Parkinson’s disease is one of the most common movement disorders and is characterized by dopaminergic cell loss and the accumulation of pathological α-synuclein, but its precise pathogenetic mechanisms remain elusive. To develop disease-modifying therapies for Parkinson’s disease, an animal model that recapitulates the pathology and symptoms of the disease, especially in the prodromal stage, is indispensable. As subjects with α-synuclein gene (SNCA) multiplication as well as point mutations develop familial Parkinson’s disease and a genome-wide association study in Parkinson’s disease has identified SNCA as a risk gene for Parkinson’s disease, the increased expression of α-synuclein is closely associated with the aetiology of Parkinson’s disease. In this study we generated bacterial artificial chromosome transgenic mice harbouring SNCA and its gene expression regulatory regions in order to maintain the native expression pattern of α-synuclein. Furthermore, to enhance the pathological properties of α-synuclein, we inserted into SNCA an A53T mutation, two single-nucleotide polymorphisms identified in a genome-wide association study in Parkinson’s disease and a Rep1 polymorphism, all of which are causal of familial Parkinson’s disease or increase the risk of sporadic Parkinson’s disease. These A53T SNCA bacterial artificial chromosome transgenic mice showed an expression pattern of human α-synuclein very similar to that of endogenous mouse α-synuclein. They expressed truncated, oligomeric and proteinase K-resistant phosphorylated forms of α-synuclein in the regions that are specifically affected in Parkinson’s disease and/or dementia with Lewy bodies, including the olfactory bulb, cerebral cortex, striatum and substantia nigra. Surprisingly, these mice exhibited rapid eye movement (REM) sleep without atonia, which is a key feature of REM sleep behaviour disorder, at as early as 5 months of age. Consistent with this observation, the REM sleep-regulating neuronal populations in the lower brainstem, including the sublaterodorsal tegmental nucleus, nuclei in the ventromedial medullary reticular formation and the pedunculopontine nuclei, expressed phosphorylated α-synuclein. In addition, they also showed hyposmia at 9 months of age, which is consistent with the significant accumulation of phosphorylated α-synuclein in the olfactory bulb. The dopaminergic neurons in the substantia nigra pars compacta degenerated, and their number was decreased in an age-dependent manner by up to 17.1% at 18 months of age compared to wild-type, although the mice did not show any related locomotor dysfunction. In conclusion, we created a novel mouse model of prodromal Parkinson’s disease that showed RBD-like behaviour and hyposmia without motor symptoms.

No abstract

We investigated the impact of neutropenia on the development of early bloodstream and pulmonary infections in hematopoietic stem cell transplantation (HSCT) recipients, and evaluated the utility of an index (D-index) that reflects both the intensity and duration of neutropenia. Fifty-eight patients (23 autologous, 35 allogeneic HSCT recipients) were enrolled in this retrospective study. The D-index was defined as the area over the neutrophil curve during neutropenia. We also evaluated the utility of the cumulative D-index from the start of neutropenia until the development of infection (c-D-index), which may enable real-time assessment of the risk for infection. The patients showed 12 and 7 episodes of bloodstream and pulmonary infection, respectively. The D-index, days of neutropenia (<500/microL) and days of profound neutropenia (<100/microL) had at least a nearly significant impact on the development of both bloodstream and pulmonary infections. On the other hand, the c-D-index, cumulative days of neutropenia, and cumulative days of profound neutropenia significantly affected pulmonary infection, but not bloodstream infection. The c-D-index had a high negative predictive value of 97.4% for pulmonary infection with a cutoff of 5500, but the area under the receiver operating characteristic curve was similar to that of the cumulative days of neutropenia and profound neutropenia. Our results showed that although the c-D-index may be useful for identifying patients who are at low risk for early pulmonary infection after HSCT, its performance was similar to that of the simple duration of neutropenia.

The clinical features and outcome of small intestinal lymphoma remain unclear. We retrospectively analyzed 23 patients who had non-Hodgkin lymphoma with a small intestinal lesion. With a median follow-up of 37 months, the 5-year overall survival and failure-free survival (FFS) were 64% and 60%, respectively. In a univariate analysis, a worse performance status at the start of treatment and the occurrence of abdominal symptoms or perforation during treatment were associated with poor survival. Perforation often resulted in a dismal prognosis in patients with uncontrollable lymphoma, but not in patients with lymphoma in remission. The role of surgery in small intestinal lymphoma remains equivocal. In the current study, surgery before other therapies favorably influenced FFS, and all patients who underwent complete resection of the small intestinal lesion had extremely favorable results. Further studies are warranted to establish optimal therapeutic strategies.

Adult T-cell leukemia (ATL) is a lymphoproliferative malignancy associated with human T-cell lymphotropic virus type 1 (HTLV-1) infection. Recently, it has been shown that allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for ATL, and that HTLV-1 Tax-specific CD8 + cytotoxic T cells (CTL) contribute to the graft-versus-ATL effect. In the present study, we, for the first time, analyzed the T-cell receptor (TCR) repertoire of isolated Tax 301-309 (SFHSLHLLF)-specific CTLs in HLA-A*2402 + ATL patients before and after allo-HSCT by single-cell reverse transcription-PCR. The Tax 301-309 -specific CTLs in bone marrow and peripheral blood showed highly restricted oligoclonal diversity. In addition, a unique conserved amino acid motif of "P-D/P-R" in TCR-β complementarity-determining region 3 in either BV7-or BV18-expressing CTLs was observed not only in all of the samples from ATL patients, but also in samples from the same patient before and after HSCT. Furthermore, the P-D/P-R motif-bearing CTL clones established from peripheral blood samples after HSCT exhibited strong killing activity against the HTLV-1-infected T cells of the patient. CTL clones were not established in vitro from samples prior to allo-HSCT. In addition, CTL clones with a strong killing activity were enriched in vivo after HSCT in the patient. Hence, Tax 301-309 -specific CTLs in ATL patients might have a preference for TCR construction and induce strong immune responses against the HTLV-1-infected T cells of patients, which contribute to the graft-versus-ATL effects after allo-HSCT. However, further analyses with a larger number of patients and more frequent sampling after allo-HSCT is required to confirm these findings. Cancer Res; 70(15);