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Most neurodegenerative disorders are associated with the accumulation of ubiquitin-positive protein aggregates.

We therefore investigated the occurrence of age-related accumulation of poly-ubiquitinated proteins in three regions of the brain of octodons: SN, striatum and frontal cortex Fig. A Representative ubiquitin immunoblot in the mesencephalon. Ub: monomeric ubiquitin.

Our investigation was prompted by previous reports suggesting that Octodon degus might be a spontaneously occurring model of AD 5 , 6 , 7 , Since we did not detect overt synucleinopathy or nigrostriatal lesion, we also characterized the AD-related pathology, in an attempt to replicate previous findings.

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We focused on two brains regions commonly affected in AD: hippocampus and cortex, as reported affected in previous reports We first examined the occurrence of cortical, hippocampal or nigral neurodegeneration by immunohistochemistry with pan-neuronal markers, neuronal nuclear antigen NeuN and microtubule-associated protein-2 Map2 Fig. Aged animals displayed a small decrease in NeuN staining in both cortical and hippocampal region without a specific pattern Fig.

High magnification investigations revealed a normal neuronal morphology Fig. We did not observe any age-related abnormal patterns of Map-2 immunolabeling in cortical, hippocampal and nigral regions Fig. Direct comparison of young 1year-old and aged 5—6 years-old octodons Fig. Similarly, no intracellular deposits such as neurofibrillary tangles and hyperphosphorylation of tau could be observed in young or aged animals Supp.

A — C Show representative cortical A , hippocampal B , nigral C images with low and high magnifications in young and aged octodons without clear changes in average density of neurons. D — F Show representative images of Map2 immunostaining in cortical D , hippocampal E , and nigral F areas from young and aged octodons. Table 2 Fig. This method is used to create principal components that are linear combinations of measured variables to emphasize variations in the dataset and allow to unravel overall patterns.

Careful examination of the location of each animal in the space create by PC1 and PC2 suggest that, as reported by Ardiles et al. Interestingly, individual scores along PC1 according for This analysis suggest that an age-related phenomenon can be unravel through multivariate analysis. Each animal is represented as a colored dot in the new space created by PC1—2. B Boxplot represent mean PC1 score of 1—2 years-old compared to 3—6 years-old animals.

Altogether these data suggest that no AD-related pathology can be found in aged octodons, in conflict with previous reports 5 , 6 , 7 , but in accordance with a more recent contribution 8. We here assessed the relevance of Octodon degus as a suitable natural model of neurodegenerative disorders associated with protein inclusion formation. We considered four groups of age i.

Overall, our investigation has not unveiled any specific pattern of age-related pathology therefore questioning the relevance of such rodent as a natural model for age-related disorders. Interestingly, a recent study came to the same conclusions with the same groups of age while focusing on AD-related pathology 8. Although the common max life expectancy is 3—4 years in the wild, captivity allows prolonged life span up to 5—8 years, thus suggesting that our age-groups are relevant for the study of age-related phenomenons 8 , Neurodegenerative disorders are and will increasingly be a significant burden for the society as these age-related disorders require intensive care 1.

Thus, the need for relevant disease models to test putative therapeutic strategies is strong. High levels of overexpression are often needed to obtain significant levels of neurodegeneration and protein aggregation thus questioning the relevance of such models. Such high overexpression levels are often associated with a downregulation of the endogenous protein Recent models based on the injection of misfolded aggregates are promising but their predictive value remain to be established.

Natural or ecological models are therefore attractive alternatives. Several papers have documented age-related dysfunctions and brain pathologies in aged octodons 5 , 6 , 7. More recently, astrocytic activation and oxidative stress have also been reported 7. Interestingly, Ardiles and collaborators described that most age-related changes occurred between 12 and 36 months 5. However, most of these deficits could not be identified in our cohort as well as in, a recently published independent study that also failed to identify AD-related brain pathology 8.

However, to go beyond the gross changes, we decided to conduct multivariate analysis to unravel complex phenotypes thanks to linear combination of variables Fig. The three main contributors of PC1 nicely depict what we could expect from a PD model. Although some interesting phenotype arise from multivariate analysis, we failed to replicate most of the results of the previous anatomo-pathological studies.

As noted by Steffen et al. Indeed, most published studies used a wide variety of source for the animals including animals that were caught from the wild 5 , 6 , 7 , 8 while animals of the present study come from a breeding facility that allows precise date of birth as well as homogeneity in individual histories. Ageing is a process that affects each individual but only some of us will develop age-related diseases such as neurodegenerative disorders.

It is therefore difficult to decipher between normal ageing and pathological ageing. The most common characteristic among neurodegenerative disorders is the presence of protein aggregates 1. Although such incidental brain pathology is often considered as a prodromal phase of neurodegenerative diseases, the fact that such individual will indeed convert to a disease state later-on remain without clear evidence.

Ardiles et al. This observation is coherent with what we could expect from a natural model of a given age-related pathology i. However, the global trend that we observed Fig. This argues against octodons being a suitable natural model of AD or PD but it might be a highly valuable model for age-related processes. In conclusion, we performed a thorough analysis of the occurrence of AD and PD brain pathology in young and aged octodons. Our study is entirely consistent with a recently published independent study 8 and accordingly argues against the use of Octodon degus as a natural model of neurodegenerative disorders but supports its use as an animal model of ageing.

Animals were purchased from the research animal facility of the University of Alicante Alicante, Spain.

Brain Death

Brains were removed quickly after death. Each brain was then dissected along the midline. To assess the integrity of the nigrostriatal pathway, tyrosine hydroxylase TH immunohistochemistry was performed on striatal free-floating sagittal sections. Briefly, sections were incubated with a mouse monoclonal antibody raised against human TH Millipore, MAB, performed as previously reported Sagittal sections were mounted on gelatinized slides, counterstained with 0. Briefly, selected sections were specifically identified and incubated in a same well to allow direct comparison of immunostaining intensity.

Sections were incubated over-night at room temperature with the aforementioned antibodies. Sections were then mounted on gelatinized slides, dehydrated, counter-stained if necessary and cover-slipped until further analysis. Grey level quantification or immunostaining-positive surface quantification were performed as previously described Hyper-phosphorylated tau p-tau deposits were stained with AT8 antibody ThermoFisher, Immunoblot analyses were performed on mesencephalon, striatum and cortex.

For detection of ubiquitinated proteins, proteins were transferred on polyvinylidene fluoride membranes Millipore and subjected to Western blot analysis using a rabbit anti-Ubiquitin Sigma U Signals were revealed with horseradish peroxydase-conjugated secondary antibodies. Book Review Editor. Bibliographic Data: Springer, Description: This monograph describes recent work culminating in the contemporary approach to diagnosis of brain death. Purpose: A senior neuroscientist with 20 years of experience provides a detailed review of the contributions from leading figures in this field. Audience: Neurologists, neurosurgeons, intensivists, and transplanters are an appropriate audience for this work from the Institute of Neurology in Havana, Cuba.

Features: The author first presents a clinical view of brain death and its relevance. He follows with a detailed discussion of radiologic and other modalities to make the diagnosis of brain death, along with difficult issues including the diagnosis of brain death in children and consciousness states bordering on brain death, including the locked-in syndrome and the minimally conscious state.

The book provides a clear discussion from an international perspective on the social and religious furor arising over management of patients with varying levels of consciousness. Given the single authorship of this work, chapters have a consistent style which contributes to easy reading. Each chapter contains an extensive reference list with citations, typically of original work, dating to within one year of publication.

Black-and-white line drawings are done well and a selection of good color plates is grouped together. Black-and-white photographs, however, reproduce with limited quality. The table of contents easily describes the book while a subject index of approximately 10 pages provides adequate access to content with separate citations for figures and tables. Assessment: This book smoothly sheds light on the biology and controversy surrounding an important clinical topic. This work is attractive for its historical scope coupled with clinical clarity.

Reviewer: David J. Some 35 years after the original meeting of the Harvard medical committee, there is neither universal recognition of the concept of brainstem death, 12 13 nor standardization of the method of diagnosis. A questionnaire was mailed to the consultant members of the Neuroanaesthesia Society of Great Britain and Ireland, on the basis that this group should have regular experience of brainstem death if their work includes responsibility in neurosurgical intensive care.

The questionnaire Appendix comprised five sections, namely: clinician details; initiation of support; criteria for testing; conduct of the tests; and the process of organ donation. Limits for preconditions accepted by respondents are given in Table 1. The criteria used to determine that narcotics, hypnotics, and anaesthetic agents do not invalidate the tests were varied. Nineteen per cent of correspondents did not assess whether there was any endocrine disturbance.

Forty per cent assessed neuromuscular function with a nerve stimulator even if relaxants had not been prescribed or not administered for some time previously. Twenty per cent of respondents considered it appropriate to test for brainstem death immediately after the clinical diagnosis was made, regardless of triggering pathology. Fifteen per cent always waited 24 h.

Thirty per cent maintained a differential delay based on the pathology but there was no clear consensus, with a range between 6 and 72 h, after a hypoxic brain injury. Fifteen per cent of practitioners routinely spoke to the family between tests and others sought to normalize the P a CO 2 before embarking on the second tests. Five per cent considered a wait between sets of tests obligatory with certain pathologies such as hypoxia. The minimum P a CO 2 considered acceptable ranged from 4.

The results of this survey show marked variations in the interpretation of the UK guidelines for confirming brainstem death by practitioners involved in intensive care medicine. In interpreting these results, it must be remembered that guidelines accommodate professional judgement rather than rigidly prescribe process.

This would account for some of the variability in their application but does not explain the variations in practice where the recommendations are very specific. Although the diagnosis of conventional death shares a diversity of approach, it should be noted that this has led to a call for more precise guidelines to ensure diagnostic accuracy. Despite this, every UK neurosurgical unit was represented in these results. It is possible that questions may have been misunderstood and freehand replies are additionally prone to errors of interpretation. If a patient on a sedative regime displays: the cardiovascular changes of brainstem death; dilated and unreactive pupils; loss of gag and cough reflexes; no response to painful stimuli; and additional markers such as diabetes insipidus, there is no theoretical restriction on testing the patient immediately.

There is no absolute indication to wait for drug clearance or indeed normalization of temperature or biochemistry as clinically the patient is brainstem dead rather than unresponsive as a result of sedatives. UK practice could not accommodate the former level and would not routinely meet the latter threshold, but otherwise there is commonality. A logical solution to this problem is not obvious. If permissible upper and lower limits were set for temperature, sodium, and other biochemical markers such as urea and creatinine, practitioners would have an explicit template to work within.

The guidelines state that endocrine disturbance should be eliminated but are not specific about how this should be undertaken. Whilst failure of corticosteroid production is associated with shock, the impact of this on brain function is unknown but probably limited.

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Tests of thyroid function are also notoriously difficult to interpret in the context of critical illness. Even if the circumstances in which specific tests should be conducted were defined, difficulties would still arise with interpretation and recommendations for correction of any deficit. Given however that the tests revolve around the absence of a motor response, and that muscle relaxants may be slowly cleared, 24 or have been administered inadvertently, there is a strong argument for making testing of the neuromuscular junction compulsory.

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  6. The elimination of depressant drugs as a confounding factor warrants scrutiny because there are no directives as to whether the drug should have been cleared completely, reached minimal levels with regard to impact in the normal population, or reached a level incompatible with the picture of brainstem death. Within the guidelines, there is no reference to the use of opioid and benzodiazepine antagonists to either validate or expedite testing.

    Furthermore, there is no consensus as to an appropriate minimum level. Potential donation is lost because of destabilization of the patient or unwillingness on the part of family or staff to continue support for a protracted period. When donation is delayed, organ function may deteriorate because of systemic changes, infection, and the use of chemical and mechanical support. There is also emerging evidence of graft dysfunction as a result of immunological activation of the donor organ. There is no basis for these concerns, as the brainstem death criteria evolved to avoid the need for such technically demanding interventions, not because of inherent error in the technique.

    Angiography is clearly not a bedside investigation but TCD is gaining validity as a confirmatory test for brain death, 26 — 28 particularly in the presence of residual sedative drugs. Serial absence of activity on the EEG is mandatory in certain jurisdictions, but this would be an inappropriate test in the presence of residual sedatives. Evoked potentials have been promoted, 34 and refined, 35 as a confirmatory technique even in the presence of depressant drugs, but it would be unrealistic to rely on a tool that is vulnerable to errors of interpretation in inexperienced hands.

    However, this test is only applicable when ICP monitoring is indicated clinically as in the management of traumatic brain injury and, in common with any clinical monitoring technique or investigation, is vulnerable to measurement error.

    Brain death : a reappraisal, Calixto Machado

    As failure to meet criteria for testing as a result of the prolonged effects of agents such as thiopental was cited as the third commonest cause of lost donors, the issue of confirmatory tests does need to be revisited. Use of thiopental will predictably be in the context of ICP control within neurosurgical units, where angiography and TCD expertise should be available. The conceptual diagnosis of brainstem death should stand independently of triggering pathology, and there is no logic in delaying either the first or second set of tests after cerebral hypoxia as the guidelines suggest.

    The value of repeated testing has been questioned, but the suggestion that there is a place when confounding factors such as drug therapy are present, 36 offers little reassurance about the validity of the first set of tests.

    Brain Death: A Reappraisal

    The guidelines would therefore benefit from clarification regarding the timing, repetition of, and intervals between tests. There was significant variability in the conduct of the tests themselves, particularly in areas where the Code of Practice is quite specific. The Code 19 specifies the injection of at least 50 ml of ice cold water over 1 min and practice was at variance with this. The Code requires that no motor responses within the cranial nerve distribution can be elicited by adequate stimulation of any somatic area.

    Given that false negatives may occur in the presence of a cord injury, the role of this test as a measure of brainstem function is questionable and the failure of full compliance may reflect a need to reconsider its value. Peripheral painful stimulation is not included in recommendations from other countries because it is only an indirect test of brainstem function.

    Calixto Machado: Brain Death a Reappraisal | SpringerLink

    There are no precise recommendations as to whether the apnoea test should be conducted independently of the other tests as in other jurisdictions, 37 so it is not surprising that individual practice varies. The observation that clinicians are prepared to accept less than recommended thresholds for P a CO 2 is worrying particularly in view of observations that in certain patient groups much higher levels may be needed to stimulate respiratory effort, 38 39 and that the UK figure is already lower than other countries.

    Regardless of the potential for aggravating incomplete brain injury, 41 primary carbon dioxide narcosis may confound the clinical picture, particularly if the tests are conducted sequentially without normalization of P a CO 2 before the second set. There are, therefore, arguments for a more prescriptive approach to these tests and the setting of a higher P a CO 2 level equivalent to the 8 kPa used in other countries. In summary, this survey demonstrates a wide variation in interpretation of the UK guidelines for certification of brainstem death.

    The elimination of confounding factors, the timing and repetition of testing and the conduct of the tests themselves, particularly the apnoea test, would benefit from refinement and clearer definition. The results also indicate that specific recommendations in the existing guidelines are not accurately followed and although this is unlikely to invalidate the determination of death, 42 reinforcement is warranted.