A 13-year study of Japanese cedar pollinosis in Japanese schoolchildren.

BACKGROUND: Japanese cedar pollen (JCP) sensitization and Japanese cedar pollinosis (JCPS) appear to be increasingly prevalent in younger children. The present study investigated factors affecting JCP sensitization and JCPS development in school children. METHODS: In May or June each year from 1994 to 2006, 275-510 children were assessed for serum JCP-IgE and house dust mite (HDM)-IgE levels, and surveyed regarding rhinoconjunctival symptoms. RESULTS: Strong JCP sensitization (IgE > or = 17.5 U(A)/ml) was associated with age (odds ratio (OR) = 2.65), the amount of dispersed pollen in the observed year (OR = 2.03) and in the year following birth (OR = 1.51), the month of birth (OR = 2.18), and the recent birth cohort (OR = 1.96). Symptoms were negatively correlated with the recent birth cohort (OR = 0.69) after adjusting for JCP-IgE levels. Strong HDM sensitization was associated with gender (OR = 0.65 for girls) and the recent birth cohort (OR = 1.76). CONCLUSIONS: JCP sensitization appeared to be associated with the recent birth cohort and to increases in dispersed pollen just after birth and in the observed season. Although the recent birth cohort was more easily sensitized, they were not more likely to develop symptoms. In contrast to JCP sensitization, strong HDM sensitization appeared to develop prior to commencement of primary school and was more likely to affect boys.     

Bloodstream infection by multidrug‐resistant Streptococcus oralis in a leukemic patient with febrile neutropenia after hematopoietic stem cell transplantation

We reported the case of a patient with leukemia who developed febrile neutropenia after hematopoietic stem cell transplantation. Blood culture results revealed the presence of Streptococcus oralis, while antimicrobial susceptibility testing showed the resistance to penicillin and cephem. Furthermore, isolates were not susceptible to either meropenem or daptomycin but not to vancomycin. S oralis is known to belong to Streptococcus mitis group and be a causative agent of bacteremia in the neutropenic patients, but multidrug resistance of S oralis is rare. Our findings suggest that we might pay attention to the emergence of the microorganisms acquiring multidrug resistance in neutropenic patients.     

Hematological,Hepatic, and Retinal Phenotypes in Mice Deficient for Prolyl Hydroxylase Domain Proteins in the Liver

Prolyl hydroxylase domain (PHD) proteins catalyze oxygen-dependent prolyl hydroxylation of hypoxia-inducible factor 1α and 2α, tagging them for pVHL-dependent polyubiquitination and proteasomal degradation. In this study, albumin Cre (Alb^Cre)–mediated, hepatocyte-specific triple disruption of Phd1, Phd2, and Phd3 (Phd(1/2/3)hKO) promoted liver erythropoietin (EPO) expression 1246-fold, whereas renal EPO was down-regulated to 6.7% of normal levels. In Phd(1/2/3)hKO mice, hematocrit levels reached 82.4%, accompanied by severe vascular malformation and steatosis in the liver. In mice double-deficient for hepatic PHD2 and PHD3 (Phd(2/3)hKO), liver EPO increase and renal EPO loss both occurred but were much less dramatic than in Phd(1/2/3)hKO mice. Hematocrit levels, vascular organization, and liver lipid contents all appeared normal in Phd(2/3)hKO mice. In a chronic renal failure model, Phd(2/3)hKO mice maintained normal hematocrit levels throughout the 8-week time course, whereas floxed controls developed severe anemia. Maintenance of normal hematocrit levels in Phd(2/3)hKO mice was accomplished by sensitized induction of liver EPO expression. Consistent with such a mechanism, liver HIF-2α accumulated to higher levels in Phd(2/3)hKO mice in response to conditions causing modest systemic hypoxia. Besides promoting erythropoiesis, EPO is also known to modulate retinal vascular integrity and neovascularization. In Phd(1/2/3)hKO mice, however, neonatal retinas remained sensitive to oxygen-induced retinopathy, suggesting that local EPO may be more important than hepatic and/or renal EPO in mediating protective effects in the retina.Prolyl hydroxylase domain (PHD) proteins PHD1, PHD2, and PHD3 use molecular oxygen as a substrate to hydroxylate specific prolyl residues in HIF-1α and HIF-2α,^1–3 tagging them for von Hippel–Lindau protein (pVHL)–dependent polyubiquitination and proteasomal degradation.⁴ PHD-regulated HIF-α stability is important for multiple processes, including angiogenesis,^5–7 erythropoiesis,^8–10 cardiomyocyte function,^11–13 cell survival,¹⁴ and metabolism.¹⁵ PHD1 and PHD2 also hydroxylate IKKβ, thus regulating the assembly of NF-κB and functions of monocytic cells and proangiogenic macrophages.^16–19 Besides PHDs, a transmembrane prolyl hydroxylase in the endoplasmic reticulum (P4H-TM) may also regulate HIF-α stability.^20,21In normal adults, renal interstitial cells are responsible for the bulk of plasma erythropoietin (EPO) and thus play a key role in regulating erythropoiesis and blood homeostasis. Loss or dysfunction of renal interstitial cells due to acute renal injury or chronic kidney disease can lead to EPO deficiency and severe anemia.²² Normal liver expresses EPO only at very low levels, but possesses latent capacity for EPO expression that can be reactivated by manipulations that lead to hepatic HIF-2α stabilization. For example, hepatocyte-specific Vhl knockout in mice resulted in the accumulation of HIF-1α and HIF-2α to high levels, and subsequent studies showed that HIF-2α was responsible for elevated liver EPO expression and polycythemia.^23,24 Other studies have also demonstrated critical roles of HIF-2α in regulating EPO expression.^25,26Our research group has previously shown that germline Phd1 and Phd3 double knockout leads to increased liver EPO expression.⁸ In a more recent study, Minamishima and Kaelin²⁷ showed that more dramatic liver EPO up-regulation can be induced by triple Phd knockout, with Phd1 and Phd3 knockout being germline null mutations and Phd2 knockout induced in a hepatocyte-restricted manner. These studies raised the possibility that the liver may be exploited as an alternative source for endogenous EPO production in case of renal failure. Indeed, siRNA-mediated knockdown of hepatic PHD rescued erythropoiesis in mice subjected to 5/6 nephrectomy.²⁸ Although these findings are highly encouraging, it is not known how the liver itself is affected by PHD deficiency.In the present study, we examined hematological effects of hepatic PHD deficiency in an established chronic renal failure model,^29–32 and compared blood, vascular, and lipid phenotypes associated with the disruption of different combinations of PHD isoforms in the liver. Hepatic triple deficiency of all three isoforms caused multiple abnormalities, including severe erythrocytosis, vascular malformation, and massive lipid accumulation in the liver. By contrast, mice double-deficient for hepatic PHD2 and PHD3 did not exhibit any of these defects, but yet gained the ability to maintain normal hematocrit (Hct) levels in a chronic renal failure model. These data provide the proof of principle that selective combinations of hepatic PHD isoforms could offer suitable therapeutic targets for maintaining normal blood homeostasis without accompanying vascular malformation or liver steatosis.