Therapeutic approaches for treating hemophilia A using embryonic stem cells

Hemophilia A is an X-linked rescessive bleeding disorder that results from F8 gene aberrations. Previously, we established embryonic stem [ES] cells [tet-226aa/N6-Ainv18] that secrete human factor VIII [hFVIII] by introducing the human F8 gene in mouse Ainv18 ES cells. Here, we explored the potential of cell transplantation therapy for hemophilia A using the ES cells. Transplant tet-226aa/N6-Ainv18 ES cells were injected into the spleens of severe combined immunodeficiency [SCID] mice, carbon tetrachloride [CCl4]-pretreated wild-type mice, and CCl4-pretreated hemophilia A mice. F8 expression was induced by doxycycline in drinking water, and hFVIII-antigen production was assessed in all cell transplantation experiments. Injecting the ES cells into SCID mice resulted in an enhanced expression of the hFVIII antigen; however, teratoma generation was confirmed in the spleen. Transplantation of ES cells into wild-type mice after CCl4-induced liver injury facilitated survival and engraftment of transplanted cells without teratoma formation, resulting in hFVIII production in the plasma. Although CCl4 was lethal to most hemophilia A mice, therapeutic levels of FVIII activity, as well as the hFVIII antigen, were detected in surviving hemophilia A mice after cell transplantation. Immunolocalization results for hFVIII suggested that transplanted ES cells might be engrafted at the periportal area in the liver. Although the development of a safer induction method for liver regeneration is required, our results suggested the potential for developing an effective ES-cell transplantation therapeutic model for treating hemophilia A in the future

Chediak-Higashi syndrome presenting in accelerated phase:a case report and literature review

Chediak-Higashi syndrome [CHS] is a rare autosomal recessive lysosomal disorder characterized by frequent infections, oculocutaneous albinism, bleeding diathesis, and progressive neurologic deterioration. In 85% of cases, CHS patients develop the accelerated phase characterized by pancytopenia, high fever, and lymphohistiocytic infiltration of liver, spleen, and lymph nodes. Treatment of accelerated-phase CHS is difficult and the prognosis is poor. Here, we report a case of CHS in a 2-year-old boy who presented in the accelerated phase of the disease. CHS diagnosis was made on the basis of clinical characteristics, hair analysis, and identification of pathognomonic giant azurophilic granules in peripheral blood and bone marrow

Two Cases of Aortic Regurgitation with Dove-coo Murmur: Operative Findings of the Valves / 日本心臓血管外科学会雑誌

We describe two cases of aortic regurgitation with dove-coo murmur that required aortic valve replacements. In the first case, there were three small perforations of the cusps, two in the noncoronary cusp and one in the right coronary cusp. The cause of the cusp perforations was unclear. In the second case, there were two perforations of the cusps, one in the left coronary cusp and another small one in the right coronary cusp, along with a subannular pseudoaneurysm. The cause of the cusp perforations was an infective endocarditis. Before 1955, aortic regurgitations with dove-coo murmur were mostly reported to be originated by retroversion of the valve cusps due to syphilis. After 1960, syphilis was replaced by various diseases that bring about perforations, tears and retroversions of the cusps. The condition which is concerned in the development of the dove-coo murmur is that the aortic valve cusps have lesions without calcification and preserve the flexibility.