Coordinate expansion of murine hematopoietic and mesenchymal stem cell compartments by SHIPi.

Promoting the expansion of adult stem cell populations offers the potential to ameliorate radiation or chemotherapy-induced bone marrow failure and allows for expedited recovery for patients undergoing these therapies. Previous genetic studies suggested a pivotal role for SH2 domain-containing inositol-5-phosphatase 1 (SHIP1) in limiting the size of the hematopoietic stem cell (HSC) compartment. The aim of this study was to determine whether our recent development of small molecule SHIP1 inhibitors offers the potential for pharmacological expansion of the HSC compartment in vivo. We show here that treatment of mice with aminosteroid inhibitors of SHIP1 (SHIPi) more than doubles the size of the adult mesenchymal stem cell (MSC) compartment while simultaneously expanding the HSC pool sixfold. Consistent with its ability to target SHIP1 function in vivo, SHIPi also significantly increases plasma granulocyte colony-stimulating factor (G-CSF) levels, a growth factor that supports proliferation of HSC. Here, we show that SHIPi-induced G-CSF production mediates HSC and MSC expansion, as in vivo neutralization of G-CSF abrogates the SHIPi-induced expansion of both the HSC and MSC compartments. Due to its expansionary effect on adult stem cell compartments, SHIPi represents a potential novel strategy to improve declining stem cell function in both therapy induced and genetically derived bone marrow failure syndromes.

Loss of wild-type Jak2 allele enhances myeloid cell expansion and accelerates myelofibrosis in Jak2V617F knock-in mice.

JAK2V617F is the most common mutation found in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). Although a majority of MPN patients carry heterozygous JAK2V617F mutation, loss of heterozygosity (LOH) on chromosome 9p (9pLOH) involving the JAK2 locus has been observed in ∼30% of MPN patients. JAK2V617F homozygosity via 9pLOH has been associated with more severe MPN phenotype. However, the contribution of 9pLOH in the pathogenesis of MPNs remains unclear. To investigate the roles of wild-type JAK2 (JAK2 WT) and JAK2V617F alleles in the development of MPNs, we have used conditional Jak2 knock-out and Jak2V617F knock-in mice and generated heterozygous, hemizygous and homozygous Jak2V617F mice. Whereas heterozygous Jak2V617F expression results in a polycythemia vera-like MPN in mice, loss of Jak2 WT allele in hemizygous or homozygous Jak2V617F mice results in markedly increased white blood cells, neutrophils, reticulocytes and platelets in the peripheral blood, and significantly larger spleen size compared with heterozygous Jak2V617F mice. Hemizygous or homozygous Jak2V617F mice also exhibit accelerated myelofibrosis compared with mice expressing heterozygous Jak2V617F. Together, these results suggest that loss of Jak2 WT allele increases the severity of the MPN. Thus, the Jak2 WT allele functions as a negative regulator of MPN induced by Jak2V617F.

A survey of potential risk factors for HIV transmission through dental practice in Japan.

A survey was conducted to find potential risk factors for HIV transmission through dental practice. Self-administered questionnaires were distributed to the members of the dental associations of various prefectures and small cities in Japan. A total of 747 questionnaires was returned by dentists. The findings revealed several problems. Gloves, masks, and other protective garments were generally worn, but most dentists did not always use them during the full course of treatment limiting usage to surgical treatment, and when treating patients in "high-risk groups" and in dental practice the exact percentage of the dentists who reused a used anesthetic liquid cartridge is 12.7%. The effectiveness of the education for dentists regarding AIDS was statistically clarified. It is obviously necessary to provide important information regarding AIDS and HIV transmission to the dentists. Potential risk for HIV transmission through dental practice will be prevented by AIDS education for the dentists.

[A survey on infection control practices, knowledge and attitudes toward AIDS/HIV among dental practitioners].

A survey was conducted in December 1993 by sending questionnaires to all 566 dentists of the Iwate Dental Association. The questionnaires consisted of 68 items including infection control practices, knowledge, and attitudes towards AIDS/HIV. The response rate was 51.1 percent (N = 289). The average age of dentists in the sample was 43.7 +/- 9.5 (S.D.) (range: 28 to 85). Data was evaluated statistically by Kruskal-Wallis test, Mann-Whitney's U test and Chi-square test, and significant differences were observed. Gloves, masks, and other protective garments were generally worn, but most dentists did not always use them during the full course of treatment limiting usage to surgical treatment, and when treating patients in "high-risk groups". Other infection control procedures, such as instrument sterilization, did not comply with the guidelines of the Ministry of Health and Welfare. Two dentists responded that they had treated AIDS patients and three dentists treated possible AIDS/HIV patients in their dental offices. Despite 71.3% expressing a belief that they have a moral responsibility as a dentist to treat AIDS/HIV patients only 15.6% were willing to treat AIDS/HIV patients. Over 40% of the respondents were not certain as to whether they had treated AIDS/HIV patients or not, and over 60% believed AIDS/HIV patients would come to their dental offices in the near future. Therefore, to practice dentistry on AIDS/HIV patients safely, dentists must provide effective infection control in their dental offices on the assumption that all patients are AIDS/HIV positive, and additional information about AIDS/HIV and adequate training on procedures in the care of AIDS/HIV patients are needed.

Serological relationships between serotype-III Streptococcus sanguis and Lancefield group-H streptococci.

Certain strains of Streptococcus sanguis and group-H streptococci have been shown to have similar physiological properties and serological specificities. Serological studies revealed that serotype-III S. sanguis shared a common antigen with the so-called "British" group-H streptococci, but not with the "American" group-H streptococci. Serotype-III antigen was extracted in cold 5% trichloroacetic acid from isolated cell walls of S. sanguis ATCC 10558, and purified chromatographically. The purified serotype-III antigen consisted of neutral and amino sugars and some phosphorus, and was negatively charged. Hapten inhibition of the quantitative precipitin reaction between serotype-III antigen and antiserum indicated the strong possibility of alpha-glucosidic linkages being an immunodeterminant of the antigen.

Purification and immunochemical characterization of Streptococcus sanguis serotype I carbohydrate antigen.

The serotype-specific antigen of Streptococcus sanguis ST3 (serotype I, biotype A) was extracted, chromatographically purified, and characterized by immunological and chemical methods. The antigen was extracted from purified cell walls with hot trichloroacetic acid, followed by ion-exchange chromatography on a DEAE-Sephadex A-25 column and gel filtration through a Sephadex G-100 column. A peak fraction was obtained that gave a single precipitin band when reacted with anti-type I serum. The type I antigen was a polysaccharide composed of glucose, rhamnose, and N-acetylglucosamine in a molar ratio of 1.4:2.5:1.0. Quantitative precipitin inhibition tests with various haptenic sugars indicated that an alpha-glucosidic linkage is the immunodeterminant of the type I antigen.