Heterozygous deletion of the PU.1 locus in human AML

The transcription factor PU.1 is essential for myeloid development. Targeted disruption of an upstream regulatory element (URE) decreases PU.1 expression by 80% and leads to acute myeloid leukemia (AML) in mice. Here, we sequenced the URE sequences of PU.1 in 120 AML patients. Four polymorphisms (single nucleotide polymorphisms [SNPs]) in the URE were observed, with homozygosity in all SNPs in 37 patients. Among them, we compared samples at diagnosis and remission, and one patient with cytogenetically normal acute myeloid leukemia M2 was identified with heterozygosity in 3 of the SNPs in the URE at remission. Loss of heterozygosity was further found in this patient at 2 polymorphic sites in the 5' promoter region and in 2 intronic sites flanking exon 4, thus suggesting loss of heterozygosity covering at least 40 kb of the PU.1 locus. Consistently, PU.1 expression in this patient was markedly reduced. Our study suggests that heterozygous deletion of the PU.1 locus can be associated with human AML.

[Hyperreactive luteomas during pregnancy--symptoms and complications: a case report]

A 27-year-old Caucasian (gravida 2 para 1) presented in week 16 of her twin pregnancy with worsening of hyperandrogenic symptoms. In week 17, she developed an acute abdomen due to a twisted, incarcerated right ovary, which was surgically removed. Histological analysis revealed a diffuse steroid cell hyperplasia. Postsurgery testosterone levels fell temporarily within normal limits, diminishing the hyperandrogenic symptoms. Over time androgen levels rose again slowly above normal values with clinical worsening of hirsutism. In the 32nd week of gestation, a cesarean section of two healthy female infants was necessary due to the development of preeclampsia. An ovarian biopsy revealed again the picture of hyperreactio luteinalis. Postpartum peripheral hormone levels fell within normal limits and the hyperandrogenic symptoms subsided.

[Irreversible bilateral amaurosis in a 36-year-old immigrant]

We report on a 36-year-old man with a history of mild head trauma. The initial clinical findings and the CT-scan of the brain revealed no pathological result, although the patient suffered from weakness of the right arm and bilateral blindness. Those findings were interpreted as psychogenic disorder. Nine days later he developed an instable gait, a child like attitude, amnesia and enuresis. The CT-scan revealed a subacute bilateral occipital stroke in the region of the arteriae cerebri posteriors. No cause for the stroke was found. In spite of the rareness of cortical blindness in young people as a cause of stroke, a detailed medical history and clinical examination should always be performed, and by unclearness additional investigations should be considered.

Mice deficient in interleukin-4 (IL-4) or IL-4 receptor alpha have higher resistance to sporozoite infection with Plasmodium berghei (ANKA) than do naive wild-type mice

BALB/c interleukin-4 (IL-4(-/-)) or IL-4 receptor-alpha (IL-4ralpha(-/-)) knockout (KO) mice were used to assess the roles of the IL-4 and IL-13 pathways during infections with the blood or liver stages of plasmodium in murine malaria. Intraperitoneal infection with the blood-stage erythrocytes of Plasmodium berghei (ANKA) resulted in 100% mortality within 24 days in BALB/c mice, as well as in the mutant mouse strains. However, when infected intravenously with the sporozoite liver stage, 60 to 80% of IL-4(-/-) and IL-4ralpha(-/-) mice survived, whereas all BALB/c mice succumbed with high parasitemia. Compared to infected BALB/c controls, the surviving KO mice showed increased NK cell numbers and expression of inducible nitric oxide synthase (iNOS) in the liver and were able to eliminate parasites early during infection. In vivo blockade of NO resulted in 100% mortality of sporozoite-infected KO mice. In vivo depletion of NK cells also resulted in 80 to 100% mortality, with a significant reduction in gamma interferon (IFN-gamma) production in the liver. These results suggest that IFN-gamma-producing NK cells are critical in host resistance against the sporozoite liver stage by inducing NO production, an effective killing effector molecule against Plasmodium. The absence of IL-4-mediated functions increases the protective innate immune mechanism identified above, which results in immunity against P. berghei infection in these mice, with no major role for IL-13.