renders it deserving of attention and respect. For instance, it highlights the worthlessness of the Confederate currency, a situation which underscores the sheer lack of administrative competence displayed in the South at all stages of the war. Not only did the Confederates fight the North, they also had to contend with the inherent weaknesses of their fledgling nation, as they sought to envision it. Many things weakened â€Å"The Cause†, most notably slavery’s lack of long-term viability as an economic model. The South was heavily invested in a system which had no hope of succeeding beyond a few years. To a great extent, the Confederacy fell under its own weight, much to the past and continuing chagrin if its champions and much to the edification of the nation of which it is a part as well as humankind in general. If only the proof of that assertion would not have required the death of so many and the maiming of still more. Bibliography Frank, Lisa Tendrich. Women in the American Civil War Vol. II. Santa Barbara: ABC-CLIO, Inc. , 2008 Parish, Peter J. American Civil War, the. New York: Holmes and Meier, 1975.

Nonverbal Communication and Service Users

Be able to meet the communication and language needs, wishes and preferences of individuals 1. Find out an individual’s communication and language needs, wishes and preferences. 2. Demonstrate communication methods that meet an individual’s communication needs, wishes and preferences. 3. Show how and when to seek advice about communication. It is always important to find out about each individual’s particular communication and language needs, wishes and preferences.Effective communication happens when the right method is used to send a message, so it can be received and understood. Health and social care practitioners need to know about a range of communication methods. They should also be skilled at identifying the communication and language needs, wishes and preferences of the people with whom they work and interact. Health and social care settings are used by people from a diverse range of backgrounds who will want to communicate in different ways.Finding out about each individual’s language needs, wishes and preferences is an important part of my role. I can do this by: †¢asking people whether they or their relatives have particular language or communication needs †¢reading reports and notes about service users that provide information on speech and language issues, learning difficulties, disabilities (e. g. hearing or visual impairment) or physical conditions (e. g. troke, cleft palate) that may affect their ability to communicate †¢being aware that an individual’s culture, ethnicity and nationality may affect their language preferences and needs †¢observing the people who use my setting to see how they use their communication and language skills †¢asking my supervisor/mentor, senior staff and specialist professionals such as speech and language therapists, occupational therapists and social workers for information, advice and support about how best to communicate with adults who have special comm unication needs.Hearing impaired people Make sure that my face can be seen clearly,face the light and the person I am speaking to at all times, speak clearly and slowly – repeat and rephrase if necessary, minimise background noise,use my eyes, facial expressions and gestures to communicate, where appropriate, do not be tempted to shout into a person’s ear or hearing aid. Visually impaired people Speak in the same way as I would to a sighted person – not louder or more slowly! say who I am in my greeting as my voice won’t necessarily be recognised even if I have met the person before, always introduce other people who are with me and explain what is going on if a visually impaired adult joins me in a group, let the visually impaired person know when I am about to do something that is likely to affect communication (such as leave the room or move away), end conversations clearly and let the person know that I amleaving – do not just walk away, ask th e person if they need any particular help – to sit down or to move about, for example – but do not assume that this is always necessary or wanted.Health and social care practitioners use two main types of communication as part of their work roles. These are verbal and non-verbal communication. Verbal communication is based on the use of words. Health and social care practitioners need effective verbal skills to: ? obtain information from colleagues, service users and others who use the setting ? respond to questions ?contribute to team meetings ?give feedback and report observations about service users ? provide support to service users, relatives and colleagues ? eal with problems and complaints ?write notes and reports Non-verbal communication occurs when a person uses their body, behaviour and appearance to communicate with others. For example, an individual’s body language may tell a health or social care practitioner that they are uncomfortable or need to g o to the toilet even when they say they’re okay. Non-verbal communicationWhat does it involve? Examples Eye contactLooking another person directly in the eyesShort or broken eye contact can express nervousness, shyness or mistrust.Long unbroken eye contact can express interest, attraction or hostility. Touch Physically touching or holding a personHolding someone’s hand Placing a hand on a person’s arm or shoulder to reassure them Physical gesturesDeliberate movements of the hands to express meaningThumbs-up gesture to show agreement or pleasure Shaking a fist to show anger or aggression Body language Facial expressionMovements of the face that express a person’s feelingsSmiling FrowningProximityThe physical closeness between people during interactionsBeing very close may be reassuring and may be seen as accepting the person. It might also make the person feel uncomfortable and threatened. People need less personal space (increased proximity) when they hav e a close, trusting relationship. To be an effective communicator in my work setting, I need to be able to use methods of communication that meet each individual’s needs, wishes and preferences. My goal is always to ensure that the messages I send can be received and understood.Perhaps I will be aware that I am struggling to communicate effectively with somebody. In situations like these, I should seek advice and obtain support. I can do this by: ?talking to my supervisor, mentor or line manager about the difficulty – ask for their advice about how to deal with the problem ? talking to communication or language support specialists (teachers, psychologists or speech and language therapists) who work at or spend time in my work setting.

Summary Of My Antonia - 2373 Words

My à ntonia Quotes â€Å"There in the shelter draw-bottom the wind did not blow very hard, but I could hear it singing its humming tune up on a level, and I could see the tall grasses wave.†pg. 14 This quote tells readers how even small things such as the soft blow of the wind can cause many things to happen, such as the humming of the wind and the grass’s movements.It also symbolizes how the world is at peace right now. The tone of this quote is in a describing manner by the details they provide in this quote. These all contribute to helping the reader understand the scene in Jim’s point of view. â€Å"Perhaps we feel like that when we die and become part of something entire, whether it is sun and air, or goodness and knowledge. At any rate, that is happiness; to be dissolved into something complete and great. When it comes to one, it comes as naturally as sleep.†pg. 14 This is a theme in this story telling us how real happiness lies with something greater such as knowledge rather than stuff bought. The tone of this quote is very serious to help the reader understand what he is talking about. â€Å"This is reality, whether you like it or not. All those frivolities of summer, the light and shadow, the living mask of green that trembled over everything, they were lies, and this is what was underneath. This is truth.† pg. 112 This quotes tone is very straightforward and it serves as a theme showing how some things are not real. The way this quote is written helps tells the reader that thisShow MoreRelatedSummary Of My Antonia Written By Willa Cather1006 Words    |  5 Pageshistorical drama of My Antonia written by Willa Cather, describes a special bond between Jim and Antonia. 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