Programmed death-1 pathway in host tissues ameliorates Th17/Th1-mediated experimental chronic graft-versus-host disease.

Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity after allogeneic hematopoietic cell transplantation, but its pathogenesis remains unclear. We investigated the role of the programmed death-1 (PD-1) pathway in chronic GVHD using a well-defined mouse model of B10.D2 (H-2(d)) donor to BALB/c (H-2(d)) recipients. PD-1 expression on allogeneic donor T cells was upregulated continuously in chronic GVHD development, whereas PD-L1 expression in host tissues was transiently upregulated and declined to basal levels in the late posttransplant period. Blockade of the PD-1 pathway by anti-PD-1, anti-PD-L1, or anti-PD-L2 mAbs exacerbated clinical and pathologic chronic GVHD. Chimeric mice revealed that PD-L1 expression in host tissues suppressed expansion of IL-17(+)IFN-γ(+) T cells, and that PD-L1 expression on hematopoietic cells plays a role in the development of regulatory T cells only during the early transplantation period but does not affect the severity of chronic GVHD. Administration of the synthetic retinoid Am80 overcame the IL-17(+)IFN-γ(+) T cell expansion caused by PD-L1 deficiency, resulting in reduced chronic GVHD damage in PD-L1(-/-) recipients. Stimulation of the PD-1 pathway also alleviated chronic GVHD. These results suggest that the PD-1 pathway contributes to the suppression of Th17/Th1-mediated chronic GVHD and may represent a new target for the prevention or treatment of chronic GVHD.

Assessment of reasons for referral and activities of hospital palliative care teams using a standard format: a multicenter 1000 case description.

CONTEXT: The many benefits of hospital palliative care teams (PCTs) are well known. However, their specific activities have not been fully clarified, and no standardized methods for reporting PCT activities are available. OBJECTIVES: The aim of this study was to investigate, through the use of a standard format, the activities performed by hospital PCTs in Japan. METHODS: This was a prospective observational study. A total of 21 hospital PCTs were included in this study, and each recruited approximately 50 consecutively referred patients. Participating PCTs filled in a standard form for reporting activities. RESULTS: We obtained data from 1055 patients who were referred to PCTs. Of the 1055 patients, 1005 patients (95%) had cancer. The median number of reasons for referral and problems identified by PCTs was two (0-22) and four (0-18), respectively. The two major reasons for referral were pain (63%) and anxiety/depression/grief/emotional burden (22%). The major recommendations were pharmacological treatment (74%), care for the patient's physical symptoms (49%), and support for patient's decision making (38%). The major activities performed by the PCTs were comprehensive assessment (90%), care for the patient's physical symptoms (77%), and pharmacological treatment (74%). CONCLUSION: The components of hospital PCT activities were successfully measured using the Standard Format for Reporting Hospital PCT Activity. The results of this study and the format for reporting hospital PCT activity could be effective in improving hospital PCT practice and for the education of new hospital PCT members.

[Rectal metastasis from lung cancer; report of a case].

A 70-year-old male underwent left pneumonectomy for lung cancer in November 2008. Although he was diagnosed as pT2bN1M0 (stage II B) after the operation, adrenal metastasis was found 8 months later. Positron emission tomography (PET) revealed accumulation in the adrenal gland and rectum. Gastrointestinal tract examination revealed a type 1 tumor in the rectum. Histological examination of biopsy specimens obtained from the lesion suggested papillary adenocarcinoma of rectum. Abdominoperineal resection was performed. The resected rectal tumor was reported immunohistochemically as metastasis from primary lung cancer.

Synthetic retinoid Am80 ameliorates chronic graft-versus-host disease by down-regulating Th1 and Th17.

Chronic GVHD (cGVHD) is a main cause of late death and morbidity after allogeneic hematopoietic cell transplantation, but its pathogenesis remains unclear. We investigated the roles of Th subsets in cGVHD with the use of a well-defined mouse model of cGVHD. In this model, development of cGVHD was associated with up-regulated Th1, Th2, and Th17 responses. Th1 and Th2 responses were up-regulated early after BM transplantation, followed by a subsequent up-regulation of Th17 cells. Significantly greater numbers of Th17 cells were infiltrated in the lung and liver from allogeneic recipients than those from syngeneic recipients. We then evaluated the roles of Th1 and Th17 in cGVHD with the use of IFN-γ-deficient and IL-17-deficient mice as donors. Infusion of IFN-γ(-/-) or IL-17(-/-) T cells attenuated cGVHD in the skin and salivary glands. Am80, a potent synthetic retinoid, regulated both Th1 and Th17 responses as well as TGF-ß expression in the skin, resulting in an attenuation of cutaneous cGVHD. These results suggest that Th1 and Th17 contribute to the development of cGVHD and that targeting Th1 and Th17 may therefore represent a promising therapeutic strategy for preventing and treating cGVHD.

Successful voriconazole treatment of invasive pulmonary aspergillosis in a patient with acute biphenotypic leukemia.

A 23-year old woman with acute biphenotypic leukemia (ABL) complained of chest pain with cough, high fever and hemoptysis during induction chemotherapy, although she had been treated with anti-biotics and micafungin. We made a clinical diagnosis of invasive pulmonary aspergillosis (IPA) based on a consolidation in the right upper lung field on a chest radiograph as well as a high level of serum beta-D-glucan (with no evidence of tuberculosis and candidiasis). We changed her treatment from micafungin to voriconazole. Later, we discovered an air-crescent sign by CT scan that supported the diagnosis of IPA. Following voriconazole treatment, clinical symptoms ceased and abnormal chest shadows improved gradually and concurrently with a recovery of neutrophils. IPA must be considered in immunocompromised patients with pulmonary infiltrates who do not respond to broad-spectrum antibiotics. Serological tests and CT findings can aid in early diagnosis of IPA, which, along with treatment for IPA, will improve clinical outcomes.

Clinical outcomes of unrelated donor umbilical cord blood transplantation for 30 adults with hematological malignancies.

BACKGROUND: Umbilical cord blood transplantation (CBT) has increasingly been used as a therapeutic option for adult patients for whom allogeneic stem-cell transplantation is not indicated, due to the availability of cord blood. However, myeloablative conditioning regimens are associated with significant mortality, and high relapse rates in reduced-intensity regimens may result in a poor rate of disease-free survival for those with advanced stages of hematological malignancies. Therefore, it remains unknown whether CBT is a truly effective option for such adults with high-risk disease, as well as for those with standard-risk disease. PATIENTS AND METHODS: Thirty adult patients with a median age of 45 years (range: 16-67) with standard or high-risk disease underwent CBT from unrelated donors at Okayama University Hospital between October 2002 and May 2007. Twenty-one patients had diseases classified as high-risk for transplantation. The median number of nucleated cells in infused cord blood was 2.65 x 10(7)/kg (range: 1.73-4.87). RESULTS: Twenty-three patients achieved neutrophil engraftment at a median time of 22 days (range: 13-42) after CBT. The cumulative incidence of grade II to IV acute graft-versus-host disease (GVHD) was 53.6% . Out of the 30 patients, 11 were alive and disease-free at a median time of 446 days (range: 124-1153) after CBT. The cumulative 1-year overall survival in patients with standard-risk or high-risk disease was 63.5% and 15.4%, respectively (p=0.01). CONCLUSION: Although from a retrospective study, these results suggest that unrelated donor CBT could be safe and effective for adult patients with standard-risk disease who cannot find a suitable HLA-matched volunteer marrow or peripheral blood donor.

A newly designed and constructed 20 kHz magnetic field exposure facility for in vivo study.

Exposure to man-made electromagnetic fields has increased over the past century. As a result of exposure to these fields, concerns have been raised regarding the relationship between electromagnetic fields and human health. Interest in the biological and health effects of intermediate frequency (IF) magnetic fields has grown recently because of the increase in public concern. In order to investigate whether IF magnetic fields have biological effects, we have developed a 20 kHz (IF) magnetic field exposure system for in vivo studies. The exposure facility was designed to study the biological effects of IF magnetic field on laboratory animals. The facility consists of a 9 m x 9 m x 5 m high room containing seven separate rooms including a 5.3 m x 4.5 m x 3 m high specific-pathogen free exposure room. The dimensions of the exposure system are 1.6 m x 1.6 m x 1.616 m high located inside this exposure room. The system is designed to provide magnetic fields up to 200 microT at 20 kHz with the uniformity within +/-5% over the space occupied by animals. After constructing the facility, performance tests were carried out. As a result, it was confirmed that our facility met requirements for evaluation of the biological effects of IF magnetic field on small animal experiments. In this paper, the design, construction, and results of evaluation of an animal exposure facility for the in vivo biological effects of an IF magnetic field are described.

Construction of a three-dimensional outline of the heart and conduction pathway by means of a 64-channel magnetocardiogram in patients with atrial flutter and fibrillation.

BACKGROUND: Magnetocardiography (MCG) has the potential for collecting three-dimensional (3D) intracardiac electric information, because the magnetic field is unaffected by the shape of the lungs and torso. In the present study, we report on the generation of a 3D heart outline and conduction pathway by means of a current density map using a 64-channel SQUID system, and an evaluation of its significance in patients with atrial flutter (AFL) and atrial fibrillation (AFIB). METHODS: The subjects consisted of 20 healthy volunteers, and 3 patients with AFL and 4 patients with AFIB. A 64-channel MCG was recorded after digitization at 500 Hz, and a 3D current density was reconstructed from the magnetic fields using a space filter in conjunction with the minimum normalization method of Tikhonov. A 3D heart outline was generated from the integrated current density by the space filter. The conduction pathway was superimposed on a heart outline generated by a magnetic field. The heart outline was verified by the silhouette on the magnetic resonance (MR) images. An MCG was recorded pre- and post interventional therapy, and therapeutic efficacy was evaluated. RESULTS: The 3D heart outline of the atrium and ventricle corresponded to the silhouette of the right atrium and left ventricle, respectively, on an MR image. The serial conduction pathway of the QRS segment superimposed on the 3D heart outline map demonstrated the conduction pattern generated within the heart. The MCG revealed a counter-clockwise rotation in patients with AFL, and random micro-reentry in the case of AFIB. After interventional therapy, restoration of the sinus rhythm was verified in patients with both AFL and AFIB. CONCLUSIONS: A 64-channel MCG was used to evaluate the 3D heart outline and conduction pathway in patients with AFL and AFIB without the need for MR images. Condensed Abstract A 64-channel MCG was used to evaluate the 3D heart out line and conduction pathway in patients with AFL and AFIB.

Long-range EEG phase synchronization during an arithmetic task indexes a coherent cortical network simultaneously measured by fMRI.

An open question lies in whether or not distributed activities in the distant brain regions are integrated into a coherent ensemble for cognitive information processing. Long-range phase synchronization is often observed by scalp EEG measurements during cognitive tasks and is considered to provide a possible neural principle for the functional integration of distributed neural activities. Synchronization could be reflected at the neuron firing level or at the local field potential and could appear in the scalp EEG under certain conditions on neural spatial and temporal coherence. To examine if phase synchronization is concerned with the integration of distant regions, we proposed a method to extract brain activities associated with task-dependent phase synchronization by combining simultaneous fMRI and EEG. By applying this method in a mental arithmetic task, we found a dominant task-dependent increase of phase synchronization around 14 Hz (in beta frequency) across bilateral parietal sites that were associated with both negative and positive BOLD responses. Functional connectivity analyses of these regions demonstrated that an increase in hemispheric beta synchronization was associated with a linking between the cross-hemispheric regions (left angular gyrus and right superior parietal gyrus) and also among the anterior-posterior regions (right dorsolateral prefrontal cortex, putamen, and right superior temporal gyrus). These findings indicate that the positive BOLD regions (dorsolateral prefrontal cortex and superior parietal lobule) are linked with other negative BOLD regions. We also discussed the possible importance of beta synchronization in the formation of a working memory network.

A long-range cortical network emerging with theta oscillation in a mental task.

Human scalp EEG has demonstrated that global coherence among distant areas increases during cognitive tasks, suggesting that oscillating neural activities work to generate global neuronal assemblies for cognitive functions. The theta oscillation in a frequency range of 4-8 Hz with large amplitudes which emerges during mental tasks around the frontal midline region is called fm theta. If theta oscillation concerns the global neuronal assemblies, fm theta should be associated with regional activities that depend on task conditions. In the present study, we examine the EEG-related brain activities by developing simultaneous EEG and fMRI during a mental calculation task. EEG-related negative BOLD was dominant over anterior medial regions, suggesting a major contribution of negative BOLD to fm theta. Negative and positive BOLD were found over distant regions. Functional connectivity analyses revealed that the connectivity varied remarkably according to mental conditions. In the rest condition, the connectivity was localized, whereas in the task condition, a long-range coherent network was formed by the anterior midline, posterior cingulate and right middle temporal cortices with linking between the right middle temporal and left lateral cortices during numerical processing. Further EEG analyses indicate that the long-range coherent network executing cognitive functions is coordinated in the time window of theta oscillations.