Hemoglobin genotype, fertility, and the malaria hypothesis

Epidemiological and clinical studies (Fleming et al. 1985; Perrin et al. 1982) indicate that hemoglobin (Hb) AS individuals have a selective advantage in malarial environments. Thus the high frequency of Hb S in human populations has been attributed to the decreased malarial morbidity and mortality experienced by Hb AS heterozygotes. It has also been suggested that Hb AS women have a higher fertility than that of Hb AA women, thus contributing to the elevated frequency of Hb S in malarial environments (Livingstone 1957). Firschein (1961) demonstrated a significantly greater fertility among Hb AS females, whereas Custodio and Huntsman (1984) documented no fertility differential between Hb AS and Hb AA women. Here I examine the reproductive careers of Hb AA and Hb AS subjects 40 years of age and older from Limon, Costa Rica. The purpose is to determine whether normal homozygotes and heterozygotes have significantly different fertilities. The research shows that these groups do not have significantly different completed family sizes (t = 0.38, ns) or significantly different numbers of pregnancies (t = 0.34, ns), live births (t = 0.36, ns), or abortions (t = 0.20, ns). My results support previous suggestions that differential fertility does not contribute to the maintenance of the Hb S polymorphism.     

Ethnic fertility differentials in Peninsular Malaysia and Singapore

Differences in fertility between the three major ethnic groups (Malays, Chinese and Indians) in Peninsular Malaysia and Singapore have existed since before the onset of fertility decline in the late 1950s and remain today, although the relative positions and the actual differences have changed due to the varying rates of decline. By 1987, the Malays experienced the highest fertility and the Chinese the lowest in both countries but in Singapore the Malay fertility was lower than the Chinese fertility in Peninsular Malaysia. The fertility differentials will lead to changes in the ethnic composition in both countries but more so in Peninsular Malaysia.     

Parasites that cause problems in Malaysia: soil-transmitted helminths and malaria parasites

Malaysia is a developing country with a range of parasitic infections. Indeed, soil-transmitted helminths and malaria parasites continue to have a significant impact on public health in Malaysia. In this article, the prevalence and distribution of these parasites, the problems associated with parasitic infections, the control measures taken to deal with these parasites and implications for the future will be discussed.     

Continuing fertility transitions in a plural society: ethnic trends and differentials in Peninsular Malaysia

Fertility in Peninsular Malaysia has declined continuously from the late 1950s, reaching a total fertility rate of 3735 in 1983. All ethnic groups in Malaysia have contributed to this modern demographic transition but the rate of change has been most rapid for Chinese and Indians, Malay fertility having reached a plateau in the early 1980s. The effect of age structure, marital patterns and marital fertility (by parity) on the fertility declines for each ethnic community are analyzed. There has been a tendency, in each ethnic group, for the age distribution within the group of reproductive-age women to grow younger, reflecting the entry into the younger reproductive ages of the large birth cohorts of the 1950s and early 1960s. The effect of this on crude birth rates is hard to determine, because rising age at marriage and increasing use of contraception meant that fertility was increasingly concentrated in the more central reproductive ages. By the 1990s, the earlier declines in fertility will bring about a decline in the proportion of the total population made up of females in the main reproductive ages. After that point, further declines in fertility will be reflected in a sharper decline in the crude birth rate and hence the rate of population increase. Between 1947 and 1980, the age at marriage changed dramatically for females of all ethnic groups. The transition to higher age at marriage for Chinese was completed earlier, and since 1970 has risen by only a year. For Malays and Indians, the rise began later, proceeded faster and continued right up to 1980 when the medium ages at 1st marriage were Malays 22, Indians 23, Chinese 24 years. In 1980, Malay women on average were marrying 5 years later, and Indian women 6 years later than had their mothers' generation in 1947. The proportion never-married among Malay and Indian women aged 20-24 rose from 1/10 to 1/2 over this period; relatively greater changes are evident at ages 25-29. Other factors are the almost complete shift from parent-arranged to self-arranged marriages. Family size desired has decreased for all groups and the decline in breastfeeding has been offset by the sharp increase in the practice of contraception. Continuation of these trends would lead to replacement-level fertility for Malaysian Chinese and Indians by the year 2000. Malay fertility is likely to continue to decline but at a more moderate pace.     

Male fertility of malaria parasites is determined by GCS1, a plant-type reproduction factor

Malaria, which is caused by Plasmodium parasites, is transmitted by anopheline mosquitoes. When gametocytes, the precursor cells of Plasmodium gametes, are transferred to a mosquito, they fertilize and proliferate, which render the mosquito infectious to the next vertebrate host. Although the fertilization of malaria parasites has been considered as a rational target for transmission-blocking vaccines, the underlying mechanism is poorly understood. Here, we show that the rodent malaria parasite gene Plasmodium berghei GENERATIVE CELL SPECIFIC 1 (PbGCS1) plays a central role in its gametic interaction. PbGCS1 knockout parasites show male sterility, resulting in unsuccessful fertilization. Because such a male-specific function of GCS1 has been observed in angiosperms, this indicates, for the first time, that parasite sexual reproduction is controlled by a machinery common to flowering plants. Our present findings provide a new viewpoint for understanding the parasitic fertilization system and important clues for novel strategies to attack life-threatening parasites.     

Copper‐transporting ATPase is important for malaria parasite fertility

Homeostasis of the trace element copper is essential to all eukaryotic life. Copper serves as a cofactor in metalloenzymes and catalyses electron transfer reactions as well as the generation of potentially toxic reactive oxygen species. Here, we describe the functional characterization of an evolutionarily highly conserved, predicted copper‐transporting P‐type ATPase (CuTP) in the murine malaria model parasite Plasmodium berghei. Live imaging of a parasite line expressing a fluorescently tagged CuTP demonstrated that CuTP is predominantly located in vesicular bodies of the parasite. A P. berghei loss‐of‐function mutant line was readily obtained and showed no apparent defect in in vivo blood stage growth. Parasite transmission through the mosquito vector was severely affected, but not entirely abolished. We show that male and female gametocytes are abundant in cutp^? parasites, but activation of male microgametes and exflagellation were strongly impaired. This specific defect could be mimicked by addition of the copper chelator neocuproine to wild‐type gametocytes. A cross‐fertilization assay demonstrated that female fertility was also severely abrogated. In conclusion, we provide experimental genetic and pharmacological evidence that a healthy copper homeostasis is critical to malaria parasite fertility of both genders of gametocyte and, hence, to transmission to the mosquito vector.     

Deaths due to Plasmodium knowlesi malaria in Sabah, Malaysia: association with reporting as Plasmodium malariae and delayed parenteral artesunate

ABSTRACT: BACKGROUND: The simian parasite Plasmodium knowlesi is recognized as a common cause of severe and fatal human malaria in Sabah, Malaysia, but is morphologically indistinguishable from and still commonly reported as Plasmodium malariae, despite the paucity of this species in Sabah. Since December 2008 Sabah Department of Health has recommended intravenous artesunate and referral to a general hospital for all severe malaria cases of any species. This paper reviews all malaria deaths in Sabah subsequent to the introduction of these measures. Reporting of malaria deaths in Malaysia is mandatory. METHODS: Details of reported malaria deaths during 2010-2011 were reviewed to determine the proportion of each Plasmodium species. Demographics, clinical presentations and management of severe malaria caused by each species were compared. RESULTS: Fourteen malaria deaths were reported, comprising seven Plasmodium falciparum, six P. knowlesi and one Plasmodium vivax (all PCR-confirmed). Of the six P. knowlesi deaths, five were attributable to knowlesi malaria and one was attributable to P. knowlesi-associated enterobacter sepsis. Patients with directly attributable P. knowlesi deaths (N = 5) were older than those with P. falciparum (median age 51 [IQR 50-65] vs 22 [IQR 9-55] years, p = 0.06). Complications in fatal P. knowlesi included respiratory distress (N = 5, 100%), hypotension (N = 4, 80%), and renal failure (N = 4, 80%). All patients with P. knowlesi were reported as P. malariae by microscopy. Only two of five patients with severe knowlesi malaria on presentation received immediate parenteral anti-malarial treatment. The patient with P. vivaxassociated severe illness did not receive parenteral treatment. In contrast six of seven patients with severe falciparum malaria received immediate parenteral treatment. CONCLUSION: Plasmodium knowlesi was responsible, either directly or through gram-negative bacteraemia, for almost half of malaria deaths in Sabah. Patients with severe non-falciparum malaria were less likely to receive immediate parenteral therapy. This highlights the need in Sabah for microscopically diagnosed P. malariae to be reported as P. knowlesi to improve recognition and management of this potentially fatal species. Clinicians need to be better informed of the potential for severe and fatal malaria from non-falciparum species, and the need to treat all severe malaria with immediate intravenous artesunate.     

The influence of permethrin-impregnated bednets and mass drug administration on the incidence of Plasmodium falciparum malaria in children in Sabah, Malaysia

A small-scale trial was carried out in the Upper Kinabatangan district of Sabah, Malaysia, to determine the effect of using permethrin-impregnated bednets on malaria transmission. A total of 306 nylon bednets with cotton borders, impregnated at a dose estimated to have been 0.062 g permethrin/m2 of nylon netting, were distributed to 139 households in five villages. At the time of distributing bednets, mass drug administration with Fansidar plus primaquine was also administered to the human population to clear all parasitaemias due to Plasmodium falciparum Welch. In another village, for comparison, mass drug administration was the only intervention. After intervention measures in December 1984 and January 1985, the parasite rates in children declined in all villages during the first month, significantly more in the villages with impregnated bednets than in the control, thus proving that the nets had an impact on malaria. However, after about 2 months, parasite rates started to increase again. After 4-6 months, parasite rates in the villages with bednets approached the rate in the control village without nets. The increase in parasite rates was paralleled by a significant deterioration in the quality, physical condition and the degree of non-utilization of bednets. Entomological evaluation proved the efficacy of permethrin-impregnated nets for controlling Anopheles balabacensis Baisas and other anophelines. Bioassays (1 h exposure) of permethrin-impregnated bednets gave 100% mortality initially and 44-61% mortality after 85-106 days. Mosquito collections in treated bednets were significantly reduced for at least 217 days. The project failed to achieve prolonged suppression of malaria transmission for a combination of entomological, sociological and practical reasons which are discussed in relation to the objectives and implementation of future bednet studies.     

A central role for P48/45 in malaria parasite male gamete fertility

Fertilization and zygote development are obligate features of the malaria parasite life cycle and occur during parasite transmission to mosquitoes. The surface protein PFS48/45 is expressed by male and female gametes of Plasmodium falciparum and PFS48/45 antibodies prevent zygote development and transmission. Here, gene disruption was used to show that Pfs48/45 and the ortholog Pbs48/45 from a rodent malaria parasite P. berghei play a conserved and important role in fertilization. p48/45- parasites had a reduced capacity to produce oocysts in mosquitoes due to greatly reduced zygote formation. Unexpectedly, only male gamete fertility of p48/45- parasites was affected, failing to penetrate otherwise fertile female gametes. P48/45 is shown to be a surface protein of malaria parasites with a demonstrable role in fertilization.     

Genetic dissection of embryo sac fertility, pollen fertility, and their contributions to spikelet fertility of intersubspecific hybrids in rice

The partial sterility of hybrids has been a major barrier for utilization of the strong heterosis expressed in hybrids between Oryza sativa ssp. indica and O. sativa ssp. japonica. Wide-compatibility varieties, comprising a special class of germplasm, are able to produce fertile hybrids when crossed to both indica and japonica varieties. However, all the work on wide compatibility and majority of studies on indica/japonica hybrid sterility reported so far were based only on spikelet fertility; thus, it is not known to what extent male and female gamete abortions influence hybrid sterility. In this study, we investigated pollen fertility, embryo sac fertility, and spikelet fertility in an F₁ population of 202 true hybrid plants derived from a three-way cross (02428/Nanjing 11//Balilla). A partial regression analysis showed that the pollen and embryo sac fertility contributed almost equally to spikelet fertility. QTL analysis based on a linkage map of 191 polymorphic marker loci identified two QTLs for pollen fertility, one QTL for embryo sac fertility, and three QTLs for spikelet fertility. The S5 locus, previously identified as a locus for wide compatibility by spikelet fertility analysis, is a major locus for embryo sac fertility, and a QTL on chromosome 5 had a major effect on pollen fertility. These two loci coincided with the two major QTLs for spikelet fertility. The study also detected a QTL on chromosome 8, showing a large effect on spikelet fertility but no effect on either pollen or embryo sac fertility. Very little interaction among the QTLs was detected. The implications of the findings in rice breeding programs are discussed.     

Hormones, sexuality and fertility in women

The extent to which the sexuality of women shows a predictable menstrual cyclicity varies considerably from woman to woman, though the most common times for peaks of sexual interest are the pre- and post-menstrual weeks, not the middle of the cycle. Evidence is presented suggesting that mood is an important determinant of the post-menstrual peak of sexuality, whereas the pre-menstrual peak may depend on other mechanisms such as a delayed effect of the mid-cycle rise in testosterone.
Generally, the evidence for a relationship between hormones and sexual behaviour is much more variable and inconsistent in women than in men. Various explanations for this difference have been proposed, including a greater genetic variability of hormone-behaviour relationships in women. Evidence, relevant to this hypothesis, of a relationship between frequency of sexual activity and the fertility of the ovarian cycle is reviewed and alternative explanations for the findings are considered.