Ancient Plasmodium genomes shed light on the history of human malaria.

Malaria-causing protozoa of the genus Plasmodium have exerted one of the strongest selective pressures on the human genome, and resistance alleles provide biomolecular footprints that outline the historical reach of these species1. Nevertheless, debate persists over when and how malaria parasites emerged as human pathogens and spread around the globe1,2. To address these questions, we generated high-coverage ancient mitochondrial and nuclear genome-wide data from P. falciparum, P. vivax and P. malariae from 16 countries spanning around 5,500 years of human history. We identified P. vivax and P. falciparum across geographically disparate regions of Eurasia from as early as the fourth and first millennia BCE, respectively; for P. vivax, this evidence pre-dates textual references by several millennia3. Genomic analysis supports distinct disease histories for P. falciparum and P. vivax in the Americas: similarities between now-eliminated European and peri-contact South American strains indicate that European colonizers were the source of American P. vivax, whereas the trans-Atlantic slave trade probably introduced P. falciparum into the Americas. Our data underscore the role of cross-cultural contacts in the dissemination of malaria, laying the biomolecular foundation for future palaeo-epidemiological research into the impact of Plasmodium parasites on human history. Finally, our unexpected discovery of P. falciparum in the high-altitude Himalayas provides a rare case study in which individual mobility can be inferred from infection status, adding to our knowledge of cross-cultural connectivity in the region nearly three millennia ago.

Screening of LHX2 in patients presenting growth retardation with posterior pituitary and ocular abnormalities.

BACKGROUND: In humans, pituitary hormone deficiency may be part of a syndrome including extra-pituitary defects like ocular abnormalities. Very few genes have been linked to this particular phenotype. In the mouse, Lhx2, which encodes a member of the LIM (Lin-11, Isl-1, and Mec-3) class of homeodomain proteins, was shown to be expressed during early development in the posterior pituitary, eye, and liver, and its expression persists in adulthood in the central nervous system Lhx2(-/-) mice display absence of posterior pituitary and intermediate lobes, malformation of the anterior lobe, anophthalmia, and they die from anemia. METHODS: We tested the implication of the LHX2 gene in patients presenting pituitary hormone deficiency associated with ectopic or nonvisible posterior pituitary and developmental ocular defects. A cohort of 59 patients, including two familial cases, was studied. Direct sequencing of the LHX2 coding sequence and intron/exon boundaries was performed. LHX2 transcriptional activity on several pituitary promoters (AGSU, PRL, POU1F1, and TSHB) was tested in vitro. RESULTS: Six heterozygous sequence variations were identified, among which two are novel missense changes (p.Ala203Thr and p.Val333Met). In vitro, LHX2 activates transcription of TSHB, PRL, and POU1F1 promoters in the HEK293 cell line. A synergistic action of POU1F1 and LHX2 was also shown on these promoters. The two missense variations were tested and no significant difference was observed, leading to the conclusion that they are not deleterious. CONCLUSIONS: These results suggest that if LHX2 is involved in pituitary hormone deficiency associated with posterior pituitary and ocular defects, it would be a rare cause of this disease condition.

Impact of early transcranial Doppler screening and intensive therapy on cerebral vasculopathy outcome in a newborn sickle cell anemia cohort.

Transcranial Doppler (TCD) is used to detect children with sickle cell anemia (SCA) who are at risk for stroke, and transfusion programs significantly reduce stroke risk in patients with abnormal TCD. We describe the predictive factors and outcomes of cerebral vasculopathy in the Créteil newborn SCA cohort (n = 217 SS/Sß(0)), who were early and yearly screened with TCD since 1992. Magnetic resonance imaging/magnetic resonance angiography was performed every 2 years after age 5 (or earlier in case of abnormal TCD). A transfusion program was recommended to patients with abnormal TCD and/or stenoses, hydroxyurea to symptomatic patients in absence of macrovasculopathy, and stem cell transplantation to those with human leukocyte antigen-genoidentical donor. Mean follow-up was 7.7 years (1609 patient-years). The cumulative risks by age 18 years were 1.9% (95% confidence interval [95% CI] 0.6%-5.9%) for overt stroke, 29.6% (95% CI 22.8%-38%) for abnormal TCD, which reached a plateau at age 9, whereas they were 22.6% (95% CI 15.0%-33.2%) for stenosis and 37.1% (95% CI 26.3%-50.7%) for silent stroke by age 14. Cumulating all events (stroke, abnormal TCD, stenoses, silent strokes), the cerebral risk by age 14 was 49.9% (95% CI 40.5%-59.3%); the independent predictive factors for cerebral risk were baseline reticulocytes count (hazard ratio 1.003/L × 10(9)/L increase, 95% CI 1.000-1.006; P = .04) and lactate dehydrogenase level (hazard ratio 2.78/1 IU/mL increase, 95% CI1.33-5.81; P = .007). Thus, early TCD screening and intensification therapy allowed the reduction of stroke-risk by age 18 from the previously reported 11% to 1.9%. In contrast, the 50% cumulative cerebral risk suggests the need for more preventive intervention.

Immunogenicity and safety of a pneumococcal conjugate 7-valent vaccine in infants with sickle cell disease.

OBJECTIVES: To evaluate safety and immunogenicity of the pneumococcal 7-valent conjugate vaccine (PCV7) when administered to infants with sickle cell disease (SCD) at 2, 3, and 4 months of age with a booster dose of a 23-valent pneumococcal polysaccharide vaccine (PS-23) at 15 to 18 months of age. METHODS: This open-label multicenter study in France enrolled 2-month-old infants with SCD. Blood samples for the determination of antibody concentrations to vaccine serotypes were obtained immediately before and 1 month after the primary immunization, and before and 1 month after the PS-23 booster. Local and systemic reactions were recorded on diary cards. RESULTS: Of the 51 infants enrolled, 49 received primary immunization and 46 received the booster dose. After primary immunization > or =95% of the subjects had antibody titers > or =0.35 microg/mL for the 7 serotypes. After boosting, geometric mean concentrations were high for all serotypes, ranging from 6.32 microg/mL (serotype 18C) to 29.49 microg/mL (serotype 4). Except for 1 case after administration of the booster dose, all fevers reported were less than 39 degrees C. No vaccine-related serious adverse events were reported. CONCLUSIONS: PCV7 administered at 2, 3, and 4 months of age in infants with SCD was well-tolerated, highly immunogenic, and primed for immune memory as indicated by the dramatic response to the PS-23 dose administered at 15-18 months in this study. However, the current recommended schedule is to boost with the PCV7 at 12-15 months of age and for these high-risk children, to enlarge the protection with a subsequent PS-23 dose at 2 years of age.