Is Broca's area involved in the processing of passive sentences? An event-related fMRI study

We used functional magnetic resonance imaging (fMRI) to investigate whether activation in Broca's area is greater during the processing of passive versus active sentences in the brains of healthy subjects. Twenty Japanese native speakers performed a visual sentence comprehension task in which they were asked to read a visually presented sentence and to identify the agent or the patient in the sentence by pressing a button. We found that the processing of passive sentences elicited no greater activation than that of active sentences in Broca's area. However, passive sentences elicited greater activation than active sentences in the left frontal operculum and the inferior parietal lobule. Thus, our neuroimaging results suggest that deficits in the comprehension of passive sentences in Japanese aphasics are induced not by lesions to Broca's area, but to the left frontal operculum and/or the inferior parietal lobule.     

Variability of parvovirus B19 to inactivation by liquid heating in plasma products

BACKGROUND AND OBJECTIVES: Previously, we reported that although human parvovirus B19 in albumin and intravenous immunoglobulin preparations was rapidly inactivated during liquid heating, in contrast to other parvoviruses such as canine parvovirus, sensitivity to heat was highly dependent on the composition of the solution. In this study, we aimed to further elucidate the sensitivity to heat of B19 in haptoglobin and antithrombin (previously named antithrombin III) preparations during liquid heating. MATERIALS AND METHODS: Two different solutions collected immediately before heat treatment of haptoglobin and antithrombin preparations were spiked with B19 and subsequently treated at 60 degrees C for 10 h. B19 DNA-positive, anti-B19 IgG/IgM-negative plasma was used as a source of B19. The residual infectivity in each sample was measured using a B19 cell-based infectivity assay with an mRNA polymerase chain reaction. RESULTS: B19 in different plasma preparations showed different heat-sensitivity patterns during liquid heating: (i) slow inactivation in haptoglobin preparations, and (ii) only limited inactivation in antithrombin preparations. The kinetics of inactivation was greatly different from that in our previous studies in which the virus was shown to be rapidly inactivated in albumin and intravenous immunoglobulin preparations. CONCLUSION: B19 has unique properties in terms of heat sensitivity, depending on the composition of the solution during liquid heating. This finding may indicate the need for caution when interpreting the sensitivity of B19 to heat.     

Leukocyte numbers correlate with plasma levels of granulocyte–macrophage colony-stimulating factor in sickle cell disease

Despite a clear role for leukocytes in modulating the pathophysiology of sickle cell disease (SCD), the mechanism by which leukocyte numbers are increased in this disorder remains unclear. Hypothesizing that the chronic inflammatory state, elicited by adhesive interactions involving various cell types, might underlie leukocytosis, we measured plasma levels of proinflammatory or myeloid cytokines that play a role in leukocytosis and examined their correlations with leukocyte numbers in patients with SCD. Our studies found that, although plasma levels of granulocyte–macrophage colony-stimulating factor (GM-CSF), interleukin 3, and macrophage colony-stimulating factor are elevated in steady-state patients with SCD, only plasma GM-CSF levels are positively correlated with the numbers of total leukocytes, neutrophils, monocytes, and eosinophils, regardless of whether they received hydroxyurea. GM-CSF levels were significantly decreased in patients on hydroxyurea therapy. These data suggest a role of GM-CSF in leukocytosis of SCD. In contrast, plasma levels of granulocyte colony-stimulating factor, a major cytokine that induces leukocytosis due to bacterial infection, were lower than those of control subjects. These results indicate that elevated GM-CSF levels may contribute, at least in part, to high leukocyte numbers in SCD. As plasma GM-CSF levels were decreased in patients on hydroxyurea therapy, hydroxyurea may decrease leukocyte numbers by reducing circulating GM-CSF levels. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible for authorized users.     

Breakthrough pulmonary mucormycosis during voriconazole treatment after reduced-intensity cord blood transplantation for a patient with acute myeloid leukemia

A 59-year-old man was admitted to our hospital with a diagnosis of acute myeloid leukemia in September 2004. He developed invasive pulmonary aspergillosis (IPA) and candidiasis, which were improved by administration of micafungin and amphotericin B (AMPH-B). He received reduced-intensity unrelated cord-blood transplantation without induction chemotherapy. He developed grade IV graft-versus-host disease (GVHD) and the administration of steroids against GVHD was prolonged. Voriconazole (VRCZ) was used for a long period to prevent recurrence of the IPA. Afterwards, infiltrates in the bilateral upper lung fields were detected on a chest CT scan, and a diagnosis of pulmonary mucormycosis was made following detection of Mucor circinelloides from the patient's sputum culture. He then began receiving AMPH-B but died of massive hemoptysis. Mucormycosis usually occurs in immunocompromised hosts such as neutropenic patients with hematologic diseases and is a fatal fungal infection characterized by a rapid and progressive clinical course. Some overseas investigators have recently reported that VRCZ prophylaxis may result in breakthrough mucormycosis in hematopoietic stem cell transplant recipients. These findings suggest that it is very important to pay attention to mucormycosis in hematopoietic stem cell transplant recipients in this country.     

Modification of the Bentall operation using the proximal double sewing technique without excision of leaflets

We present a report on reinforcement of the proximal anastomosis during the Bentall operation. The aortic wall was excised with a 5-mm remnant, and aortic valve leaflets were preserved. Interrupted horizontal mattress sutures (2-0 Polyestel) reinforced with pledgets were placed. The composite graft was placed at the intraannular position inside of the preserved leaflets. The aortic valve leaflets were then pasted to the sewing cuff with fibrin glue. A running suture with 4-0 monofilament was placed between the remnant of the aortic wall and the peripheral side of the sewing cuff wrapped with native aortic valve leaflets.     

Interleukin 6 inhibits delayed-type hypersensitivity and the development of adjuvant arthritis

We studied the effect of interleukin 6 (IL 6) on the delayed-type hypersensitivity (DTH). In mice immunized with sheep red blood cells (SRBC), a DTH response was evoked by antigen challenge into the hind paw 5 days after immunization. The magnitude of the response was assessed by footpad swelling measured 24 h after antigen challenge. IL 6 significantly suppressed the DTH in its induction phase in a dose-dependent manner when administered s.c. into the back at a dose of greater than 2.5 micrograms twice a day (5 micrograms/day) for 5 consecutive days from the day of immunization (day 0) to 1 day before antigen challenge (day 4). Heat-inactivated IL 6 did not suppress the DTH response. Furthermore, the suppressive activity of IL 6 was completely abolished by affinity chromatography on an anti-IL 6 antibody. This suppression was also obtained when IL 6 was administered only on day 0 and day 1, but not on days 3 and 4. This indicates that IL 6 acts on the early part of the induction phase of DTH development. Furthermore, footpad swelling was suppressed even by the administration of IL 6 after antigen challenge. These results show that IL 6 suppresses both the induction and effector phases of DTH. To confirm further this inhibitory effect of IL 6, we examined its effect on the development of adjuvant arthritis in rats. Administration of IL 6 also significantly suppressed the development of adjuvant arthritis.     

Whole genome association study of rheumatoid arthritis using 27 039 microsatellites

A major goal of current human genome-wide studies is to identify the genetic basis of complex disorders. However, the availability of an unbiased, reliable, cost efficient and comprehensive methodology to analyze the entire genome for complex disease association is still largely lacking or problematic. Therefore, we have developed a practical and efficient strategy for whole genome association studies of complex diseases by charting the human genome at 100 kb intervals using a collection of 27,039 microsatellites and the DNA pooling method in three successive genomic screens of independent case-control populations. The final step in our methodology consists of fine mapping of the candidate susceptible DNA regions by single nucleotide polymorphisms (SNPs) analysis. This approach was validated upon application to rheumatoid arthritis, a destructive joint disease affecting up to 1% of the population. A total of 47 candidate regions were identified. The top seven loci, withstanding the most stringent statistical tests, were dissected down to individual genes and/or SNPs on four chromosomes, including the previously known 6p21.3-encoded Major Histocompatibility Complex gene, HLA-DRB1. Hence, microsatellite-based genome-wide association analysis complemented by end stage SNP typing provides a new tool for genetic dissection of multifactorial pathologies including common diseases.     

Risk factors for evolution of acquired aplastic anemia into myelodysplastic syndrome and acute myeloid leukemia after immunosuppressive therapy in children

Long-term survivors of acquired aplastic anemia (AA) have an increased risk of developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) after immunosuppressive therapy (IST). It is uncertain whether the increased survival time simply discloses the natural history of AA as a premalignant disease or whether secondary disease is related to the therapy itself. Between November 1992 and September 1997, 113 AA children with normal cytogenetics at diagnosis were treated with IST using antithymocyte globulin, cyclosporin, and danazol with or without granulocyte colony-stimulating factor (G-CSF). We assessed risk factors for developing MDS/AML by Cox proportional hazards models. Twelve of 113 patients developed MDS between 9 and 81 months following the time of diagnosis, giving a cumulative incidence of 13.7 +/- 3.9%. The following cytogenetic abnormalities were observed at the time of diagnosis of MDS: monosomy 7 (6 patients), monosomy7/trisomy21 (1 patient), trisomy 11 (1 patient), del (11) (9?:14) (1 patient), add (9q) (1 patient), add 7 (q 32) (1 patient), and trisomy 9 (1 patient). The number of days of G-CSF therapy and nonresponse to therapy at 6 months were statistically significant risk factors by multivariate analysis. The present study suggests a close relationship between long-term use of G-CSF and secondary MDS in nonresponders to IST.