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The purpose of this study was to investigate growth changes in human plantar flexor muscle and tendons. In addition, we ascertained whether growth changes in muscle and tendon were more closely related to skeletal age than chronological age. 22 elementary school children (ESC), 19 junior high school students (JHS), and 23 young adults (ADT) men participated in this study. Maximal strain and hysteresis of tendon structures and cross-sectional area of Achilles tendon were measured using ultrasonography. In addition, skeletal age was assessed using Tanner-Whitehouse III method. Maximal strain of ESC was significantly greater than that of other groups, while no significant difference was observed between JHS and ADT. There was no difference in hysteresis among 3 groups. Relative cross-sectional area (to body mass2/3) of ADT was significantly smaller than that of other groups. For ESC and JHS, measured variables of muscle and tendon were significantly correlated to both chronological and skeletal ages. These results suggested that immature musculoskeletal system was protected by more extensible and larger tendon structures in ESC and only by larger tendon structures in JHS, respectively. Furthermore, there were no differences in correlation coefficient values between measured variables of muscle and tendon and chronological or skeletal ages. [ABSTRACT FROM AUTHOR]

Abstract: This paper describes a centrifuge-based dynamic microarray system using small amount of samples for application in multistep assays. The system uses meander-shaped microchannel and arrayed trapping spots to trap the samples with fluid stream generated by centrifugal force. Producing an array of samples suspended in only 1μl of solution is achieved in 3s with this system. After the loading solution is introduced, air is infused into the microchannel, keeping the sample and loading solution at the trapping spot. This air infusion allows us to immobilize and isolate the trapped samples suspended in the loading solution. In addition, the solution around the trapped sample can be repeatedly exchanged by introducing another solution. This system is applicable for multistep assays using small amount of rare samples. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Abstract: We analyze the experimental data for , , and decay widths in a framework where and are assumed to be mainly low mass scalar mesons and mixed with high mass scalar mesons. Applied the vector meson dominance model (VDM), these decays amplitudes are expressed by coupling parameters B describing the S ( scalar meson)–V (vector meson)–V (vector meson) coupling and describing the ( scalar meson)–V–V coupling. Adopting the magnitudes for B and as and , respectively, the mixing angle between and as , and the mixing parameter causing the mixing between state and state as , we can interpret these experimental data, consistently. [Copyright &y& Elsevier]

Despite a 10-fold increase of T cell dose, the incidence and severity of acute GVHD following allogeneic transplantation of G-CSF-mobilized PBSC is not increased compared to BMT. Experimental murine studies demonstrate that G-CSF polarizes donor T cells toward a type 2 cytokine response. To determine whether G-CSF alters T cell cytokine responses, we investigated the effects of G-CSF administration on T cell proliferative and cytokine responses to alloantigen and Con A in nonadherent PBMC (NAC) and CD3+ T cells obtained from normal individuals before and after G-CSF administration (10 μg/kg × 4 days). Although T cell proliferative and cytokine (IFN-γ and IL-4) responses to alloantigen stimulation and Con A were significantly reduced in post-G-CSF NAC, they were restored by the removal of non-T cells from post-G-CSF NAC. Furthermore, there was less T cell alloreactivity in MLR in the presence of autologous post-G-CSF monocytes than in the presence of pre-G-CSF monocytes. This alteration was not replicated in vitro by culturing PBMC with G-CSF. These results suggest that G-CSF administration suppresses T cell proliferative and cytokine (IFN-γ and IL-4) responses to allogeneic stimulation by indirectly modulating monocyte function. Bone Marrow Transplantation (2000) 25, 1035–1040. [ABSTRACT FROM AUTHOR]

Presents a correction to the article 'Acute graft-versus-host disease does not require alloantigen expression on host epithelium,' published in the September 2002 issue of the journal 'Nature Medicine.'

Human herpesvirus-6 (HHV-6) encephalitis following allogeneic hematopoietic cell transplantation is a serious and often fatal complication accompanying reactivation of HHV-6B. Incidence varies among studies, but is reportedly 0-11.6% after bone marrow or PBSC transplantation and 4.9-21.4% after umbilical cord blood transplantation, typically around 2-6 weeks post transplant. Symptoms are characterized by memory loss, loss of consciousness and seizures. Magnetic resonance imaging (MRI) typically shows bilateral signal abnormalities in the limbic system. This complication is considered to represent acute encephalitis caused by direct virally induced damage to the central nervous system, but our understanding of the etiologies and pathogenesis is still limited. The mortality rate attributable to this pathology remains high, and survivors are often left with serious sequelae such as impaired memory and epilepsy. Despite the poor prognosis, no validated treatments or preventative measures have been established. Establishment of preventative strategies represents an important challenge. This article reviews the current knowledge of the clinical features, incidence, pathogenesis and treatment of HHV-6 encephalitis, and discusses issues needing clarification in the future to overcome this serious complication. [ABSTRACT FROM AUTHOR]

Background Systolic dysfunction is associated with poor outcomes in dogs with myxomatous mitral valve disease. However, assessment of systolic variables by conventional echocardiographic methods is difficult in these dogs because of mitral regurgitation ( MR). Hypothesis We hypothesized that assessment of systolic function by dobutamine stress may identify systolic dysfunction in dogs with MR, and that 2-dimensional speckle-tracking echocardiography (2D- STE) could quantitatively evaluate myocardial function. Animals Anesthetized dogs with experimentally induced MR. Methods Dogs were examined for systolic myocardial deformations using 2D- STE during dobutamine infusion before and 3 and 6 months after MR induction. We evaluated peak systolic rotation and rotation rate in each basal and apical view; peak systolic torsion and torsion rate were also calculated. Results Invasive peak positive first derivatives of left ventricular pressure (dp/dt) were significantly decreased in dogs 6 months after induction of MR compared with pre- MR results. After 3 and 6 months of MR, dogs had diminished peak systolic torsion values and torsion rates in response to dobutamine infusion compared with pre- MR results (3 months, P < .001 and P = .006; 6 months, P = .003 and P = .021). These results were significantly correlated with overall invasive dp/dt ( r = 0.644, P < .001; r = 0.696, P < .001). Conclusions and Clinical Importance Decreased torsion during dobutamine infusion in dogs with MR may reflect latent systolic dysfunction. Dobutamine infusion, therefore, may be useful for the assessment of systolic function in dogs with MR. [ABSTRACT FROM AUTHOR]

Background Left ventricular torsional motion plays an important role for effective pump function. However, noninvasive clinical assessment of torsional deformations by two-dimensional speckle-tracking echocardiography (2D- STE) in dogs with myxomatous mitral valve disease ( MMVD) has not been reported. Hypothesis Left ventricular torsion is determined by the native orientation of the helical myocardial fibers, such that it might provide better assessment of myocardial function than conventional methods. Animals Sixty-seven client-owned dogs with MMVD were classified into 3 classes based on the International Small Animal Cardiac Health Council classification and 16 weight- and age-matched healthy dogs. Methods Dogs were examined for myocardial deformations by 2D- STE and were evaluated for peak systolic rotation and rotation rate at each basal and apical view. Dogs also were evaluated for peak systolic torsion and torsion rate. Results Peak systolic torsion was higher in class II than in class I ( P < .001) dogs. Peak systolic torsion was lower in class III than in class II ( P = .001) dogs and controls ( P = .003). Conclusions and Clinical Importance Torsional deformations assessed by 2D- STE differed among clinical classes of MMVD. Myocardial torsional deformations by 2D- STE may provide more detailed assessment of contractile function in dogs with MMVD. [ABSTRACT FROM AUTHOR]

BACKGROUND: Allogeneic peripheral blood progenitor cell (PBPC) transplantation requires granulocyte-colony-stimulating factor (G-CSF) administration to mobilize PBPCs in healthy donors. The effects of G-CSF on pulmonary functions, however, have not been clearly elucidated in PBPC donors. STUDY DESIGN AND METHODS: Respiratory status by measurements of arterial blood gas was prospectively evaluated serially in 25 healthy donors (9 men, 16 women; age, 18-61 years) administered a dose of 10 microg per kg for 5 days. RESULTS: White blood cell (WBC) counts increased in all the subjects after G-CSF administration; means on Days 0, 3, and 5 were 6 x 10(9), 33.4 x 10(9), and 33.6 x 10(9) per L, respectively. The mean PaO(2) values on the respective days were 93.1, 85.8, and 81.8 mmHg, and these changes were significant (p < 0.0001), remaining significant after adjustment for the WBC count. Levels of both PaCO(2) and AaDO(2) were significantly higher after G-CSF administration than those before G-CSF administration (p < 0.0001 and p = 0.0004, respectively). SaO(2) was significantly decreased after G-CSF administration (p = 0.0002). Age was identified as a significant predictive factor for the increase of AaDO(2) and PaO(2) decline. These observations clearly indicate that the gas exchange was significantly affected during G-CSF administration in healthy PBPC donors. CONCLUSION: Considering an increasing use of PBPC mobilization by G-CSF, careful monitoring of the respiratory status is important to ensure safety of PBPC donors, especially elderly donors. [ABSTRACT FROM AUTHOR]

Background: Enumeration of CD34+ cells in peripheral blood (PB) before apheresis predicts the number of CD34+ cells collected, although flow cytometric techniques used are complex and expensive. In an attempt to determine the optimal timing for peripheral blood progenitor cell (PBPC) collection, the usefulness of circulating immature cell (CIC) counts in PB was evaluated.Study Design and Methods: CIC counts in PB and CD34+ cell counts in the apheresis product from 249 collections were assessed, and the relationship between these two parameters was evaluated by with the Pearson rank correlation analysis, the Fisher exact test, and the U-test.Results: CIC counts were correlated significantly with the number of CD34+ cells per kg of patient's body weight in the apheresis product (Pearson rank correlation analysis: r = 0.635, p < 0.0001). When a level of 1 x 10(9) CICs per L was selected as a cutoff value, the sensitivity and specificity for collecting more than 1 x 10(6) CD34+ cells per kg of body weight were 75.7 and 85.5 percent, respectively.Conclusion: The present study strongly suggests that the number of CICs in PB may estimate the number of CD34+ cells collected. The data indicate that CIC counts above 1 x 10(9) per L can be used as a good predictor for PBPC collections containing more than 1 x 10(6) CD34+ cells per kg of body weight in a single apheresis procedure. [ABSTRACT FROM AUTHOR]

We analyze the solar, terrestrial and atmospheric neutrino experiments including SuperKamiokande data using the three-flavor neutrinos framework and obtain the allowed region for parameters (Δm[sup 2, sub 12], sin² 2θ[sub 12], Δm[sup 2, sub 23], θ[sub 13], θ[sub 23]). In solar neutrino experiments, we obtain the large angle solution (Δm[sup 2, sub 12], sin² 2θ[sub 12]) = (4 × 10[sup -6] -7 × 10[sup -5] eV², 0.6-0.9) and small angle solution (3 × 10[sup -6] - 1.2 × 10[sup -5] eV², 0.003 - 0.01) for θ[sub 13] = 0° - 20°. From the terrestrial and atmospheric neutrino experiments including the sub-GeV and multi-GeV zenith angle dependence in SuperKamiokande 535 days data, we found that the ν[sub µ] - ν[sub τ] mixing is large and the range of Δm[sup 2, sub 23] as 0.02 ∼ 0.0002 eV². There is no significant difference between large θ[sub 12] angle solution and small one. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the effect of the saline flush (SF) technique on the depiction of lesions and the reduction of perivenous artefacts in the head and neck region using dual-energy computed tomography (CT) with virtual monochromatic imaging (VMI).Materials and Methods: Fifty patients with head and neck cancer were divided into two groups: group A, without a SF and group B, with a 30-ml SF. All images were acquired using fast kilovolt-switching CT (Revolution HD, GE Healthcare, Milwaukee, WI, USA). Contrast-to-noise ratios (CNRs) of the lesions were calculated at VMI energy levels ranging from 40 to 80 keV. Subjective analysis of overall image quality, delineation of lesions, and perivenous artefacts was conducted by two reviewers at both VMI energy level 40 keV and the optimal energy level (which showed optimal CNR by objective analysis).Results: Optimal energy level was 63 keV for group A and 61 keV for group B. At VMI energy levels ranging from 40 to 80 keV, the CNR was higher for group B. The highest subjective overall image quality was shown for group B at the optimal energy level (subjective image quality mean value, 3.40). Subjective delineation of lesions was comparable. The perivenous artefact score was significantly higher for group B (2.44 versus 2.74 [p<0.05] at 40 keV, 3.20 versus 3.46 [p<0.05] at the optimal energy level).Conclusion: The SF technique results in an improvement of lesion CNR and a reduction of perivenous artefacts in VMI using duel-energy CT, especially at 40 keV. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine the organ specific dose constraints in head and neck carcinoma treated with intensity-modulated radiation therapy (IMRT) using data from a multi-institutional clinical trial (JCOG1015). Dose constraints used in the JCOG1015 were as follows; Spinal cord Dmax <50 Gy, Brain Dmax <70 Gy, Brainstem Dmax <54 Gy, Optic nerve Dmax <50 Gy, Eyeball Dmax <40 Gy, Lens Dmean <6 Gy, Parotid gland Dmean <26 Gy, pharyngeal constrictor muscle (PCM) Dmean <54 Gy, Larynx Dmean <54 Gy, Inner ear Dmean <45 Gy. Brain D1cc, brainstem D1cc, and thyroid Dmean were not stated but recorded. Patient data and dose-volume histograms (DVH) of organs-at-risk (OARs) were collected from 74 patients with nasopharyngeal carcinoma treated with IMRT who enrolled in the JCOG1015 trial. The incidence of late toxicities was evaluated using the cumulative incidence method or prevalence. ROC analysis was used to estimate the optimal DVH cut-off value that predicted toxicities. Estimated DVH cut-off values were brainstem D1cc:55.8 Gy for G1 myelitis, brain D1cc:72.1 Gy for ≥G1 central nerve necrosis, optic nerve Dmax:53.3 Gy for G2 vision impaired, eye-ball Dmax:36.6 Gy for G2 impaired, PCM Dmean:41.2 Gy for ≥G2 dysphagia, ipsilateral inner ear Dmean:44.0 Gy for ≥G2 hearing impaired, ipsilateral inner ear Dmean:51.5 Gy for ≥G2 middle ear inflammation, and thyroid Dmean: 45.6 Gy for G1 hypothyroidism. The 3- and 5-year cumulative incidence of late toxicity by dose metrics were shown in Table 1. The estimated cut-off values were similar to dose constraints criteria used in the JCOG1015 except for PCM. In patients who received higher dose than the dose constraints in brainstem and inner ear, incidence of myelitis and hearing impaired were notably high. The dose constraints criteria of the JCO1015 were appropriate for most OARs, although more strict dose constraints might be necessary for PCM. Dose constraints for inner ear and brainstem should be archived with higher priority. [ABSTRACT FROM AUTHOR]

Abstract Objective To elucidate the mechanisms by which orally administered tacrolimus was not absorbed in a patient following allogeneic hematopoietic stem cell transplantation. Clinical Course A 17-year-old girl with acute myeloid leukemia underwent HLA-haploidentical peripheral blood stem cell transplantation following fludarabine, busulfan, and total-body irradiation. Graft-vs-host disease prophylaxis was post-transplant cyclophosphamide, followed by intravenous tacrolimus and mycophenolate mofetil. When tacrolimus was switched to oral administration, its blood level declined rapidly, resulting in development of acute graft-vs-host disease, which was ameliorated by switching back to intravenous administration. Methods/Results To elucidate if impaired tacrolimus absorption could be related to genetic polymorphism of tacrolimus-metabolizing enzymes, we analyzed gene polymorphisms of cytochrome P450 3A4, cytochrome P450 3A5, and multidrug resistance 1 (MDR1). The patient had wild-type cytochrome P450 3A4 (*1/*1) and variant-type cytochrome P450 3A5 (*3/*3), while MDR1 genes (2677A/G, 3435C/C) were wild-type. Conclusion Wild-type MDR1 gene product P-glycoprotein expressed in the intestine reduces drug absorption from the gastrointestinal tract and may have contributed to low blood levels of tacrolimus in this patient when tacrolimus was orally administered. Highlights • The patient's gene polymorphism of tacrolimus-metabolizing enzymes, especially MDR1, may be associated with insufficient absorption and lack of increase in blood level of tacrolimus when orally administered following allogeneic hematopoietic stem cell transplantation. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to compare the clinical and demographic features of 62 patients presenting sporadic odontogenic keratocysts (OKCs) or OKCs associated with nevoid basal cell carcinoma syndrome (NBCCS). In conjunction with this, we also evaluated the immunohistochemical expression of Shh, Ptch1, Ptch2, Smo, Gli1, Gli2 and Gli3 proteins in 86 OKCs. By doing this, we add to the understanding of the biology of this type of lesion, providing tools that will help facilitate the early diagnosis of NBCCS in those patients where the first manifestation is that of OKCs.Methods: This is a retrospective study; patients were classified into two groups: group 1 which consisted of those who were not affected by NBCCS (49 patients and 57 OKCs) and group 2 which consisted of those who were diagnosed with NBCCS (13 patients and 29 OKCs). The clinical and demographic features were studied and the immunohistochemical expression of Sonic Hedgehog proteins (Shh, Ptch1, Ptch2, Smo, Gli1, Gli2, and Gli3) was analyzed in all samples.Results: There was an increase in the expression of three proteins in the syndromic OKC, when compared to that of sporadic cysts. Shh and Gli1 showed higher cytoplasmic expression, while Smo revealed stronger nuclear and cytoplasmic expressions.Conclusion and clinical relevance: Our findings suggest that the expression patterns of important Shh pathway proteins can represent valuable markers for early diagnosis of NBCCS-associated OKCs, as the major criterion for the diagnosis of NBCCS is currently based on the late appearance of basal cellular carcinomas. Thus, standardizing a new diagnostic tool for diagnosis of NBCCS could be of great importance in the identification of therapeutic targets. We therefore suggest, as based on our findings, that OKCs showing high expression of Shh, Smo, and Gli1 are potentially associated with NBCCS. [ABSTRACT FROM AUTHOR]

Background: We assessed the non-inferiority of accelerated fractionation (AF) (2.4 Gy/fraction) compared with standard fractionation (SF) (2 Gy/fraction) regarding progression-free survival (PFS) in patients with T1-2N0M0 glottic cancer (GC). Patients and methods: In this multi-institutional, randomized, phase III trial, patients were enrolled from 32 Japanese institutions. Key inclusion criteria were GC T1-2N0M0, age 20-80, Eastern Cooperative Oncology Group performance status of 0-1, and adequate organ function. Patients were randomly assigned to receive either SF of 66-70 Gy (33-35 fractions), or AF of 60-64.8 Gy (25-27 fractions). The primary end point was the proportion of 3-year PFS. The planned sample size was 360 with a non-inferiority margin of 5%. Results: Between 2007 and 2013, 370 patients were randomized (184/186 to SF/AF). Three-year PFS was 79.9% (95% confidence interval [CI] 73.4-85.4) for SF and 81.7% (95% CI 75.4-87.0) for AF (difference 1.8%, 91% CI-5.1% to 8.8%; onesided P=0.047>0.045). The cumulative incidences of local failure at 3 years for SF/AF were 15.9%/10.3%. No significant difference was observed in 3-year overall survival (OS) between SF and AF. Grade 3 or 4 acute and late toxicities developed in 22 (12.4%)/21 (11.5%) and 2 (1.1%)/1 (0.5%) in the SF/AF arms. Conclusion: Although the non-inferiority of AF was not confirmed statistically, the similar efficacy and toxicity of AF compared with SF, as well as the practical convenience of its fewer treatment sessions, suggest the potential of AF as a treatment option for early GC. [ABSTRACT FROM AUTHOR]

Background. Pre-emptive therapy with valganciclovir (VGCV) has become the standard therapy for preventing cytomegalovirus (CMV) infection after allogeneic hematopoietic stem cell transplantation (HSCT). The effectiveness of low-dose VGCV (900 mg per day) has been shown to be equal to that of standard-dose VGCV (900 mg twice daily); however, individualized optimal dosing and toxicity of VGCV have not been reported. Methods. We conducted a retrospective study to evaluate the optimal dose of VGCV as pre-emptive therapy for preventing CMV infection by comparing the frequency of adverse events (AEs) and clinical efficacy in a low-dose VGCV group with those in a standard-dose VGCV group. Thirty-eight patients who were administered VGCV because of CMV antigenemia after HSCT were analyzed. Results. Neutropenia (standard-dose group: 33%, low-dose group: 15%, P = 0.26) and thrombocytopenia (standard-dose group: 39%, low-dose group: 15%, P = 0.14) were frequent AEs of VGCV, and a significantly higher frequency of overall AEs was detected in the standard-dose group than in the low-dose group (P < 0.01). In comparison of dosage based on weight, dosage of VGCV >27 mg/kg was closely related to onset of AEs (P = 0.04). Conclusions. Low-dose VGCV was not inferior in clinical efficacy, including clearance rate of CMV antigenemia and incidence of consequent CMV disease, to standard-dose VGCV as was previously reported. Initial low-dose VGCV for pre-emptive CMV therapy markedly reduces hematologic toxicity and has clinical efficacy equivalent to that of standard-dose VGCV. It is therefore reasonable for patients, except for noticeably overweight patients, to be given initial low-dose VGCV. [ABSTRACT FROM AUTHOR]

Background Intestinal microbial ecology is actively regulated by Paneth cell-derived antimicrobial peptides, α-defensins. Graft-versus-host disease ( GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation ( SCT). We previously demonstrated that Paneth cells are targeted by GVHD, and their expression of antimicrobial peptide α-defensins is impaired, leading to a loss of physiological diversity among the microflora and development of bloodstream infection. Herein, we evaluated whether fecal levels of α-defensins could be surrogate marker of intestinal dysbiosis. Methods We directly measured α-defensin cryptdin-1 (Crp1) in fecal pellets of mice with GVHD by using a novel enzyme-linked immunosorbent assay. Results Fecal levels of Crp1 were significantly decreased in mice with GVHD but unchanged in mice without GVHD after SCT. These were correlated with intestinal flora diversity. Conclusion We demonstrate a link between reduced secretion of Paneth cell α-defensins and dysbiosis of intestinal flora in GVHD. Fecal levels of α-defensins could be surrogate markers for intestinal microbial homeostasis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Dabigatran is an oral intake thrombin inhibitor for preventive administration against stroke accompanied by atrial fibrillation. Although dabigatran causes prolonged activated partial thromboplastin time (APTT), the effect of dabigatran on each coagulation factor and coagulation factor inhibitor remains to be investigated. Our aim was to analyze the influence of dabigatran on coagulation factors and coagulation factor inhibitors. Methods: We administered dabigatran to 40 patients. In 26 of these 40, we analyzed the activity of several coagulation factors and their inhibitors. We used Fisher's exact test to determine statistical significance. Results: The activities of many coagulation factors changed during the dabigatran therapy. Factor II levels decreased in all patients showing prolongation of partial thromboplastin (PT) and APTT. The antifactor VIII inhibitor was positive in the majority of patients with prolonged PT and APTT, while activities of protein C, protein S, and antifactor IX inhibitor were not associated with PT and APTT prolongation. Conclusion: Dabigatran affects the activities of many coagulation factors, including factors II, V, VIII, and IX, as well as the antifactor VIII inhibitor. [ABSTRACT FROM AUTHOR]

The impact of the conditioning intensity and TBI on acute GVHD (aGVHD) is still a matter of debate. We analyzed 6848 adult recipients who received allogeneic hematopoietic cell transplants (HCT) between 2006 and 2011 in Japan. The subjects were divided into groups who had received myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC), either with or without TBI. There was a significant difference in the incidence of aGVHD 2-4 among the different conditioning types: 39% in TBI-MAC, 35% in TBI-RIC and 32% in both no-TBI MAC and no-TBI-RIC (P<0.001). In a multivariate analysis, TBI-MAC, but not no-TBI MAC, was significantly associated with an increased risk of aGVHD 2-4 (hazard ratio (HR) 1.33, P<0.01), whereas TBI-RIC was associated with an increased risk of GVHD 3-4 (HR 1.36, P=0.048). TBI-MAC and TBI-RIC were significantly associated with skin and gastrointestinal aGVHD. Subgroup analyses demonstrated that not only TBI-MAC, but also TBI-RIC, was significantly associated with aGVHD 2-4 in older patients. Furthermore, high-dose TBI only had an adverse impact on aGVHD 2-4 in HLA-matched HCT. Impacts of intensity and TBI on aGVHD differ by patient backgrounds, and this difference should be considered to establish a risk-adapted strategy for the prevention of aGVHD. [ABSTRACT FROM AUTHOR]

Background Reactivation of hepatitis B virus ( HBV) infection, reverse seroconversion ( RS), is a serious complication after allogeneic stem cell transplantation (allo HSCT). We previously conducted a post-transplant hepatitis B vaccine intervention trial and demonstrated the vaccine efficacy in preventing HBV- RS. This report is an update of the hepatitis B vaccine study. Methods In this trial, 21 patients were enrolled and received a standard 3-dose regimen of hepatitis B vaccine after discontinuation of immunosuppressants, whereas 25 transplant recipients with previous HBV infection did not receive the vaccine and served as controls. Results None of the 21 patients in the vaccine group developed HBV- RS and 12 controls developed HBV- RS in median follow-up periods of 60 months (range 13-245). HBV vaccine resulted in a positive value of hepatitis B surface antibody ( HBsAb) titer in 9 patients, while HBsAb remained negative in 12 patients. Presence of a high titer of HBsAb before vaccination was associated with conversion into HBsAb positivity after vaccination. Conclusion These results demonstrated the long-term effects of HBV vaccine for preventing HBV- RS after allo HSCT. Of note, no HBV- RS occurred, even in patients who did not achieve conversion into HBsAb positivity after vaccination. [ABSTRACT FROM AUTHOR]

The Graft Processing subcommittee of the Worldwide Network for Blood and Marrow Transplantation wrote this guideline to assist physicians and laboratory technologists with the setting up of a cell processing laboratory (CPL) to support a hematopoietic stem cell transplant program, thereby facilitating the start-up of a transplant program in a new location and improving patient access to transplantation worldwide. This guideline describes the minimal essential features of designing such a laboratory and provides a list of equipment and supply needs and staffing recommendations. It describes the typical scope of services that a CPL is expected to perform, including product testing services, and discusses the basic principles behind the most frequent procedures. Quality management (QM) principles specific to a CPL are also discussed. References to additional guidance documents that are available worldwide to assist with QM and regulatory compliance are also provided. [ABSTRACT FROM AUTHOR]

Graft rejection remains a major obstacle in allogeneic hematopoietic SCT following reduced-intensity conditioning (RIC-SCT), particularly after cord blood transplantation (CBT). In a murine MHC-mismatched model of RIC-SCT, primary graft rejection was associated with activation and expansion of donor-reactive host T cells in peripheral blood and BM early after SCT. Donor-derived dendritic cells are at least partly involved in host T-cell activation. We then evaluated if such an expansion of host T cells could be associated with graft rejection after RIC-CBT. Expansion of residual host lymphocytes was observed in 4/7 patients with graft rejection at 3 weeks after CBT, but in none of the 17 patients who achieved engraftment. These results suggest the crucial role of residual host T cells after RIC-SCT in graft rejection and expansion of host T cells could be a marker of graft rejection. Development of more efficient T cell-suppressive conditioning regimens may be necessary in the context of RIC-SCT. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Pituitary-dependent hyperadrenocorticism (PDH) caused by pituitary corticotroph adenoma is a common endocrine disorder in dogs. The ratio between pituitary height and the area of the brain (P/B) has been used to evaluate the pituitary size. A P/B ratio > 0.31 indicates an enlarged pituitary, whereas a P/B ratio ≤ 0.31 indicates a nonenlarged pituitary. The aim of this study was to investigate the expression of proliferation markers Ki-67 and minichromosome maintenance-7 (MCM7) in canine corticotroph adenomas in enlarged and in nonenlarged pituitaries and to evaluate their relation with the size of canine pituitary corticotroph adenomas. Ki-67 and MCM7 expression in ACTH-positive tumor cells was determined by dual-labeling immunohistochemistry in resected corticotroph adenomas from 15 dogs with PDH. The mean ± SD Ki-67 labeling index (LI) was 0.55% ± 0.59% in corticotroph adenomas with nonenlarged pituitaries and 1.6% ± 0.6% in adenomas with enlarged pituitaries. The MCM7 LI in corticotroph adenomas with nonenlarged pituitaries and in adenomas with enlarged pituitaries was 2.9% ± 2.2% and 10.9% ± 3.7%, respectively. The Ki-67 LI and MCM7 LI were significantly greater in the adenomas with enlarged pituitaries than in the adenomas with nonenlarged pituitaries (P < 0.01 and P < 0.01, respectively). The MCM7 LI was significantly greater than the Ki-67 LI in adenomas (P < 0.01). The Ki-67 LI was positively correlated with the MCM7 LI (r = 0.820, P < 0.01), and the P/B ratio was positively correlated with the Ki-67 LI (r = 0.560, P = 0.03) and the MCM7 LI (r = 0.854, P < 0.01). In conclusion, canine corticotroph adenomas in enlarged pituitaries show greater proliferation potential than do adenomas in nonenlarged pituitaries. MCM7 expression was significantly greater than Ki-67 expression in canine pituitary corticotroph adenomas. Thus, MCM7 may be superior to Ki-67 as a proliferation marker in pituitary tumors. [Copyright &y& Elsevier]

We retrospectively analyzed the outcomes of 26 patients with acute promyelocytic leukemia (APL) in the first CR (CR1) or second CR (CR2), who underwent autologous PBSCT (auto-PBSCT) between 1992 and 2008. All patients received all-trans retinoic acid-based induction therapy. After two courses of consolidation chemotherapy, upfront auto-PBSCT was performed in 20 patients in the CR1. Five patients had a high WBC count of more than 10 × 109/L (high risk), while 15 patients had a count of less than 10 × 109/L (low risk) at initial presentation. In addition, six patients, who were considered as low-risk patients at presentation, had a relapse after three cycles of consolidation and 2 years of maintenance therapy, but gained the molecular remission after re-induction and consolidation, and underwent auto-PBSCT in the CR2. In 26 recipients, engraftment was rapid and no TRM was documented. All 20 patients autotransplanted in CR1 were still in CR at a median of 133 months (73-193 months), and six patients who underwent auto-PBSCT in CR2 were also still in CR at a median of 41 months (2-187 months) without maintenance therapy. PML/RARα chimeric mRNA was undetectable in PBSC or BM samples examined before auto-PBSCT. Despite a small number of cases studied, our retrospective observations suggest that auto-PBSCT may be an effective treatment option to continue durable CR in the treatment of high-risk APL. We review previous reports and discuss the role of autotransplantation in the treatment of APL patients in CR. [ABSTRACT FROM AUTHOR]

Abstract: This paper was intended as a study of the radiological characteristics of a polymer gel detector in a clinical proton beam irradiation. The depth dose distributions in the detector were examined with regard of dose and dose rate dependences in the response. Our experimental results indicated that the dose response depended considerably on the depth from the incident position, and also the dose rate in the proton irradiation. We estimated the dose response at different depth of the incident proton beam from the depth-R 2 relations with various dose, and the spread-out depth dose in a single field irradiation derived from these dose responses obtained the good agreement with a planned dose distribution. In conclusion, our method with MAGAT type polymer gel is effective in a quality assurance of fundamental reproducibility test for three dimensional radiation therapy planning system, such as monitor unit verification and standard isodose verification using a single field proton beam. However the depth dose distribution should be evaluated depending on irradiation dose rate, SOBP width, and maximum energy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Ulcerative colitis (UC) is an intractable disease; therefore new therapies need to be developed. CD4+ CD25high regulatory T cells (Treg) significantly ameliorate colitis in animal models. In active UC patients, although Treg are functionally preserved, their proportion in peripheral blood decreases. Thus Treg transfer therapy is expected to be efficacious for UC. During leukapheresis for UC, Treg are depleted, as well as colitogenic effector leukocytes. We therefore designed a leukapheresis/Treg transfer therapy in which Treg are isolated from leukapheresis products and transfused to patients, and studied large-scale germ-free methods of Treg preparation. Methods Using the CliniMACS cell selection system, we conducted Treg isolation experiments from leukapheresis products in which B and CD8+ T cells were depleted, followed by positive selection of CD25+ cells. In some experiments, isolated Treg or non-Treg were expanded with interleukin-2 (IL-2) ± transforming growth factor (TGF)-β1. Expression of a Treg-specific marker, FOXP3, and gut-homing receptors, and suppressor activity of isolated or cultured cells, were analyzed. Results CD4+ CD25high T cells were collected and efficiently enriched with a good recovery rate. Isolated cells preferentially expressed FOXP3 and significantly suppressed T-cell proliferation in vitro. In addition, isolated Treg could be efficiently expanded, and Treg could be induced from non-Treg with TGF-β1 in vitro. TGF-β1 significantly up-regulated αEβ7 and α4β7 integrins. Discussion We have established a method of Treg isolation from leukapheresis products that can be used clinically; therefore, Treg transfer therapy is feasible in combination with leukapheresis for UC. Expansion or induction of Treg in vitro may be another approach to Treg-based immunotherapy. [ABSTRACT FROM AUTHOR]

To assess infectious complications associated with chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) with reduced- and conventional-intensity conditioning regimens (RIC, n=91; CIC, n=54, respectively), we retrospectively analyzed data from 145 consecutive patients with cGVHD after allogeneic HSCT from a human leukocyte antigen-matched related or unrelated donor. In the present retrospective analysis, 57% (83/145) of patients with cGVHD developed infections, with a mortality rate of 27% (22/83). The incidences of bacteremia ( n=28), central venous catheter-related infections ( n=11), bacterial pneumonia ( n=4), invasive aspergillosis ( n=7), and adenoviral hemorrhagic cystitis ( n=8) were significantly higher in patients with prednisolone dose ≥1 mg/kg at the time of diagnosis of cGVHD. The present results suggest that infections associated with cGVHD, especially after high-dose prednisolone, are predictive of poor outcome regardless of whether the patient received RIC or CIC. [ABSTRACT FROM AUTHOR]