Preserved in vivo reconstitution ability of PBSCs cryopreserved for a decade at -80 °C.

PBSC products for auto- and allografting can be cryopreserved in liquid nitrogen with controlled-rate freezing until their use. Alternatively, they can be stored at -80 °C in a mechanical chest freezer, but it remains to be clarified whether PBSCs can be stored for the long term. We evaluated viability and functions of PBSCs cryopreserved for more than 10 years with this simplified method. Although recovery rate and viability of CD34(+) cells were significantly decreased, myeloid differentiation potential and in vivo reconstitution and self-renewal potential of CD34(+) cells in a xenogeneic engraftment assay were maintained for more than 10 years. These results indicate that PBSCs can be stored at -80 °C for years. Although accumulation of clinical engraftment data is required to confirm our results, this simplified cryopreservation will thus meet the increasing worldwide demand for PBSC transplantation in a region with limited resources.

Superconducting pairing and the pseudogap in the nematic dynamical stripe phase of La2-xSrxCuO4.

Fully absorption coefficient corrected Raman spectra were obtained in La2-xSrxCuO4. The B1g spectra have a Fleury-Loudon type two-magnon peak (resonant term) whose energy decreases from 3180 cm(-1) (394 meV) to 440 cm(-1) (55 meV) on increasing the carrier density from x = 0 to 0.25, while the B2g spectra have a 1000-3500 cm(-1) (124-434 meV) hump (hill) whose lower-edge energy increases from x = 0 to 0.115 and then stays constant to x = 0.25. The B2g hump is assigned to the electronic scattering (non-resonant term) of the spectral function with magnetic self-energy. The completely different carrier density dependence arises from anisotropic magnetic excitations of spin-charge stripes. The B1g spectra were assigned to the sum of k âˆ¥  and k⊥ stripe excitations and the B2g spectra to k⊥ stripe excitations according to the calculation by Seibold and Lorenzana (2006 Phys. Rev. B 73 144515). The k âˆ¥  and k⊥ stripe excitations in fluctuating spin-charge stripes were separately detected for the first time. The appearance of only k⊥ stripe excitations in the electronic scattering arises from the charge hopping perpendicular to the stripe. This is the same direction as the Burgers vector of the edge dislocation in metal. The successive charge hopping in the Burgers vector direction across the charge stripes may cause Cooper pairs as predicted by Zaanen et al (2004 Ann. Phys. 310 181). Indeed, this is supported by the experimental fact that the superconducting coherent length coincides with the inter-charge stripe distance in the wide carrier density range. The one-directional charge hopping perpendicular to the stripe causes the flat Fermi surface and the pseudogap near (π,0) and (0,π), but the states around (π/2,π/2) cannot be produced. The low-energy Raman scattering disclosed that the electronic states at the Fermi arc around (π/2,π/2) are coupled to the A1g soft phonon of the tetragonal-orthorhombic phase transition. This suggests that the Fermi arc is produced by the electron-phonon interaction. All the present Raman data suggest that Cooper pairs are formed at moving edge dislocations of dynamical charge stripes.

Correlation between Raman sum and optical conductivity sum in La(2-x)Sr(x)CuO4.

In a strongly correlated electron system, the single-particle spectral function changes into a coherent peak and incoherent humps which extend over 1 eV. The incoherent parts lose the symmetry and k dependence, so that the Raman spectra with different symmetries become identical and they are expressed by the optical conductivity. We found that the B1g and B2g spectra in La(2-x)Sr(x)CuO4 become identical above 2000 cm(-1) in the underdoped phase, if Fleury-Loudon type B1g two-magnon scattering is removed. The first Raman susceptibility moment correlates with the generalized optical conductivity moment. The good correlation arises from the incoherent states of a hump from 1000 to 4000 cm(-1). The hump is the only structure of the incoherent electronic states in the mid-infrared absorption spectra below 1.4 eV at low carrier densities. The energy is twice the separated dispersion segments of the spin wave in the k(perpendicular) stripe direction. The incoherent state is formed by the magnetic excitations created by the hole hopping in the antiferromagnetic spin stripes in the real space picture.

Evaluating the association between histological manifestations of cord colitis syndrome with GVHD.

Cord colitis syndrome (CCS) is a recently proposed clinical entity characterized by a persistent diarrheal illness after cord blood transplantation (CBT), which is not caused by GVHD or CMV colitis. CCS is histologically characterized by chronic active colitis with granulomatous inflammation and Paneth cell metaplasia suggesting chronicity. However, the specificity of these pathological features to CCS remains to be validated. We conducted a retrospective study of 49 patients who had diarrhea and underwent diagnostic colonoscopy with biopsy following allogeneic hematopoietic SCT. None of the patients met the clinical criteria for CCS. Chronic active colitis with granulomatous inflammation and Paneth cell metaplasia was present in 12/33 (36%) patients with biopsy-proven GVHD, 4/6 (67%) patients with CMV colitis and 2/15 (13%) patients with nonspecific colitis. In patients with GVHD and/or CMV colitis, these pathological features were present in 4/8 (50%) patients after CBT and in 11/26 (42%) patients undergoing BMT or PBSCT. These results demonstrate that chronic active colitis with granuloma and Paneth cell metaplasia is not only a specific feature of CCS but also is present in GVHD and CMV colitis, irrespective of stem cell source.

A novel filtration method for cord blood processing using a polyester fabric filter.

INTRODUCTION: Cord blood (CB) is being increasingly used as a source of hematopoietic stem cells for transplantation to treat diseases of the blood and immune systems, and there is an urgent need to expand CB banking worldwide. CB processing requires costly machinery or a clean room that hampers wider application of CBT particularly in the developing countries. METHODS: We developed a novel filtration system using a nonchemical-coated and nonwoven polyester fabric filter, which traps cells through affinity and does not require centrifugation or potentially toxic chemicals. RESULTS: Cell processing with the device resulted in minimum cell loss of total cells and CD34⁺ cells, without impairing the ability of CD34⁺ cells to engraft and differentiate both in vivo and in vitro. CONCLUSION: CB processing with this device is simple, cost-effective, and nontoxic without requiring costly equipment will thus facilitate international CB banking, which helps in meeting the increasing worldwide demand for CB for allogeneic hematopoietic stem cell transplantation.

[Lung cancer accompanied by active pulmonary tuberculosis].

We report 2 patients with lung cancer accompanied by active pulmonary tuberculosis. Case1 was a 82-year-old woman with stage I A bronchioloalveolar carcinoma and tuberculosis in right upper lobe. Right upper lobectomy was performed after the histological diagnosis of lung cancer by intraoperative frozen section. Case2 was a 69-year-old man with papillary adenocarcinoma in right lower lobe and tuberculosis in bilateral upper lobe. Partial resection in right lower lobe was performed for diagnosis of lung cancer. Smear-positive tuberculosis was diagnosed by sputum examination after the operation. Post-operative anti-tuberculosis chemotherapy was added in both patients.

Validation of pretransplantation assessment of mortality risk score in the outcome of hematopoietic SCT in non-Caucasians.

The Pretransplantation Assessment of Mortality (PAM) score is a risk score for mortality after allogeneic hematopoietic SCT (HSCT). Ethnicity is a genetically determined factor that correlated with immune-mediated outcomes of allogeneic HSCT. We evaluated the predictive value of the PAM score for transplant outcome in 276 Japanese populations in which transplant-related complications occur less frequently than Caucasians. The PAM score effectively risk-stratified these patients for survival; overall survival (OS) at 2 years was 100%, 80.2%, 49.4%, and 13.9% in the categories 1, 2, 3, and 4, respectively, showing a clear distinction of OS by categories (P<0.001). In addition, the PAM score is useful for the prediction of transplant outcomes both in patients with standard-risk underlying diseases and those with high-risk diseases. The PAM score developed in Caucasian populations is thus useful in non-Caucasian populations.

Evidence for a correlated insulator to antiferromagnetic metal transition in CrN.

We investigate the electronic structure of chromium nitride (CrN) across the first-order magnetostructural transition at T(N)∼286 K. Resonant photoemission spectroscopy (PES) shows a gap in the 3d partial density of states at the Fermi level and an on-site Coulomb energy U∼4.5 eV, indicating strong electron-electron correlations. Bulk-sensitive high-resolution (6 meV) laser PES reveals a clear Fermi edge indicating an antiferromagnetic metal below T(N). Hard x-ray Cr 2p core-level PES shows T-dependent changes across T(N) which originate from screening due to coherent states as substantiated by cluster model calculations using the experimentally observed U. Electrical resistivity confirms an insulator above T(N) (E(g)∼70 meV) becoming a disordered metal below T(N). Thus, CrN transforms from a correlated insulator to an antiferromagnetic metal, coupled to the magnetostructural transition.

FRS2beta, a potential prognostic gene for non-small cell lung cancer, encodes a feedback inhibitor of EGF receptor family members by ERK binding.

An adaptor protein FRS2beta inhibits epidermal growth factor-receptor (EGFR) tyrosine kinase without being phosphorylated at tyrosine residues after EGF stimulation. Although binding to ERK appears to be important for this inhibition, the precise molecular mechanisms and the role of FRS2beta in signal transduction mediated by other EGFR family members, as well as its role in human cancer, remain unclear. In this study, we demonstrate that FRS2beta inhibits anchorage-independent cell growth induced by oncogenic ErbB2, another member of EGFR family, and that it inhibits heterodimer formation between EGFR and ErbB2. We mapped the residues important for the FRS2beta and ERK interaction to two docking (D) domain-like sequences on FRS2beta and two aspartic acid residues in the common docking (CD) domain of ERK. Moreover, in response to EGF, ERK translocated to the plasma membrane in cells expressing FRS2beta but not an FRS2beta mutant in which four arginine residues in the D domains were replaced with alanines, suggesting that FRS2beta serves as a plasma membrane anchor for activated ERK. Finally, a low mRNA expression level of FRS2beta was significantly correlated with poor prognosis in a cohort of 60 non-small cell lung cancer patients. Therefore, we have identified the molecular mechanisms by which FRS2beta acts as a feedback inhibitor of EGFR family members and suggest a role for FRS2beta as a tumor suppressor.

Long-term outcomes of autologous PBSCT for peripheral T-cell lymphoma: retrospective analysis of the experience of the Fukuoka BMT group.

Peripheral T-cell lymphoma (PTCL) is generally characterized by poor prognosis after conventional chemotherapy compared with aggressive B-cell lymphoma. To elucidate the role of high-dose chemotherapy (HDCT) with auto-SCT, we retrospectively analyzed the outcomes of 39 patients with PTCL who received HDCT and auto-SCT between 1990 and 2005. Eleven patients were histologically typed as angioimmunoblastic, nine as anaplastic large-cell lymphoma, seven as natural killer/T-cell lymphoma and twelve as PTCL unspecified. Clinical conditions at transplantation were complete response (CR) in 27 patients and non-CR in 12 patients. Thirty-two patients received a pre-transplant conditioning regimen (MCEC) comprising ranimustine, carboplatin, etoposide and CY, and seven did other TBI-based regimens. Rapid engraftment was obtained in all cases, and transplant-related death was not seen. An estimated 5-year OS was 62.1% with a median follow-up of 78 months. The 5-year OS was significantly higher in patients transplanted during complete response than in those during other disease status (71.4% vs 27.3%, P=0.046). HDCT supported by auto-SCT may therefore be effective as consolidation in CR for PTCL treatment.

Infectious complications in patients receiving autologous CD34-selected hematopoietic stem cell transplantation for severe autoimmune diseases.

Long-term analysis of infectious complication after high-dose immunosuppressive therapy with CD34-selected autologous hematopoietic stem cell transplantation for patients with severe autoimmune diseases (AD) was performed. Theoretically, CD34 selection can reduce the risk of reinfusion of autoreactive lymphocytes. However, it is also associated with a significant reduction in T cells, natural killer cells, and monocytes, which in turn may compromise immune reconstitution, thereby increasing the risk of infection. Moreover, AD compromises host immunity and causes organ damage resulting in dysfunction of the cutaneous or mucosal barrier. In this study, the incidence rate of infections is reported in 14 patients who underwent high-dose (200 mg/kg) cyclophosphamide therapy followed by reinfusion of CD34-selected autologous peripheral blood stem cells. Bacterial complication occurred in 3 of 14 (21%) patients. Cytomegalovirus reactivation and adenovirus hemorrhagic cystitis were observed in 9 (64%) and 2 (14%) patients, respectively. As for late infectious complications, 7 patients (50%) developed dermatomal varicella zoster virus infection. No infection-related mortality was seen in this case series. Because the risk for infections approaches that seen in allogeneic transplant recipients, infection surveillance, diagnostic workup, and prophylactic strategies similar to those applicable to allogeneic recipients are warranted.

Disseminated tuberculosis following second unrelated cord blood transplantation for acute myelogenous leukemia.

Here we report the case of a 43-year-old Japanese woman with acute myelogenous leukemia who underwent 2 unrelated cord blood transplantations (UCBT), terminating in fatal disseminated tuberculosis (TB). The patient did not achieve remission despite intensive chemotherapy, and subsequently underwent UCBT with a standard conditioning regimen. However, engraftment was not achieved. Fifty days after the first UCBT, the patient underwent a second UCBT with a reduced-intensity conditioning regimen. She developed a pre-engraftment immune reaction, which responded well to prednisolone, and engraftment was documented. However, 50 days after the second UCBT, the patient presented with high fever and developed pneumonia despite antibiotic and antifungal treatments. Thereafter, Mycobacterium tuberculosis was detected in blood cultures and specimens of bronchoalveolar lavage, thus indicating disseminated TB. Despite anti-tuberculous treatment, she died on day 85. TB should always be considered as a possible diagnosis when treating febrile immunocompromised patients.

Administration of pigment epithelium-derived factor prolongs bleeding time by suppressing plasminogen activator inhibitor-1 activity and platelet aggregation in rats.

We have recently found that pigment epithelium-derived factor (PEDF), a glycoprotein with potent neuronal differentiating activity, not only inhibits endothelial cell damage, smooth muscle cell proliferation and platelet aggregation in vitro, but also suppresses occlusive thrombus formation in rats. These observations suggest PEDF may play a protective role against atherothrombosis. However, effects of PEDF on hemostasis, fibrinolysis and platelet function in vivo are not fully understood. In this study, we examined the effects of PEDF on tail vein bleeding time, plasminogen activator inhibitor-1 (PAI-1) activity and ex vivo-platelet aggregation in rats. Intravenous injection of 30 microg PEDF significantly prolonged the tail vein bleeding time by about 25%. Administration of 30 microg PEDF was also found to reduce the PAI-1 activity in rats. Further, ADP-induced platelet aggregation was suppressed in PEDF-treated rats. The present study demonstrated first that PEDF exerted anti-hemostatic effects in rats, at least in part by suppressing PAI-1 activity and platelet aggregation. PEDF may be a novel therapeutic target for the treatment of patients with thrombogenic tendency and hypercoagulability.

Local lattice distortion in the giant negative thermal expansion material Mn3Cu1-xGexN.

Giant negative thermal expansion is achieved in antiperovskite manganese nitrides when the sharp volume change associated with magnetic ordering is broadened by substitution. In this Letter, we address the unique role of the ''magic" element, Ge, for such broadening in Mn3Cu1-xGexN. We present evidence for a local lattice distortion well described by the low-temperature tetragonal (T4) structure of Mn3GeN for a range of x, where the overall structure remains cubic. This structural instability shows a strong correlation with the broadness of the growth of the ordered magnetic moment and, hence, is considered to trigger the broadening of the volume change.

Autosomal dominant moyamoya disease maps to chromosome 17q25.3.

BACKGROUND: Moyamoya disease (MMD) is an idiopathic steno-occlusive cerebrovascular disease that represents an important cause of stroke. However, etiology of the disease has remained largely unknown. METHODS: We previously showed that the inheritance pattern of MMD is autosomal dominant with incomplete penetrance. Here, we report the genome-wide parametric linkage analysis for MMD in 15 extended Japanese families. We conducted linkage analyses under two diagnostic classifications: narrow and broad. Affected member-only analysis was applied due to incomplete and age-dependent penetrance of the disease. RESULTS: Under both classifications, significant evidence of linkage was only observed on chromosome 17q25.3, with maximum multipoint logarithm of odds (lod) scores of 6.57 (under the narrow classification) and 8.07 (under the broad classification) at D17S704. Haplotype analysis revealed segregation of a disease haplotype in all families but one, and informative crossovers enabled mapping of the MMD locus to a 3.5-Mb region between D17S1806 and the telomere of 17q, encompassing 94 annotated genes. CONCLUSIONS: Our data suggest that there is a major gene locus for autosomal dominant moyamoya disease on chromosome 17q25.3.

Development of ET, primary myelofibrosis and PV in mice expressing JAK2 V617F.

An acquired JAK2 V617F mutation is found in most patients with polycythemia vera (PV), and about half of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF). Mice transplanted with bone marrow cells in which JAK2 V617F was retrovirally expressed developed PV-like features, but not ET or PMF. To address the contribution of this mutation to the pathogenesis of these three MPDs, we generated two lines of JAK2 V617F transgenic mice. One line showed granulocytosis after 4 months of age. Among 43 mice, 8 (19%) showed polycythemia and 15 (35%) showed thrombocythemia. The second line showed extreme leukocytosis and thromobocytosis. They showed anemia that means Hb value from 9 to 10 g per 100 ml when 1 month old. Myeloid cells and megakaryocytes were predominant in the bone marrow of these animals, and splenomegaly was observed. The expression of JAK2 V617F mRNA in bone marrow cells was 0.45 and 1.35 that of endogenous wild-type JAK2 in the two lines, respectively. In vitro analysis of bone marrow cells from both lines showed constitutive activation of ERK1/2, STAT5 and AKT, and augmentation of their phosphorylations by cytokine stimulation. We conclude that in vivo expression of JAK2 V617F results in ET-, PMF- and PV-like disease.

Correlation-driven heavy-fermion formation in LiV2O4.

Optical reflectivity measurements were performed on a single crystal of the d-electron heavy-fermion (HF) metal LiV2O4. Our results evidence the highly incoherent charge dynamics above T* approximately 20 K and the redistribution of the spectral weight of the optical conductivity over broad energy scales ( approximately 5 eV) as the quantum coherence of the charge carriers is recovered. This reveals that LiV2O4 is close to a correlation-driven insulating state and indicates that, in sharp contrast to f-electron HF Kondo-lattice systems, strong electronic correlation effects dominate the heavy quasiparticle formation in LiV2O4.

[Indication and timing of mitral valvular surgery].

Patients with mitral regurgitation are increasing while those with mitral stenosis are decreasing. In addition, percutaneous transluminal mitral commissurotomy (PTMC) technique has dramatically reduced surgical indication of mitral stenosis. At the present time, the most important topic would be the surgical indication of asymptomatic patients with severe mitral regurgitation and preserved left ventricular function. In this context, feasibility of mitral valve repair, in other words, the skill and experience of the surgeon becomes very important. In this paper, we described issues about the timing and indication of mitral valvular surgery based on "American College Cardiology/American Heart Association (ACC/AHA) 2006 practice guidelines for the management of patients with valvular heart disease".

Rituximab does not compromise the mobilization and engraftment of autologous peripheral blood stem cells in diffuse-large B-cell lymphoma.

To investigate effects of the preautografting administration of rituximab on the mobilization and engraftment of peripheral blood stem cells (PBSC), we retrospectively analyzed the outcomes of 43 newly diagnosed diffuse-large B-cell lymphoma patients who received CHOP chemotherapy with or without rituximab as a first-line treatment before autologous PBSC transplantation (PBSCT). There was no difference in the number of CD34(+) cells among PBSC between the non-rituximab and the rituximab groups. Although B-cells were completely depleted from PBSC in the rituximab group, we found no difference in the expression of CXCR-4, VLA-4 and c-Kit on PBSC, indicating that rituximab did not affect the expression of these adhesion molecules, which might be involved in the mechanism of mobilization. There was no significant difference in the recovery of neutrophils and platelets, transplant-related toxicity and post-transplant complications between the two groups. Despite the short follow-up, there was no significant difference in progression-free survival between the two groups. These results indicated no adverse effect of rituximab on the mobilization and engraftment of PBSC. Larger studies are required to determine the impact of rituximab on the mobilization and function of PBSC as well as whether a survival advantage exists in patients who undergo auto-PBSCT with rituximab.