The Consequences of Vagueness in Consent to Organ Donation

In this article I argue that vagueness concerning consent to post‐mortem organ donation causes considerable harm in several ways. First, the information provided to most people registering as organ donors is very vague in terms of what is actually involved in donation. Second, the vagueness regarding consent to donation increases the distress of families of patients who are potential organ donors, both during and following the discussion about donation. Third, vagueness also increases the chances that the patient's intention to donate will not be fulfilled due to the family's distress. Fourth, the consequent reduction in the number of donated organs leads to avoidable deaths and increased suffering among potential recipients, and distresses them and their families. There are three strategies which could be used to reduce the harmful effects of this vagueness. First, recategorizing the reasons (commonly referred to as ‘overrules’ under the current system) given by families who refuse donation from registered donors would bring greater clarity to donation discussions. Second, people who wish to donate their organs should be encouraged to discuss their wishes in detail with their families, and to consider recording their wishes in other ways. Finally, the consent system for organ donation could be made more detailed, ensuring both that more information is provided to potential donors and that they have more flexibility in how their intentions are indicated; this last strategy, however, could have the disadvantage of discouraging some potential donors from registering.     

<Emphasis Type="Italic">Plasmodium falciparum</Emphasis> glycosylphosphatidylinositol induces limited apoptosis in liver and spleen mouse tissue

Plasmodium falciparum malaria affects about 500 million people worldwide and is responsible for approximately 2.5 million deaths per year. Glycosylphosphatidylinositol (GPI) is the major anchor for membrane-associated proteins of P. falciparum and GPI plays a major role as a toxin in the pathology of malaria. Therefore, we tested the hypothesis that GPI, like LPS, induces apoptosis in vitro and in vital organs of mice. Our data does not provide evidence for direct cardiomyocyte apoptosis induced by GPI in vitro. However, in vivo injection of GPI induced limited apoptosis in mouse liver and spleen tissue. Apoptosis may be due to a direct GPI apoptotic effect or to an indirect effect via the induction of TNFα and nitric oxide production.     

Developmental study of tripeptidyl peptidase I activity in the mouse central nervous system and peripheral organs

Tripeptidyl peptidase I (TPPI) — a lysosomal serine protease — is encoded by the CLN2 gene, mutations that cause late-infantile neuronal ceroid lipofuscinosis (LINCL) connected with profound neuronal loss, severe clinical symptoms and early death at puberty. Developmental studies of TPPI activity levels and distribution have been done in the human and rat central nervous systems (CNS) and visceral organs. Similar studies have not been performed in mouse. In this paper, we follow up on the developmental changes in the enzyme activity and localization pattern in the CNS and visceral organs of mouse over the main periods of life — embryonic, neonate, suckling, infantile, juvenile, adult and aged — using biochemical assays and enzyme histochemistry. In the studied peripheral organs (liver, kidney, spleen, pancreas and lung) TPPI is present at birth but further its pattern is not consistent in different organs over different life periods. TPPI activity starts to be expressed in the brain at the 10th embryonic day but in most neuronal types it appears at the early infantile period, increases during infancy, reaches high activity levels in the juvenile period and is highest in adult and aged animals. Thus, in mice TPPI activity becomes crucial for the neuronal functions later in development (juvenile period) than in humans and does not decrease with aging. These results are essential as a basis for comparison between normal and pathological TPPI patterns in mice. They can be valuable in view of the use of animal models for studying LINCL and other neurodegenerative disorders.     

Altruism or solidarity? The motives for organ donation and two proposals

Proposals for increasing organ donation are often rejected as incompatible with altruistic motivation on the part of donors. This paper questions, on conceptual grounds, whether most organ donors really are altruistic. If we distinguish between altruism and solidarity--a more restricted form of other-concern, limited to members of a particular group--then most organ donors exhibit solidarity, rather than altruism. If organ donation really must be altruistic, then we have reasons to worry about the motives of existing donors. However, I argue that altruism is not necessary, because organ donation supplies important goods, whatever the motivation, and we can reject certain dubious motivations, such as financial profit, without insisting on altruism. Once solidaristic donation is accepted, certain reforms for increasing donation rates seem permissible. This paper considers two proposals. Firstly, it has been suggested that registered donors should receive priority for transplants. While this proposal appears based on a solidaristic norm of reciprocity, it is argued that such a scheme would be undesirable, since non-donors may contribute to society in other ways. The second proposal is that donors should be able to direct their organs towards recipients that they feel solidarity with. This is often held to be inconsistent with altruistic motivation, but most donation is not entirely undirected in the first place (for instance, donor organs usually go to co-nationals). While allowing directed donation would create a number of practical problems, such as preventing discrimination, there appears to be no reason in principle to reject it.     

Estimating population cause-specific mortality fractions from in-hospital mortality: validation of a new method

Background

Cause-of-death data for many developing countries are not available. Information on deaths in hospital by cause is available in many low- and middle-income countries but is not a representative sample of deaths in the population. We propose a method to estimate population cause-specific mortality fractions (CSMFs) using data already collected in many middle-income and some low-income developing nations, yet rarely used: in-hospital death records.

Methods and Findings

For a given cause of death, a community''s hospital deaths are equal to total community deaths multiplied by the proportion of deaths occurring in hospital. If we can estimate the proportion dying in hospital, we can estimate the proportion dying in the population using deaths in hospital. We propose to estimate the proportion of deaths for an age, sex, and cause group that die in hospital from the subset of the population where vital registration systems function or from another population. We evaluated our method using nearly complete vital registration (VR) data from Mexico 1998–2005, which records whether a death occurred in a hospital. In this validation test, we used 45 disease categories. We validated our method in two ways: nationally and between communities. First, we investigated how the method''s accuracy changes as we decrease the amount of Mexican VR used to estimate the proportion of each age, sex, and cause group dying in hospital. Decreasing VR data used for this first step from 100% to 9% produces only a 12% maximum relative error between estimated and true CSMFs. Even if Mexico collected full VR information only in its capital city with 9% of its population, our estimation method would produce an average relative error in CSMFs across the 45 causes of just over 10%. Second, we used VR data for the capital zone (Distrito Federal and Estado de Mexico) and estimated CSMFs for the three lowest-development states. Our estimation method gave an average relative error of 20%, 23%, and 31% for Guerrero, Chiapas, and Oaxaca, respectively.

Conclusions

Where accurate International Classification of Diseases (ICD)-coded cause-of-death data are available for deaths in hospital and for VR covering a subset of the population, we demonstrated that population CSMFs can be estimated with low average error. In addition, we showed in the case of Mexico that this method can substantially reduce error from biased hospital data, even when applied to areas with widely different levels of development. For countries with ICD-coded deaths in hospital, this method potentially allows the use of existing data to inform health policy.     

Initiation of [36Cl]hexachlorobenzene dechlorination in three different soils under artificially induced anaerobic conditions

The potential for reductive dechlorination of hexachlorobenzene was investigated in samples of three different, naturally oxic soils held under conditions of high oxygen deficiency. The soils were water-saturated and the influence on dechlorination of adding different electron donors, a surfactant and an anaerobic microbial consortium was tested. The influence of supplied electron donors seems to depend on the organic matter content of the soils. Dechlorination in the organic-matter-rich soil from Maulach was not affected by amendment with organic electron donors. A release of about 40% chloride within 140 days was observed for this soil in all biotic-treated assays. By contrast, the organic-matter-poor soil of Eppingen showed no dechlorination in unamended assays. However, when it was supplemented with organic electron donors dechlorination of 2%–37% occurred within 140 days, depending on the type of electron donor. Complex substrate (wheat strawdust), from which carbon is slowly liberated, gave the best results. These two soils had an indigenous dechlorinating anaerobic microflora, whereas the third soil (Rastatt) required inoculation with an anaerobic consortium for dechlorination. The addition of electron donors alone did not cause dechlorination in this sandy soil. The addition of a surfactant (Tween 80) to increase the bioavailability of hexachlorobenzene did not enhance dechlorination. This process was not inhibited by inherent alternative electron acceptors in soil (NO³⁻, SO₄ ²⁻, Fe³⁺). The dechlorination did not require methanogenic conditions. Received: 12 December 1996 / Received revision: 14 March 1997 / Accepted: 15 March 1997     

A rat monoclonal anti-(human CD2) andL-leucine methyl ester impacts on human/SCID mouse graft and B lymphoproliferative syndrome

 The transfer of human peripheral blood mononuclear cells (hu-PBMC) from adult Epstein-Barr- virus(EBV)-seropositive donors in SCID (severe combined immunodeficiency) mice frequently leads to the development of a human B lymphoproliferative syndrome (hu-BLPS). Therefore, as 90% of adult potential donors are EBV-seropositive, efforts have to be made to avoid the occurrence of this B lymphoproliferative disorder. McCune et al. [Science 241:1632 (1988)] used human fetal organs for a human SCID graft. This system does not give rise to hu-BLPS but human fetal organs are much less available than peripheral blood leucocytes. The experiments reported in this paper show how crucial is the presence of functional T lymphocytes for a graft to take and for development of hu-BLPS in hu-PBMC-reconstituted SCID mice, since inhibition of T lymphocyte by a rat anti-(human CD2) monoclonal antibody (LO-CD2a) during the first 10 days of the graft prevents successful engraftment of human normal lymphocytes as well as hu-BLPS in SCID mice. The transfer of B cells alone or B cells plus monocytes in SCID mice does not permit either long-term engraftment or development of hu-BLPS. We also demonstrate that hu-PBMC treated with L-leucine methyl ester are less susceptible to the development of hu-BLPS after engraftment in SCID mice than are untreated hu-PBMC. The mechanism of action of L-leucine methyl ester on these cells is discussed. Received: 12 December 1994 / Accepted: 20 March 1995     

Gut–organ axis: a microbial outreach and networking

Human gut microbiota (GM) includes a complex and dynamic population of microorganisms that are crucial for well-being and survival of the organism. It has been reported as diverse and relatively stable with shared core microbiota, including Bacteroidetes and Firmicutes as the major dominants. They are the key regulators of body homeostasis, involving both intestinal and extra-intestinal effects by influencing many physiological functions such as metabolism, maintenance of barrier homeostasis, inflammation and hematopoiesis. Any alteration in GM community structures not only trigger gut disorders but also influence other organs and cause associated diseases. In recent past, the GM has been defined as a ‘vital organ’ with its involvement with other organs; thus, establishing a link or a bi- or multidirectional communication axis between the organs via neural, endocrine, immune, humoral and metabolic pathways. Alterations in GM have been linked to several diseases known to humans; although the exact interaction mechanism between the gut and the organs is yet to be defined. In this review, the bidirectional relationship between the gut and the vital human organs was envisaged and discussed under several headings. Furthermore, several disease symptoms were also revisited to redefine the communication network between the gut microbes and the associated organs.     

Perceive, Co-opt, Modify, and Live! Organism as a Centre of Experience

Organic appearances are largely neglected by contemporary biology; partly because they are regarded as superficial effects of causes concealed beneath the surface. The persuasion that everything what does exist is existent for some immediately non-apparent reasons belongs to a general belief of modern science. All organisms are of the same evolutionary origin and of the same world wherein appearance coincides with existence. In this study, living beings are approached as appearing centers of experience that reflects their evolutionary history. From biohermeneutic point of view the evolution of organisms, interactions between organisms, and their relationships to environment is understood as “evolution of interpretations”. I use simple conceptual framework of perception, semiotic co-option, and modification to explain the evolution of semantic organs, i.e. organs that operate through the meaning that was given to them by an animal interpreter.     

Why and How to Compensate Living Organ Donors: Ethical Implications of the New Australian Scheme

The Australian Federal Government has announced a two‐year trial scheme to compensate living organ donors. The compensation will be the equivalent of six weeks paid leave at the rate of the national minimum wage. In this article I analyse the ethics of compensating living organ donors taking the Australian scheme as a reference point. Considering the long waiting lists for organ transplantations and the related costs on the healthcare system of treating patients waiting for an organ, the 1.3 million AUD the Australian Government has committed might represent a very worthwhile investment. I argue that a scheme like the Australian one is sufficiently well designed to avoid all the ethical problems traditionally associated with attaching a monetary value to the human body or to parts of it, namely commodification, inducement, exploitation, and equality issues. Therefore, I suggest that the Australian scheme, if cost‐effective, should represent a model for other countries to follow. Nonetheless, although I endorse this scheme, I will also argue that this kind of scheme raises issues of justice in regard to the distribution of organs. Thus, I propose that other policies would be needed to supplement the scheme in order to guarantee not only a higher number of organs available, but also a fair distribution.     

Variation of sex ratio and ABO blood group composition by month of birth of blood donors in Tokyo

Sex ratio of 17,273 blood donors born during the period between 1925 and 1935 was examined according to their month of birth and ABO blood groups in comparison with 5,810 healthy non-blood donors born in the 1900s to 1930s. The sex ratio of the blood donors and the non-blood donors varied similarly according to their month of birth with a prominent peak in summer births and a trough in winter births. This birth season with a high sex ratio was different from that of the general births during the period between 1921 and 1935, in which a maximum sex ratio was found in November. A possible explanation for the difference is the different rate of male and female infant deaths according to birth month. Variation of the sex ratio according to season of birth was not similar among the four ABO blood groups. Sex ratio of the donors with blood group B showed no elevation among the summer births. Non-blood donors with blood group B, on the contrary, showed a higher sex ratio than the others in the summer births. This difference can not be explained by infant or juvenile deaths. A possibility is that a tendency to become a blood donor is modified by the season of one's birth differently according to gender and ABO blood groups.     

Ecological Equivalence: A Realistic Assumption for Niche Theory as a Testable Alternative to Neutral Theory

Background

Hubbell''s 2001 neutral theory unifies biodiversity and biogeography by modelling steady-state distributions of species richness and abundances across spatio-temporal scales. Accurate predictions have issued from its core premise that all species have identical vital rates. Yet no ecologist believes that species are identical in reality. Here I explain this paradox in terms of the ecological equivalence that species must achieve at their coexistence equilibrium, defined by zero net fitness for all regardless of intrinsic differences between them. I show that the distinction of realised from intrinsic vital rates is crucial to evaluating community resilience.

Principal Findings

An analysis of competitive interactions reveals how zero-sum patterns of abundance emerge for species with contrasting life-history traits as for identical species. I develop a stochastic model to simulate community assembly from a random drift of invasions sustaining the dynamics of recruitment following deaths and extinctions. Species are allocated identical intrinsic vital rates for neutral dynamics, or random intrinsic vital rates and competitive abilities for niche dynamics either on a continuous scale or between dominant-fugitive extremes. Resulting communities have steady-state distributions of the same type for more or less extremely differentiated species as for identical species. All produce negatively skewed log-normal distributions of species abundance, zero-sum relationships of total abundance to area, and Arrhenius relationships of species to area. Intrinsically identical species nevertheless support fewer total individuals, because their densities impact as strongly on each other as on themselves. Truly neutral communities have measurably lower abundance/area and higher species/abundance ratios.

Conclusions

Neutral scenarios can be parameterized as null hypotheses for testing competitive release, which is a sure signal of niche dynamics. Ignoring the true strength of interactions between and within species risks a substantial misrepresentation of community resilience to habitat loss.     

THE DEAD DONOR RULE,VOLUNTARY ACTIVE EUTHANASIA,AND CAPITAL PUNISHMENT

We argue that the dead donor rule, which states that multiple vital organs should only be taken from dead patients, is justified neither in principle nor in practice. We use a thought experiment and a guiding assumption in the literature about the justification of moral principles to undermine the theoretical justification for the rule. We then offer two real world analogues to this thought experiment, voluntary active euthanasia and capital punishment, and argue that the moral permissibility of terminating any patient through the removal of vital organs cannot turn on whether or not the practice violates the dead donor rule. Next, we consider practical justifications for the dead donor rule. Specifically, we consider whether there are compelling reasons to promulgate the rule even though its corresponding moral principle is not theoretically justified. We argue that there are no such reasons. In fact, we argue that promulgating the rule may actually decrease public trust in organ procurement procedures and medical institutions generally – even in states that do not permit capital punishment or voluntary active euthanasia. Finally, we examine our case against the dead donor rule in the light of common arguments for it. We find that these arguments are often misplaced – they do not support the dead donor rule. Instead, they support the quite different rule that patients should not be killed for their vital organs.     

The phenoptosis problem: What is causing the death of an organism? Lessons from acute kidney injury

Programmed execution of various cells and intracellular structures is hypothesized to be not the only example of elimination of biological systems — the general mechanism can also involve programmed execution of organs and organisms. Modern rating of programmed cell death mechanisms includes 13 mechanistic types. As for some types, the mechanism of actuation and manifestation of cell execution has been basically elucidated, while the causes and intermediate steps of the process of fatal failure of organs and organisms remain unknown. The analysis of deaths resulting from a sudden heart arrest or multiple organ failure and other acute and chronic pathologies leads to the conclusion of a special role of mitochondria and oxidative stress activating the immune system. Possible mechanisms of mitochondria-mediated induction of the signaling cascades involved in organ failure and death of the organism are discussed. These mechanisms include generation of reactive oxygen species and damage-associated molecular patterns in mitochondria. Some examples of renal failure-induced deaths are presented with mechanisms and settings determined by some hypothetical super system rather than by the kidneys themselves. This system plays the key role in the process of physiological senescence and termination of an organism. The facts presented suggest that it is the immune system involved in mitochondrial signaling that can act as the system responsible for the organism’s death.     

Brain death and organ donation in a neurosurgical unit: audit of recent practice.

OBJECTIVE--To assess the potential for increasing the yield of donors by comparing the current pattern of brain death and organ donation in a neurosurgical unit with that reported in 1981 and with a recent national audit. DESIGN--Retrospective review of all deaths for 1986, 1987, and 1988 and prospective data for 1989. SETTING--A regional neurosurgical unit serving 2.7 million population. RESULTS--Of 553 deaths, 35% (191) patients died while on a ventilator and 17% (92) after discontinuation of ventilation. Medical contraindications to donation were found in 23% (32) of 141 patients tested for brain death, in 38% (19) of 50 patients who died while being ventilated who were not tested, and in 12% (11) of 92 patients no longer being ventilated. Consent for donation was sought in 88% (96) of 109 medically suitable brain dead patients and granted in 70% (67) of these. Half those with permission for multiorgan donation had only the kidneys removed. CONCLUSIONS--More organs may be lost owing to transplant team logistics than by failure to seek consent from relatives of brain dead patients. The estimated size of the pool of potential donors depends on what types of patients might be considered. Ensuring that all who die while being ventilated are tested for brain death and considering the potential for donation before withdrawing ventilation could yield more donors. Ventilating more patients who are hopelessly brain damaged to secure more donors raises ethical and economic issues.     

Brain death in Britain as reflected in renal donors.

The diagnostic mix of 1228 brain-dead renal donors in Britain was similar to that of 479 cases of brain death recently reported from three neurosurgical units. About half the donors came from non-teaching hospitals without a neurosurgical unit, many of them small and distant from the centre. The different circumstances that preceded brain deaths were examined--namely, diagnosis and whether the fatal ictus of brain damage occurred when the patient was already in hospital--to explain why donors spend varying times on the ventilator. Head injuries accounted for half the donors, and intracranial haemorrhage for almost a third. While many potential donors are not made available, the size of the pool has been overestimated, particularly in regard to head injury. Reduction in organ donation since "Panorama" has been very uneven, with some places increasing their yield; this suggests reluctance of doctors to initiate donation rather than relatives withholding permission.     

Deaths from cerebrovascular diseases correlated to month of birth: elevated risk of death from subarachnoid hemorrhage among summer-born

It has been suggested that maternal nutrition, and fetal and infant growth have an important effect on the risk of cardiovascular disease in adult life. We investigated the population-based distribution of deaths from cerebrovascular diseases (ICD9 codes 430, 431, or 434) in Japan in 1986–1994 as a function of birth month, by examining death-certificate records. For a total of 853 981 people born in the years 1900–1959, the distribution of the number of deaths according to the month of birth was compared with the distribution expected from the monthly numbers of all births for each sex and for the corresponding birth decade. For those born between 1920 and 1949, there were significant discrepancies between the actual numbers of deaths from subarachnoid hemorrhage (ICD9 430) and the numbers expected, and these differences were related to the month of birth. Those born in summer, June–September, consistently had an elevated risk of death, particularly men, where the excess risk was 8%–23%. This tendency was also observed, less distinctly but significantly, for deaths from intracerebral hemorrhage (ICD9 431), but was not observed for those dying from occlusion of the cerebral arteries (ICD9 434). The observation that the risk of dying from subarachnoid hemorrhage was more than 10% higher among those born in the summer implies that at least one in ten deaths from subarachnoid hemorrhage has its origin at a perinatal stage. Although variations in hypertension in later life, which could possibly be ”programmed” during the intra-uterine stages, could be an explanation for this observation, the disease-specific nature of the observation suggests the involvement of aneurysm formation, which is a predominant cause of subarachnoid hemorrhage. Received: 22 October 1999 / Revised: 8 May 2000 / Accepted: 10 May 2000     

Radiation risk estimates after radiotherapy: application of the organ equivalent dose concept to plateau dose–response relationships

Estimates of secondary cancer risk after radiotherapy are becoming more important for comparative treatment planning. Modern treatment planning systems provide accurate three-dimensional (3D) dose distributions for each individual patient. The dose distributions can be converted into organ equivalent doses to describe radiation-induced cancer after radiotherapy (OED_rad-ther) in the irradiated organs. The OED_rad-ther concept assumes that any two dose distributions in an organ are equivalent if they cause the same radiation-induced cancer risk. In this work, this concept is applied to dose–response relationships, which are leveling off at high dose. The organ-dependent operational parameter of this dose–response relationship was estimated by analyzing secondary cancer incidence data of patients with Hodgkin’s disease. The dose distributions of a typical radiotherapy treatment plan for treating Hodgkin’s disease was reconstructed. Dose distributions were calculated in individual organs from which cancer incidence data were available. The model parameter was obtained by comparing dose and cancer incidence rates for the individual organs.     

Design,synthesis and antibacterial properties of pyrimido[4,5-b]indol-8-amine inhibitors of DNA gyrase

According to the World Health Organization (WHO), approximately 1.7 million deaths per year are caused by tuberculosis infections. Furthermore, it has been predicted that, by 2050, antibacterial resistance will be the cause of approximately 10 million deaths annually if the issue is not tackled. As a result, novel approaches to treating broad-spectrum bacterial infections are of vital importance. During the course of our wider efforts to discover unique methods of targeting multidrug-resistant (MDR) pathogens, we identified a novel series of amide-linked pyrimido[4,5-b]indol-8-amine inhibitors of bacterial type II topoisomerases. Compounds from the series were highly potent against gram-positive bacteria and mycobacteria, with excellent potency being retained against a panel of relevant Mycobacterium tuberculosis drug-resistant clinical isolates.