Sheila McLean

Plasmodium chabaudi: Antigenic variation during recrudescent parasitaemias in mice

Abstract The A/S strain of Plasmodium chabaudi at different times was twice mosquito passaged and cloned by limiting dilution. Large groups of NIH mice were infected with 10 5 parasitized red cells of populations of parasites which were considered to be identical or very similar to the population forming the first erythrocytic parasitaemia seen in mice after mosquito transmission of the parasite. Most of the mice were killed immediately after the first patent parasitaemia had become subpatent and their sera pooled. The parasitaemias of surviving mice were followed until recrudescences appeared. The protective activity of the immune serum was then tested against the original infecting population and recrudescent populations by passive transfer tests in naive mice. Protection was measured as a delay in patent parasitaemia reaching 2% compared with normal serum recipients. The immune serum significantly delayed the 2% parasitaemia but in different experiments six out of seven recrudescent populations were found to be less sensitive to the effects of the immune serum than the original infecting population. The recrudescent populations retained their reduced or total insensitivity to the action of the immune serum after two blood passages and after eryopreservation. It appears, therefore, that P. chabaudi can undergo antigenic variation.

Antigenic variation in Plasmodium chabaudi: analysis of parent and variant populations by cloning.

Summary Nineteen of 22 recrudescent populations of Plasmodium chabaudi AS strain were found to be significantly less sensitive to the protective activity of pools of immune serum, than the parent population from which they were derived. The immune sera were collected from donor mice which had been infected with the parent population and had just reduced the patent primary parasitaemia to subpatent levels. Clones prepared from the parent population (which had previously been cloned) and recrudescent variant populations were tested for their sensitivity to the immune sera. It was found that all the clones from the parent population were sensitive to the immune sera but some were more sensitive than others and that a recrudescent variant population could include both sensitive and insensitive parasites. Two insensitive clones of the recrudescent population were found to be different from each other

The effect of mosquito transmission of antigenic variants of Plasmodium chabaudi

Plasmodium chabaudi AS strain in mice is characterized by an acute primary parasitaemia, and one or more less acute recrudescences. Previous work has shown, using a passive protection assay, that the recrudescent parasites are usually antigenically different from parasites of the parent population with which the mice were first infected. In this study the effect of mosquito transmission on the antigenic expression of recrudescent populations of P. chabaudi was examined. In the first experiments the recrudescent population which was antigenically different from the parent population was uncloned. After transmission through Anopheles stephensi the recrudescent population appeared to revert to an antigenic type similar to that of the parent population. In the second experiment clones from a recrudescent population were mosquito transmitted and again the parasites of the primary patent parasitaemia in the mice, bitten by the infected mosquitoes, had reverted to the parental type. It is suggested that antigenic variants of P. chabaudi AS strain may revert to a basic type after mosquito transmission.

Legal and ethical aspects of the vegetative state.

The diagnosis of persistent or permanent vegetative state (PVS) raises ethical and legal problems. Strict adherence to the doctrine of the sanctity of life would require carers to continue to maintain the individual, perhaps for many years. However, few would regard this as an appropriate outcome when the person clearly has no capacity to interact with the environment and has no likelihood of recovery. However, the ethical and legal commitment to the sanctity of life has led courts to employ a variety of approaches to this situation in order to find a way in which the person in PVS can be allowed to die. It is argued that each of the approaches is disingenuous and ultimately unhelpful. What the law is doing is endorsing non-voluntary euthanasia, but dressing it up as something else. This is unhelpful for all concerned and the time has come for a review of all end of life decisions so that doctors, patients, and relatives can make honest decisions without fear of legal reprisal.

Early appearance of variant parasites in Plasmodium chabaudi infections

Summary Previous studies have shown that the recrudescence parasitaemias seen in mice infected with Plasmodium chabaudi AS strain are antigenically different from the infecting parent population. Antigenic differences between recrudescent and parent populations were demonstrated in a passive transfer assay. In the present study, using the same assay system, it has been shown that in some mice, variant parasites (i.e. different from the parent population) can be detected at a time when the primary parasitaemia is still patent but in remission. This is the first report in Plasmodium of variant parasites being detected during the course of a patent primary parasitaemic episode of an infection initiated with a cloned line.

Choosing children: intergenerational justice?

In this discussion, we argue that the concept of intergenerational justice, usually used in environmental matters, is applicable to reproductive decisions also. Additionally, we propose that this permits certain reproductive choices to be made prior to conception or during the pregnancy, and that these choices should not be confined to clinical concerns. In particular, we argue that consideration of the interests of future children should be viewed from the perspective of objective well-being. That being the case, decisions about the sex of future offspring can, in terms of intergenerational justice, be legitimate. We do not argue that every reproductive choice is legitimate; for example it would not be legitimate deliberately to choose characteristics that prevent future children from potentially successful participation in social life.

Antigenic variants of Plasmodium chabaudi chabaudi AS and the effects of mosquito transmission

Previous results, using a passive transfer assay, have shown that recrudescences of Plasmodium chabaudi chabaudi AS strain are antigenically different from the infecting parental population and also that the recrudescence appears to be a mix of antigenic types. This present study examines further these recrudescent populations using an indirect fluorescent antibody test on live, schizont‐infected red blood cells. This analysis shows that ten clones derived from a recrudescence are all antigenically different from the parent population and that some are different from each other. The use of this method to examine the antigenic types of recrudescent clones after transmission through mosquitoes also demonstrates a resulting change in antigenicity. Such results showing a link between mosquito transmission and varying antigenicity may have important implications in terms of immunity and vaccine development.

The moral and legal boundaries of fetal intervention: whose right/whose duty

There is a growing trend to identify the fetus as a patient with interests and needs independent of the pregnant woman. Medical advances have made it increasingly possible to visualize the fetus in the womb, to identify disorders and to offer therapy before birth. In addition, knowledge about the ways in which the womans behaviour can affect the health of the developing fetus has produced an impetus to police pregnancy and in some cases to seek to hold women criminally responsible, or liable to civil law constraints, in order to ensure fetal health. Finally, womens behaviour at the moment of birth is increasingly subject to scrutiny, occasionally resulting in the use of coercive legal measures. No matter how emotionally compelling, the generation of a medical and legal culture which concentrates on respecting fetal interests, or which creates fetal rights, is to be avoided as it fails to achieve equipoise between the woman (a legal person) and the fetus. Ultimately, failure to respect the womans rights may harm both her and the fetus.

Interventions in the Human Genome

dictators, the recent eugenic excesses of the twentieth century and the brave new world held out by the imminent completion of the Human Genome Project provide rich and fertile ground for speculation, debate and sometimes concern. On the other hand, genetics offers the capacity to identify disorders and hopefully in the future to cure them. As Wilkie says, the new genetical anatomy will transform medicine and mitigate suffering in the twenty-first century. Watson and Cricks discovery in 1953 of the structure of DNA - the key discovery on which the Human Genome Project rests - was probably one of the most remarkable scientific achievements of this century, and has led to the most ambitious scientific project since the space race. Its significance lies in the growing capacity to identify the molecular structures which make us who we are, at least physically. As Bodmer and McKie have said: DNA is the true chemical of life, for it is the essential component from which our genes are made. In it is encoded the genetic language that controls our destinies. And an astonishingly powerful lexicon it is. Just six million millionths of a gram of DNA carries as much information as ten volumes of the Complete Oxford English Dictionary.2 Clearly the potential of being able to unravel and translate this lexicon in both depth and detail is of enormous fascination to science. Even if not all of the information ultimately discovered is of immediate interest or applicability (socalled junk DNA3), much of what is discovered will be of theoretical and/or practical value. The capacity to identify rogue genes which cause disease or disability may lead to medical advances as yet unimagined. And the toll of genetic disorder should not be underestimated. Wexler suggests that [i]t is now estimated that gene defects underlie 3,000 to 4,000 different diseases, and this is before one considers polygenic etiologies in which there is interaction between genes and environment.4

Mapping the human genome--friend or foe?

The Human Genome Project represents one of sciences most significant advances. It offers to individuals and communities the capacity to make informed and autonomous decisions. However, it also poses fundamental questions which, it is argued, should be in contemplation now. If mechanisms for the resolution of these issues are not in place before the conclusion of the project, and are not available to guide and control its progress, individual privacy may be seriously affected. Employers, insurers and many other groups may seek access to information which would otherwise be confidential to the individual; families may be torn apart by the information held by one member in respect of the collective gene pool of the family unit. The law has a key role to play in encouraging the sensible use of this information, whilst at the same time protecting individuals and their rights.