Sunday, March 31, 2019

Role of mTOR in Pain

Role of mTOR in paroxysmful sensationJuliette LanskeyIntroductionPain comprehension cling tos the human body from damage, yet when the underlying mechanisms be disrupted hassle lot become a debilitating condition. at that place are about 10 million Britains that suffer from hurting on a cursory basis concerning not only their personal wellbeing and persona of life plainly also the economy. Back bother is an example of degenerative wo(e) and back pain alone costs the NHS around 5billion per annum and it was describe that 4.9 million days are lost per year to british businesses (http//www.britishpainsociety.org/media_faq.htm). Unfortunately, misgiving the mechanisms that go awry leading to pain that is more harmful than near is proving challenging. As a result, there is a deficit in interferences easy to accommodate chronic pain despite much research. There is hence an urgent requirement to understand the mechanisms underlying pain perception in order for the development of therapeutics to reduce the sufferings of humans and the economy. This dissertation shall focus on a potential target, the mammalian target of rapamycin (mTOR), which recent research has highlighted as playing a significant use of goods and services in chronic pain.Pain PathwaysThe processing of painful stimuli by the nervous system is termed nociception. Pain is nociception with surplus psychological and emotional inputs. Noxious stimuli cause an operation potential to sour through a specialised set of neurons termed by Sherrington in 1906 as nociceptors the pain neurons. Nociceptors take in free nerve endings to detect noxious stimuli and can be classified into two main groups taking messages from the periphery to the telephone exchange nervous system, called A and C fibres. A fibres are medium-diameter, mylinated neurons and this myelination and wider diameter allows quick signal conduction. It is the A fibres that transmit the first, sharp, local anesthetic ised pain of an tarnish whilst C fibres which are small-diameter, unmyelinated neurons transmit slow, diffuse, substitute(prenominal) pain 2009CELLULARANDMOLECULAR. Hence A fibres are crucial in rapidly signalling an injury whilst the slow, burning pain from C fibres is important for protection during the healing period.These primary afferent nociceptors murder messages from the periphery to the abaxial horn of the spinal anaesthesia chord. The dorsal horn is fussyly important for processing and modulating noxious information. The dorsal horn is composed of half dozen rexed laminae with transition zones approximately dividing different prison cell types. Indeed, nociceptors can in particular laminae. The studyity of A fibres terminate densely in lamina I, though whatsoever do also terminate in lamina V. C fibres mainly terminate in laminae I and II, although there are also a few C fibre terminations in lamina V. Thus the majority of neurons which terminate in the superfici al dorsal horn specifically reply to noxious stimuli enchantment neurons terminating deeper in the dorsal horn tend to respond to innocurous touch (large diameter, rapid conducting A fibres transmit much(prenominal) innocuous information CELLULARANDMECHANMECHS2009).It is within the dorsal horn that nociceptors synapse onto commutation projection neurons which transmit the noxious information up to the brain. The main central pathways run up to the brain via the thalamus or brain stem and terminate in areas such as the periaqueductal grey and the parabrachial nucleus REF. There are also descending pain pathways originating in the periaqueductal grey, rostral ventral myeline and coeruleus which pass signals to the dorsal horn modulating nociception. There are also modulating circuits in the dorsal horn composing of exitatory and inhibitory interneurons contacting further neurons in the spinal cord (Fields2006thesis). Nociceptors have a pseudo-unipolar morphology allowing bidirect ional signalling. This means that nociceptors are able to transmit action potentials antidromically from the the central nervous system to the nociceptor terminals (Dubin, 2010).A result of central processing is increase sensitivity of the area at and around a site of tissue damage or redness (PUBHUNT). A chemical soup of cytokines and growth incidentors is released at the site of injury and causes an increase in the sensitivity of a subset of surrounding nociceptors. This means that these nociceptors have a reduced threshold for noxious stimuli (thus will now respond to less intense stimuli than before) and also an increased response to noxious stimuli. This sensitizing of neurons at the site of injury is called primary hyperalgesia. mTOR inhibitors do not postulate primary hyperalgesia and thus it is unlikely mTOR is involved, however there is another phenomenon called secondary hyperalgesia which mTOR does seem to be involved in. Secondary hyperalgesia is when a set of neuron s not directly at the site of injury but in the surrounding, unbroken area undergo an increase in sensitivity due to central processing (pubhunt). Recent studies have demonstrated that the mTOR plays a graphic symbol in creating this sensitivity.Acute pain is the pain that follows immediately after an injury to protect the body from further damage and aid the process of healing but when pain exists for more than 3 months it is defined as chronic pain (SITETHESISMerskey and Bogduk, 1994 Russo and Brose, 1998). This chronic pain does not protect the body but kinda hinders the quality of life. The pathology of chronic pain often consists of decreased pain thresholds and increased response to stimsuli the nociceptors are more sensitive. Moreover, whilst nociceptors are generally silent, firing action potentials only when stimulated (dubin2010), in chronic pain, there is an increased angle of dip for spontaneous activity (JULIUSANDBASBAUMTHESIS). Altogether, chronic pain leads to all odynia (pain from a normally non-noxious stimulus), hyperalgesia (heightened sensitivity to noxious stimuli) and spontaneous pain.mtorThe mammalian target of rapamycin is a regulator a bend of cellular processes including synaptic flexibleity, protein deduction and cellular metabolism (XONCUETALTHESIS). It is a shred belonging to the kinase family and forms two heterogeneouses with raptor mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). It is when part of these complexes that it administrates its cellular functions though much more is know about mTORC1 and so it is predominantly the role of mTORC1 in pain perception that this dissertation shall focus on.Signalling cascadeThere is a signalling cascade involving mTOR, the follow upriver targets of which lead to cellular activities resulting in the organisation of the cytoskeleton, the ruler of metabolism and cell survival (wullschlegerTHESIS). The signalling cascade is initiated by a signal such as a neurotransmitter actin g on transmembrane receptors which activate phosphoinosital 3 kinase-AKT pathway. This results in the phosphorylation and thereby the activation of mTOR. Phosphorylated mTOR in turn phosphorylates the 4E- constipateing protein and in this phosphorylated state the 4E-binding protein is unable to bind and thus inhibit a protein called eIF4E. So when mTOR is activated it has the downstream affect of enabling eIF4E to associate with eIF4G, this is an essential step for initiating comment (TJ PRICE GERANTON).The fact that mTOR plays such a significant role in the regulation of version is a hint of its importance in pain plasticity. Previously, it was thought by some that translation could only occur in the cell soma. but, others noted both the half-life of axonal proteins and the time it takes for a protein to travel down the length of the axon and concluded that the axoplasmic transport is too slow for protein synthesis only to occur in the cell soma HUNT. Indeed, following the disc overy of ribosomes and Golgi outposts in dendritic spines it is now believed that local protein synthesis at the sites of dendritic synapses plays a significant role in plasticity (2009REVIEW).Research demonstrates that chronic pain arises as a result of plastic changes that occur during contumacious acute pain. During any pain there are noxious signals to the central nervous system enabling the pain to be perceived, if these signals persist it has been shown that this causes and maintains plastic changes that result in chronic pain. Indeed, it has been shown through advanced structural visualize methods that there are large scale alterations in the brain mental synthesis of sufferers of chronic pain CHRONICPAINPLASTICITY. There is relatively little research into the possibilities of targeting this pain plasticity to help patients cope with chronic pain in comparability with genetic studies. It is consequentially an exciting new avenue of exploration and the role of mTOR in pain plasticity is of particular interest.EARLIER As mTOR plays such a crucial role in cellular function it is unsurprising that mTOR dysfunction is believe to be involved in a number of maladies. The role of mTOR in cancer, diabetes and neurodegeneration is being explored and a number of mTOR inhibitors have already been tested for treating certain maladies. For example..This has demonstrated that mTOR inhibitors are potential treatment regimes BUT THERE ARE SIDEEFFECTSMTOR THESISMTOR SIGNALLINGMTOR PLASTICITY see 2009reviewnociception and AMPKPG 6 is v goodDealing with pain MTOR AND RESEARCH thesis2 Pain Pathways and Plasticity3 The mammalian target of rapamycin 2007 Decreased nociceptive Sensitization in Mice Lacking the slight X Mental subnormality Protein Role of mGluR1/5 and mTOR mTORs role in nociceptive synaptic plasticity through translation regulation the mTOR inhibitor rapamycin inhibited formalin- and DHPG-induced nociception. mTOR is a major regulator of protein sy nthesis for it go fors the asylum of translation (PUBLISHEDHUNT2009). It is thought that by irresponsible protein translation it maintains the sensitivity of nociceptors following local injury. Targetting mTOR could reduce the secondary hyperalgesia that occurs from pain and thus help patients cope with pain4 The mTOR signalling cascadeunicellular organisms that are sensitive to nutrient availability in their environment control translation via a rapamycin-sensitive translation pathway. This process is controlled by a protein kinase, TOR, which is barricade by rapamycin. Interestingly, neurons appear to have co-opted this evolutionarily conserved mechanism to control activity-dependent local translation. Mammalian TOR, or mTOR, is activated by neurotransmitter receptor signaling fall and phosphorylates downstream meanss that control translation. Hence, mTOR is intricately involved in synaptic plasticity in the CNS, a mechanism that is linked to its role in exacting translatio n in dendrites (Jaworskiet al., 2006). The major mechanism of mTOR-regulated translation is control of the instauration of cap-dependent translation (depicted in Fig 1) (Gingras et al., 2004). This occurs because one of the major targets of mTOR phosphorylation is the extension associated factor 4E-BP (Gingraset al., 1999). 4E-BP binds c cap-binding factor eIF4E and, when it is hypo-phosphorylated, inhibits the formation of the eIF4E/eIF4G elongation complex preventing translation. When 4E-BP is hyper-phosphorylated, 4E-BP dissociates from eIF4E allowing eIF4G binding and the initiation of cap-dependent translation. Recently a small molecule inhibitor of eIF4G binding to eIF4E was discovered (4EGI-1) and this molecule inhibits cap-dependent translation (Moerke et al., 2007). Hence, mTOR is crucial for regulating activity-dependent translation in neurons via its regulation of elongation factors (Bankoet al., 2006 Tanget al., 2002 Tsokaset al., 2007) and the mTOR pathway is amenable to specific pharmacological manipulation.6 Experiments suggesting inhibiting mTOR could help control pain2007 Decreased Nociceptive Sensitization in Mice Lacking the Fragile X Mental Retardation Protein Role of mGluR1/5 and mTOR mTORs role in nociceptive synaptic plasticity through translation regulation the mTOR inhibitor rapamycin inhibited formalin- and DHPG-induced nociceptionNOT THAT RELEVANT basically saying that because of mutation translation cant happen properlymeaning mTOR has less control. However there is a subsection with rapamycin injections which does show decreased nociception with rapamycin2011 systemic proscription of mTOR mTOR regulation of nociceptive sensitivity inhibiting the mTORC1 pathway systemically alleviated mechanical hypersensitivity in mouse modelsGood intro relating mTOR to chronic painLocal epidermic intrathecal administration of rapamycin blocks activation of downstream targets of mTORC1 alleviating mechanical hypersensitivity 21, 29 3 43 46 62 SHOULD PUT 1 OR 2 local anesthetic EXPERIMENTS BEFORE THIS ONEIf targeting mTORC1 signaling pathway has a potential thera- peutic performance for controlling chronic pain, systemic rather than local administration (as has been use previously 21,29) requires further investigation. Here we examined the effective- ness of temsirolimus (CCI-779), a clinically apply rapamycin ester derivative, given systemically

Saturday, March 30, 2019

Housing Development Legal Issues

Housing Development Legal IssuesArchitectural BIM engine roomTable of Contents (Jump to)Executive Summary1.0 Introduction2.0 St Johns College Respond house Development3.0 paygrade of Legal issues4.0 Conservation Protected expressions5.0 indebtedness of distribute6.0 area of kit and boodle7.0 Boundary Disputes8.0 Reflective LearningBibliographyTable of CasesDonoghue v Stevenson 1932 AC 562Hym some(prenominal) Pon in additionn Ltd -v- Galkil Ltd t/a Imp move Developments IEHC 188Dempsey Anor -v- Waterford Corporation 2008 IEHC 55 (29 February 2008) reference work as 2008 IEHC 55List of Images human body 1 http//www.mythen building.ie/wp-content/uploads/2014/09/St-Johns-College-Waterford.jpgFig 2 http//waterfordireland.tripod.com/stjohnscollege.jpgFig 3 http//maps.osi.ie/ taproomlicviewer/V1,661050,611123,7,10Fig 4 http//maps.osi.ie/publicviewer/V1,661050,611123,7,14Fig 5 http//maps.osi.ie/publicviewer/V1,661050,611123,7,11Fig 6- http//waterfordcouncil.maps.arcgis.com/ apps/Solutions/s2.html?appid=c6d45bb300e6463db7e9c6bd1df43441Fig 7 http//waterfordcouncil.maps.arcgis.com/apps/Solutions/s2.html?appid=c6d45bb300e6463db7e9c6bd1df43441Fig 8 http//waterfordcouncil.maps.arcgis.com/apps/Solutions/s2.html?appid=c6d45bb300e6463db7e9c6bd1df43441Executive SummaryThis document allow for rivet on identifying expanding and exploring wakeless issues which may be encountered regarding the caparison suppuration by Respond in lift offnership with Department of Environment, local Government and Communities. The labor movement is to consist of 21 apartments in the upper direct of the existing St Johns College building and 36 invigorated apartments in a freshly build block which pass on be located on the college state of affairs at Richardsons Folly, Waterford. Mythen construction will be the avowers on point for the pop which started in December 2013. The legal issues which will be focus of the project are Conservation Protected constructions , Duty of Care, Scope of whole kit and boodle and Boundary disputes. Each welkin will be intimated within the document and furthermore grow on in fix up to outline methods of resolving much(prenominal)(prenominal) issues. Legal literature regarding some(prenominal) construction and normal law will be used as will withdraw case law in order to widen the scope and hand over a more general view of the issues.1.0 IntroductionThe main rent of this document is to identify, evaluate and expand on the main legal issues probably to arise in relation to the respond housing association development at St Johns College, Richardsons Folly, and Waterford. The document will explore legal issues cogitate to Architecture which may occur or be encountered by two an Architect and Architectural Technician on site during the duration of the project mentioned above. In evaluating these issues, past legal cases associated to the topics will be reviewed in order to proffer a clearer view of t he issues in question, to the relevant laws and how these issues tush be resolved. steerage will also be provided in price of how these issues can be dealt with and also how they can be foreseen and eliminated at an early stage in the prox as to avoid any disputes between all parties composite in the project whether these disputes happen on or off site. precedent to the breakdown of the issues which may arise a short overview of St Johns College, the history of the college and a breakdown of the project at a lower placetaken by Respond will be sketch in order to provide a wider scope of the project as a whole.2.0 St Johns College Respond housing DevelopmentSt Johns College is a Catholic seminary which as mentioned, is located at Richardsons Folly in Waterford. The college which was founded in 1880 for the Waterford/Lismore diocese. The college was do up of two schoolings the first cosmos a classical school run by Rev. Thomas Flynn and the second an Academy run by Dr. Geo ffrey Keating. The College closed in closed in 1999 due to lack of bodily process and vocations with the remaining students transferred. In 2007 it was announced that Respond Housing association in partnership with Department of Environment, Local Government and Communities had acquired sections of the site which is a defend structure of approximately 3900sq.m with a proposal of redeveloping the building into social housing. Mythen construction began plant on site in December 2013. The development as it stands is to consist of the retrofit/redevelopment of the existing college building which is to include 21 apartments on the upper floors with a new building located on site which will house 36 new apartments (2400 sq.m approx.) the redevelopment will also include communal facilities. Below are images of the proposed and existing buildings with 3 OSI maps showing the site location and the proposed new site.Proposed development Fig 1 animate building Fig2OSI Site plan Fig 3 Exi sting building- Fig 4 Proposed new site Fig 53.0 Evaluation of Legal issuesThe following are the legal issues which will be identified, evaluated and expanded on. As mentioned these issues will be broken down in order to identify how these issues can arise, how they can be dealt with and how they can be prevented in the future. Previous legal cases, Legal literature regarding construction and general legal resources will be used to further the reasoning behind such issues and how they may arise.Conservation Protected structuresDuty of CareScope of WorksTrespassBoundary Dispute4.0 Conservation Protected structuresThe first area to be explored is saving and saved structures. As the main college building is a saved structure this without doubt will be an issue associated with a project. When a project is undertaken which involves preservation or that of a protected structure it is ingrained to turn out an architect who has some experience in conservation or dealing with protected structures. As stated in the Irish cooking and Development act 2000 Each owner and each resident physician shall, to the extent consistent with the rights and obligations arising out of their respective interests in a protected structure or a proposed protected structure, check out that the structure, or any element of it which contributes to its special architectural, historical, archaeological, artistic, cultural, scientific, social or technical interest, is non menace1. In keeping with the statement above it is important for a conservation survey to be carried out on the structure prior to showtime in order to ensure no part of the building is endangered.If with the project in question thither is need to either for an addition or deletion an addition as stated by the Irish Planning and Development act 2000 in the case of an addition, the addition is necessary or desirable in order to protect a structure, or part of a structure, of special architectural, historical, archaeo logical, artistic, cultural, scientific, social or technical interest, whether or non a recommendation has been made under section 532 On the opposite hand in term of a deletion the 2000 act states in the case of a deletion, the protection of the structure or part is no longer warranted In order to avoid any disputes or intermission of regulations it is essential to carry out work on a protected structure with a high degree of precaution. It is in everyones scoop out interests to ensure that a protected structure is nearly maintained and keep accordingly which in turn can eliminate any electromotive force problems which may be encountered during the duration of construction stage.5.0 Duty of CareDuty of care can be defined as person or persons responsibility to act with the same take of care, charge and cautiousness as a person in a standardised situation when carrying out an act, ensuring that there is no possibly of danger or endangerment. For example a designer should strive to achieve the same level of competency as a designer within the same subdue when carrying out full treatment ensuring that he has carried out the associated works with a likely amount of care. For example if an Architect fails to comply with building regulations this can be seen as a recess of his/her duty of care given that they founder failed to ensure the safety of the building occupants once works have been stainless failure to comply with such regulations may also lead to emf damage to the building.3 When it comes to any kind of building project there will always be a duty of care whether it be to the structure itself, to the client and the persons working on the site. Both the avower and Architect keep on a duty of care in terms of the proposed development being fit for purpose and also that the construction has been carried out in a competent manor including the drawings which were prepared for the project.To give an example in terms of duty of care being br eached by one party if the avower timbres as though the Architect is incompetent and that his/her drawings are not too a standard in which can be used to successfully and safely carry out the associated works the asseverator may feel that the Architect is in breach of their duty of care and vice versa if the tackleor/builder is not constructing the building in a safe and adequate manner then the architect may feel the builder is in breach of his/her duty of care. In terms of an example of duty of care outside of construction the case of case of Donoghue v Stevenson 1932 AC 562 is a fitting example as it came down to that it was the manufacturers duty of care to ensure the product was fit for human consumption and when it subsequently was found to not be fit for human consumption it was proven that it was a breach of duty of care on the manufactures side. 4 To ensure there are no disputes regarding duty of care it is crucial that all parties involved from the design squad to the construction team are competent enough with their responsibilities to sufficiently successfully and safely complete the project without breaching their duty of care and also that they hear they have a duty of care and that this must be adhered too.6.0 Scope of WorksAs per the RIAI step form of contract 2012 review by Tony Cunningham5 scope of works can be defined as The contractor must complete the works in accordance with the Contract Documents to the blessedness of the Architect. The contractor must also comply with Architects Instructions6. Prior to works commencing on the Respond housing development at St Johns College all works to be completed would have been draw within the contract such as the contractors roles and responsibilities on site as well as off site. Cunningham also goes onto mention within the review that if the contractor fails to deliver the specified works adumbrate then he/she may be held liable with the cost of such implications either being added to or reduced from the contract sum. The Architect also holds the power to appoint a new contractor to site in order to complete the scanty works left by the previous contractor whilst also charging fractional work to the original contractor. Given the scale of the project at St Johns College this could potentially be a problem during the duration of the works. In the case of Hymany Pontoon Ltd -v- Galkil Ltd t/a Impact Developments 2011 IEHC 1887 although the contractor had failed to complete some of the work which was outlined within the contract the judge deemed that the contractor could not be held trusty given the fact the scope of works outlined in the contract was broad and with very little specificity. Hymany Pontoon Ltd -v- Galkil Ltd t/a Impact Developments shows how in order for the contractor to fulfill the scope of works excoriately it is essential that the scope of works is carefully outlined in depth in order to eliminate confusion which in turn could cause a dispute be tween the architect and contractors or vice versa.7.0 Boundary DisputesWhen it comes to diputes involving limits there can be a number of factors or variables involved. In intimately cases involving boundary disputes it comes down to incorrect mapping which defines the boundarys of a site in position which in reality it may not be the correct position8. In order to attempt to define where a boundary lies the deployment of a professional surveyor to give his/her opinion on where the boundary lies may be crucial at the early stage in terms of elimating future disputes regarding the asscoiated boundary. In terms of St Johns College respond development from the pictures below the site of the develoment is outlined in blue with a smaller site also outlined in Fig6. There could potenially be a dispute if it is taken that the new development enchroaches onto the smaller site as this could also fall under prtivate nuisance. If there is no visible boundary between the two sites at St Johns College this may also cause a potenial dispute. In order to reslove a boundary dispute it will take a combination of both surveyors and lawyers. The lawyers will provided the releavnt information regarding the deeds and documentation which the surveyor will use in their investiagtion into providing the legal position of the boundary. The majority of boundary disputes can also be resolved using mediation as it can keep a civil relationship between both parties while preventing costly legal fees.9 10St Johns Boundary Fig 6 Proposed Site Boundary Fig 7 Secondary Site Fig 88.0 Reflective Learning boilers suit given the scale of the St Johns College project it is highly likely that one or more of these issues will arise on site during the duration of the project. Although the issues mentioned can be resolved it can also be a percentage more difficult to anticipate them. In saying this there are, as mentioned, ways in which they can be dealt with early on to picture and avoid any disputes and intern make for a easier more succesful project but this does not always happen on bigger projects.The majority of the issues which are encountered on and off site on projects can be eliminated through good detailed planning and also ensuring all parties undertand the terms outlined in the various contracts asscoiated with the works. The legal issues exlpored within the document have provided a wider scope personally which is very benifical in terms of the future and future employment as I now have a greater understanding of what each one entails. I feel as though the project as whole was worthwhile and rewarding.I feel as though my ability to compile a document of this nature has better as has my general knowledge of contracts law and construction law.BibliographyTextbooks Canny, J (2001).Construction and edifice equity. Dublin Round Hall Ltd. p23-27..57-62Speight, A Stone, G. (1996). The English Law of Tort. In Speight, A Stone, G Architects Legal Handbook. 6th ed . Great Britain reed Educational Professional Publishing Ltd 1996.Scriven, J, Pritchard, N, Delmon, J (1999).A Contractual Guide to major Construction Projects. London Sweet Maxwell. Part 2 p8-21 Part 3 p17-32.Websites Base Surveys Ltd. (2010).Causes of Boundary Disputes. addressable http//www.baselinesurveys.ie/Causes of Boundary Disputes.html. Last accessed eighteenth March 2015Cunningham, T. (2013).The RIAI Standard Form of Contract 2012 Edition a Review.Available http//arrow.dit.ie/cgi/viewcontent.cgi?article=1005context=beschreoth. Last accessed 18th March 2015.Irish Planning Development twist 200. (2000).Planning Development Act 2000.Available http//www.irishstatutebook.ie/2000/en/act/pub/0030/sec0058.htmlsec58 LastAccessed 18th March 2015Irish Planning Development Act 200. (2000).Planning Development Act 2000.Available http//www.irishstatutebook.ie/2000/en/act/pub/0030/sec0054.htmlsec54. Last accessed 18th March 2015OReilly, N, Shine, P. (2013).Beyond the bounds reso lving boundary disputes.Available http//www.surveyorsjournal.ie/index.php/beyond-bounds-resolving-boundary-disputes/. Last accessed 18th March 2015Journals Smith, H. (2011). Construction dispute avoidance newsletter. Available http//www.herbertsmithfreehills.com/-/media/HS/T21121146.pdf. Last accessed 5th March 201411 http//www.irishstatutebook.ie/2000/en/act/pub/0030/sec0058.htmlsec582 http//www.irishstatutebook.ie/2000/en/act/pub/0030/sec0054.htmlsec543 Construction dispute avoidance newsletterhttp//www.herbertsmithfreehills.com/-/media/HS/T21121146.pdf4 Donoghue v Stevenson 1932 AC 5625 Tony Cunningham Dublin Institute of Technology6 http//arrow.dit.ie/cgi/viewcontent.cgi?article=1005context=beschreoth7 Hymany Pontoon Ltd -v- Galkil Ltd t/a Impact Developments IEHC 1888 http//www.baselinesurveys.ie/Causes of Boundary Disputes.html9 http//www.surveyorsjournal.ie/index.php/beyond-bounds-resolving-boundary-disputes/10 http//waterfordcouncil.maps.arcgis.com/apps/Solutions/s2.html?app id=c6d45bb300e6463db7e9c6bd1df43441

Friday, March 29, 2019

Law Essays Negligence Damages Breach

Law Essays Negligence damage BreachNegligence Damages BreachFor the purposes of this paper, it is assumed that liability for indifference rests solely on the Umbridge settlement Fte deputation (UVFC) with regard to the damages suffered by Tony and leave as it is gener ally pass judgment that legal responsibility should lie with the number arranger/hirer.The insurance policy should indemnify the Borsetshire County Council (BCC) against all formivities on the hold land, except to the outcome that the damage is due to all act or omission of the BCC.In order to succeed in a form of address for negligence, the yellant mustiness prove that they were owed a handicraft of wish, that the avocation was violateed, and that the give way resulted in the damage complained of. The authority for duty of business organisation is the leading case of Donoghue v Stevenson (1932) and it is well completed law that suit arrangers owe a duty of flush to the participants, spectators and the general public who attend their instances.It follows that the UVFC had a duty to pick up that all foreseeable take over a chances had been adequately assessed and that the appropriate safety measures had been put in place with regard to the planned competitions. Given that a duty has been established, it must now be determined whether the UVFC has relegateed that duty.According to Alderson B, in Blyth v Birmingham water company (1856), to avoid rifting a duty of charge, the defendant must come to the sample of a well-founded man. This test is objective and recognises that the average soul can non foresee every risk. shift law has established that anyone acting within a specific area of skill must come on the same metre of care as a sightly person with that particular skill.Therefore, the question to ask is what would a reasonable event transcriber, placed in the same position as the UVFC, have through with(p), and did the UVFC meet that received? If it c an be shown that the UVFC did non use competent care with regard to the competitions, liability in negligence may arise.TonyOn the facts, it was whole indefensible to allow a competitor to use a garden trowel as a spile presumption the nature of the game. whatsoever reasonable person would have recognised that using such an apply in that manner could result in serious imperfection. Therefore, the UVFC is in breach of its duty.It is readily apparent that but for the negligent act of the event organiser in allowing the trowel to be utilize in the competition, this accidental detriment would non have occurred. Therefore, the UVFC exit be liable for the injury unless the damage is excessively remote. The test for remoteness of damage as held in The Wagon sack (1961) is that the damage must have been fair foreseeable.This is readily established be source all Tony must prove is that some personal injury was foreseeable. The precise chance need non be foreseeable, as dama ges can be recovered for an unforeseeable form of a foreseeable type of injury, and for unforeseeable consequences of a foreseeable type of injury Therefore, it is likely that the UVFC will be liable for Tonys injury.The UVFC may argue volenti non fit injuria. Case law has established that spectators assume the risk of injury when attending certain(p) events and thus indemnify the organisers. For example a person attending an methamphetamine hockey event accepts the risk they could be injured by a puck. Similarly, a spectator at a golf tournement runs the risk of the players slicing or pulling balls which may hit them with considerable velocity and damage.However, Wilks v Cheltenham Home Guard Motor Cycle and Light Car rules of order (1971) established that a spectator can recover damages for injury resulting from the negligent act of one of the competitors or the become flature of the event organiser to guard against accidents which are foreseeable and non inherent in the ple asure or entertainment, unless it can be shown that the spectator agreed to off the risk of being injured.Therefore the UVFC would need to prove that Tony freely and voluntarily, with plenteous knowledge of the nature and extent of the risk he ran, impliedly agreed to aim it.Tony is regarded as having certain the risk of injury due to foreseeable play errors but not the risk of injury due to a wise disregard of his safety. On the facts, Tony could not have assumed the risk of injury, as it was not foreseeable or inherent, that such an implement would be used in the event. If the court agreed, the defence would fail. allow for It has already been established that the UVFC owes a duty of care. Therefore, allow must demonstrate that the UFVC was in breach of its duty. Would the reasonable event organiser, having regard for the safety of the competitors, allow the game to be play in the river? It is accepted fact that football matches are compete on a pitch.Furtherto a greater e xtent, it is common knowledge that rocks are rough-cutly present on riverbeds and that they can be sheerpery. Thus, at that place was an obvious peril of a slip and draw injury. The reasonable organiser would have recognised the risk and selected a more suitable site for the match. Therefore, the UVFC is in breach of its duty.Can it be said that the accident would not have occurred but for the negligence of the UVFC? Undoubtedly, turkey cocks act of tackling forget for the ball was a contributing component in the incident. Did it constitute a novus actus? Can it be said that Will would have suffered injury but for the negligence of either the UVFC or tomcat?The courts have made it clear that they approach causation as a matter of common sense. Therefore, the judge must decide, of the two acts, which was the effective cause of Wills injury. In applying the common sense approach to this scenario, the act of a third party will not be enured as the effective cause of the damage s unless it was entirely unreasonable and freelancer of the original negligent act.It appears that the negligent act of holding the match in the river will be considered the effective cause of Wills injury. toms tackle was an incidental risk of the game and was neither unreasonable nor independent. Again there is no issue of remoteness, as personal injury was foreseeable. Does UVFC have any available defences to avoid liability?It could be argued that Will voluntarily consented to the risk of injury by participating in the match. It is accepted that a person engaged in playing a law-abiding game takes on himself the risks incidental to being a player. However, according to Gillmore v LCC (1938), he does not take on himself additional risks due to the cooking of unsuitable premises or inadequate safety precautions.Gillmore was distinguished from the usual volenti non fit injuria cases on the grounds that the council, in allowing the game to be played on a highly polished surface, added a danger beyond the usual dangers involved in the playing of the game. Will may know that holding the game in the river was an added danger. To succeed, the UVFC will have to prove that Will chose to run the risk having full knowledge of both the nature and extent of the risk, that he agreed to waive his rights in respect of such damage, and that he was not acting under any relevant pressure. If this is turn up, Wills claim will be unsuccessful as the defence operates as a full waiver of liability.In addition, a case could be made that Will accepted that playing in the river increased his risk of injury and as such, his decision to participate anyway was causative. It should be mention that while knowledge of the risk may show contributory negligence, it does not prove voluntary assumption of that risk. On that basis, it may be headstrong that Will acted carelessly and any damages awarded would be reduced pickings into account his contributory negligence.With regard to Em mas claim, the case of Cole v Davies-Gilbert and others (2007) was recently decided on similar facts. The Court ruled that there was no evidential basis on which to hold the event organiser or land owner liable for the claimants injury.The Occupiers Liability Act, 1957 (OLA 1957), introduced a common duty of care to visitors which is defined under section 2(2). This duty imposes a positive obligation on occupiers to ensure visitors are reasonably safe and is not the same as the duty of care in negligence. The definition of premises includes land and buildings, thus clearly encompassing the potassium. parting 1(2) provides that visitors are those persons who at common law would be treated as invitees and licensees. Based on the facts, Emma was a visitor because she had implied permission to walk crosswise the green and was not acting outside the scope of her permission to be there. Therefore, she was owed a common duty of care.Occupier is not defined in the Act, however, according t o Lord Denning in Wheat v Lacon (1966) an occupier is somebody who has a sufficient degree of control over premises that he ought to realise that any failure on his part to use care may result in injury to a person advance lawfully there as his visitor. There can be more than one occupier and physical occupation is not compulsory.Thus, both the BCC and the UVFC could be considered occupiers under the Act. However, Emma may wish to pursue her claim against the UVFC in negligence rather than under the Act, since it no longer has control over the premises.The standard of care required of an occupier under the Act is the same as in common law negligence. The Court must look at whether or not the occupiers conduct was below the standard of similar occupiers acting in the same mickle. If the conduct does not fall below the standard of the reasonable occupier then it will not be said to have acted negligently.It is easily accepted that a oceanic abyss hole in the centre of a public gree n poses a risk of harm and as such is a foreseeable danger. However, it is consequential to note that it is the visitor who must be reasonably safe and not the premises. Thus the fact that the exposed hole existed does not, without more, constitute a breach of duty. Thus the essential point to consider is whether the occupier acted reasonably. In so deciding, we must consider whether the hole had been adequately sealed after the event and whether a reasonable system of inspection and maintenance was in place. anticipate that this was the first incident involving the hole, it would be reasonable to believe that the hole had been properly sealed given the amount of time which passed without incident. Presumably, the UVFC would have been responsible for reinstating the green after the fte under the hirers apprehension with the BCC. It follows that the UVFC met the standard of care required of an occupier of premises and will not be liable for Emmas injury.In negligence, the UVFC owe s Emma a duty of care under the neighbour principle and as such, it could be argued that the UVFC was responsible for what went wrong. However, the Committee has acted reasonably in sealing the hole.Therefore there is no breach in negligence either. Finally, any claim against the UVFC would fail unless it could be proven that they knew, or had reasonable grounds to believe, that the hole had been exposed and did not take the necessary steps to avert the danger.In Emmas claim against the BCC, it is unclear on the facts provided, what knowledge, if any, the BCC had of the exposed hole. Assuming it had no knowledge, Emma would have to prove that the Councils system of inspection and follow up did not meet the accepted standard employed by other councils, or that it acted unreasonably.This would be uncontrollable given that there were no prior incidents and no mention of complaints by groundskeepers or subsequent hirers of the green. Thus, if it could be shown that sensible and reason able action was taken with regard to inspecting and maintaining the green, the BCC would escape liability.Conversely, if the BCC knew the hole was exposed, it could be found liable given the fact that it would not have been onerous to ensure that the hole was make full in properly and a reasonable occupier would have done so. Under s2(4)(a) OLA 1957, it is possible to discharge the duty owed by providing adequate warnings that enable the visitor to avoid the danger.However, a warning is not to be treated without more as absolving the occupier from liability, unless in all the circumstances it was enough to enable the visitor to be reasonably safe as explained in Roles v Nathan (1963). In Rae v Mars UK (1989), it was held that where an unusual danger exists the visitor should not only be warned of the danger but a barrier or additional notice should be placed to show the immediacy of the danger.On the facts of the present case, there were no warnings or barriers. Therefore the BCC did not discharge its duty under the provision and should be held liable for Emmas injury.Section 2(1) OLA 1957 provides that an occupier may turn out his duty by agreement or otherwise. Ashdown v Samuel Williams Sons Ltd (1957) held that it is sufficient for an occupier to post a clear and unequivocal notice at the point of entry excluding liability with respect to non-contractual entrants. Once again, on the facts, this was not done.A key point here is that the Unfair Contract monetary value Act 1977 controls the exclusion of liability for negligence including the common duty of care under OLA 1957. Section 2(1) of the 1977 Act prohibits any attempt to take away liability for personal injury resulting from negligence, although this is only applicable in a business context.If Emma could establish that she entered the green under contract she could successfully claim damages against the BCC even if it had posted an exclusion notice.A final status is the Compensation Act 2006 wh ich serves to remind us that the law does not shroud people who are involved in pure accidents. Furthermore, Section 1 draws attention to the fact that in determining whether there has been a breach of duty, the court will consider whether precautionary and defensive measures, if taken, would prevent worthy activities, thereby attempting to ensure that normal activities are not prevented due to awe of litigation and excessively risk-averse behaviour.Therefore, unless Emma proves causative fault against either defendant, her claim should fail as clearly, too high a duty of care obligate by the courts would interfere with the reasonable enjoyment of life. Therefore, in the absence of any evidence to the contrary, Emmas accident should be considered just that an accident.

Sindromi neurologiche paraneoplastiche

Sindromi neurologiche paraneoplasticheAnticorpi anti-antigeni onconeurali fill out strumento diagnostico di tumori maligni e sindromi neurologiche paraneoplastiche.Caratteristiche delle singole neurologiche paraneoplastiche.Le sindromi neurologiche paraneoplastiche sono stati patologici associati a tumori, riconoscono quindi un tumore maligno come il principale fattore eziologico, ma non sono patologicamente associati alla diretta azione del tumore. Nella grande maggioranza dei casi riconoscono una patogenesi autoimmunitaria e originano nel seeting di un tumore a differenziazione neuroendocrina. il modello comune della patogenesi di queste forme assunte unaberrante espressione di proteine specifiche per il sistema nervoso nel tumore a differenziazione neuroendocrina. A questo consegue una risposta a autoimmunitaria antitumore cross reattiva con antigeni neuronali del sistema nervoso centrale e periferico. I tumori dei pazienti affetti da sindrome neurologica paraneoplastica tendono ad avere unevoluzione meno aggressiva rispetto agli analoghi tipi istologici di lavorazione generale di tumori e nel momento della diagnosi sono di regola limitati alle sedi primarie o ai linfonodi linfo regionali. La diagnosi neurologica precede la diagnosi oncologica nel 70% dei casi e in un certo numero di casi, circa il 15% il tumore primario non pu essere diagnosticato. Non sar solo dopo un certo tempo, da settimane ad anni. In una piccola percentuale di casi dekalitreluno al 5%, il tumore non pu essere dimostrato per tutta la vita del paziente. peraltro nonostante la minore aggressivit di tumori associati alle sindromi neurologiche paraneoplastiche la sopravvivenza di questi pazienti non soddisfacente a causa del danno autoimmune irreversibile di vari organi sistema nervoso centrale e periferico che portano ad una malattia disabilitante, poco trattabile e mortale.lunica strategia terapeutica effettiva e la rimozione del tumore e quindi anche del introduction autoimmunitario .Si pu quindi considerare come questo sottogruppo di pazienti il problema della diagnosi precoce del tumore associato particolarmente urgente. Ma particolarmente complesso sciogliere questo problema per la difficolt che spesso limpossibilit di diagnosticare i tumori associati alle sindromi neurologiche paraneoplastiche in uno stadio precoce dato che la natura paraneoplastica non in realt patognomonica per i singoli noti processi neurodegenerativi cerebrali scatenati.Anticorpi onconeurali nella diagnosi delle sindromi neurologiche paraneoplastiche e di tumori loro associatiGli anticorpi onconeurali sono rilevati nella maggioranza dei pazienti che presentano la sindrome neurologica paraneoplastica e correlati allo sviluppo di un tumore maligno che il paziente. Questa la principale distinzione fra le anticorpi onconeurali e gli anticorpi anti-neuronali di malattia autoimmune quale la miastenia gravis e la sindrome di Lambert-Eaton, o la neuro miotonia. queste ultime malattie hanno u na trilogia sia paraneoplastica che neoplastica e gli anticorpi associati sono elevati in una comparabile frequenza tra questi due casi. In altro modo di dire sono il diretto testimone ed effettore che la risposta immunologica antitumore e la risposta anti neuronale mentre quelli che chiamiamo auto anticorpi onconeurali sono il testimone primitivo della presenza di un tumore e di una risposta antitumorale, ma sono solo secondariamente responsabili dellattacco autoimmune al sistema nervoso.una sindrome neurologica paraneoplastica non in genere sufficientemente specifica delocalizzazione del tumore mentre questa specificit maggiore, se il tumore primitivo non pu essere facilmente rintracciato, per gli specifici antigeni onconeurali induttori degli anticorpi. Questo permette di restringere larea di ricerca del tumore associato a una sindrome paraneoplastica. La descrizione degli anticorpi e antigeni ben caratterizzate riportate in tabella mentre la caratterizzazione clinica-laborator istica delle sindromi cosiddette parzialmente caratterizzate molto minore. In questo caso di anticorpi sono caratterizzati solo dalla colorazione di strutture neurologiche in immunoistochimica, mentre una possibile confermare la creativit con specifici test in Western-blotAnticorpi anti antigeni onconeurali come patsys oncologici.Se la maggioranza gli articoli si sono focalizzati sulla reattivit anticorpale ad antigeni onconeurali nel sangue dei pazienti affetti da sindromi neurologiche paraneoplastiche, ci sono ora chiare evidenze gli stessi anticorpi sono predittore in primo luogo lesistenza e istiogenesi di un tumore, in secondo luogo della sua possibile localizzazione ed infine della presenza-tipo di sindrome neurologica paraneoplastica. Ad esempio pu essere ricordato come si vede in tabella con il 20% dei pazienti con un tipo definito di tumore principalmente carcinoma a piccole cellule del polmone, sono sieropositivi per proceed antigeni onconeurali. Alla stessa tabella si nota come tutti gli anticorpi onconeurali ben caratterizzati abbiano unelevata specificit per la patologia onconeurali mentre il tipo numero di combinazione delle sindromi neurologiche paraneoplastiche associate non pu essere predetto dal pattern di sieroreattivit degli antigeni onconeurali, ad esclusione degli antigeni espresse solamente nel cervelletto, reattivit chiaramente associata solo con SCA.inoltre la presenza di pazienti sieropositivi in cui il tuo non pu essere rilevato anche dopo lunga osservazione riflette probabilmente non una sufficiente specificit del test (false positivit) e ma una alta sensibilit nella detenzione di foci microscopici di un tumore immunogenico. la loro presenza non pu essere considerata come un mero epifenomeno, cio, ad esempio riflettere sono un alto grado di necrosi apoptosi che con ulteriore iper esposizione di antigeni comuni a Sistema immunitario, ma si tratta di marker altamente specifici associati ad uneffettiva risposta antitumorale e la lor o presenza, anche nei casi di assenza della specifica sindrome neurologica paraneoplastica correttamente correlata uno stato limitato nel tumore al momento del tempo di diagnosi.Certo la sensibilit del 20% non permette a questi test di essere considerati un marker diagnostico ogni nuovo e sufficientemente potenti. Nondimeno possono essere considerati un efficace punto di partenza per il disegno di un pannello diagnostico che possa comprendere altri markers e ulteriori test.unaltra sfera di applicazione in questi marker e la predizione della risposta clinica alla chemio terapia o radioterapie. I dati ottenuti finora, a questo riguardo, sono ancora non conclusi

Thursday, March 28, 2019

King Arthur Essay -- Essays Papers

mightiness ArthurIf the name of index Arthur is menti one(a)d, I suppose what comes to mind is not so much one person as a firm array of characters and themes, a collage so to speak. Of course we do suppose first of the King, the magnificent cr possessed head of a glorified or idealized medieval realm. barely we think also of his sissy, of the fair and wayward Guinevere, we think of his enchanter, Merlin, who presided over his birth, who set him on the throne, who established him there in the early and traveled twenty-four hourss of his reign. at that place were the knights of the Round Table, vowed to the highest ideals of chivalry, and the greatest of them, Sir Lancelot, who, of course, has a tragic love affair with the Queen. on that point is another great love baloney, that of Tristan and Isolde, the theme of Wagners Opera. We think of the place where these mountain assembled, Camelot, Arthurs magnificent, personal castle and capital and then, there are stranger things the story of the quest for the Holy Grail, giving a spiritual dimension to the whole story and there is magic. Not only the magic of Merlin tho the magic also of his strange, ambiguous student, the women, the enchantress, Morgan LaFay. And at the end is the tragedy of Arthurs downfall, his laissez passer away at the isle of Avalon and another mystery that we do not know what really happened to him that he was said to be immortal, that one day he would return and restore the golden age in his country. I suppose, the version we know best is the one that was composed in the fifteenth century. This is the great English version of the story, compiled out of earlier versions by the fictive genius of a quite mysterious and cryptic figure, the knight, Sir Thomas Malory. But the story doesnt end there. The whole thing revives in the time of Queen Victoria, with Tennysons Idylls of the King. As a result of this great work on the Arthurian Cycle by Englands Poet Laureate, the story became known to everybody. Other poems, novels and plays in our own time, and almost a rebirth of it yet again in T. H. Whites novels, The steel and the Stone and The Once and Future King and other plays and musicals and films based on these works. There are Rosemary Sutcliff, Mary Stewart, Marian Bradley, Pat Godwin and others, who declare gone off on another line and tried to recall the Britain of King Arthur as it might really obtain been. What I bind personally ... ... like that than the resplendent kingdom that we see in a film like Camelot or First Knight. Well, of course, you may say Ive been rather begging the question here. What was the real setting? And the modern novelists Ive spoken of, have been moved to their work partly by the fact that there is a very slowly growing awareness of what it was and when it was, through historical need and through the work of archaeologists. And if we look at that outcome we can ask, and I think this is a better way of putting the quest ion, not did King Arthur exist, only if how did this legend originate, what fact(s) is it rooted in? Then, of course, we must ask what period? Well the medieval writers with all their fancy did know, more or less, that they were universe a bit vague. They dont give us many real dates except they place King Arthur somewhere in the period from or so 450 A.D. to 550 A.D. That, of course, is weeklong than any one man could have reigned, but they see him as living somewhere about that time, and they were right. This, in fact, is where the story we know began its career, but the foundations for the medieval romances had been laid a little before, in the old legends about Arthur.