No abstract

Hemophagocytic lymphohistiocytosis (HLH), a disorder of the mononuclear phagocyte system, can be classified into two distinct forms: primary HLH (FHL) and secondary HLH. To clarify the epidemiology and clinical outcome for each HLH subtype, we conducted a nationwide survey of HLH in Japan. Since 799 patients were diagnosed in 292 institutions of Japan between 2001 and 2005, the annual incidence of HLH was estimated as 1 in 800,000 per year. Among them, 567 cases were actually analyzed in this study. The most frequent subtype was Epstein-Barr virus (EBV)-associated HLH, followed by other infection- or lymphoma-associated HLH. Age distribution showed a peak of autoimmune disease- and infection-associated HLH in children, while FHL and lymphoma-associated HLH occurred almost exclusively in infants and the elderly, respectively. The 5-year overall survival rate exceeded 80% for patients with EBV- or other infection-associated HLH, was intermediate for those with FHL or B-cell lymphoma-associated HLH, and poor for those with T/NK cell lymphoma-associated HLH (<15%). Although this nationwide survey establishes the heterogeneous characteristics of HLH, the results should be useful in planning prospective studies to identify the most effective therapy for each HLH subtype.

Summary Sleep is a behavior conserved from invertebrates to vertebrates, and tightly regulated in a homeostatic manner. The molecular and cellular mechanism determining the amount of rapid eye movement sleep (REMS) and non-REMS (NREMS) remains unknown. Here we identified two dominant mutations affecting sleep/wakefulness through an electroencephalogram/electromyogram-based screening of randomly mutagenized mice. A splicing mutation of the Sik3 protein kinase gene causes a profound decrease in total wake time, due to an increase in inherent sleep need. Sleep deprivation affects regulatory-site phosphorylation of the kinase. Sik3 orthologues regulate sleep also in fruit flies and roundworms. A missense mutation of the leak cation channel NALCN reduces the total amount and episode duration of REMS, apparently by increasing the excitability of REMS-inhibiting neurons. Our results substantiate the utility of forward genetic approach for sleep behaviors in mice, demonstrating the role of SIK3 and NALCN in regulating the amount of NREMS and REMS, respectively.

The canonical model of sex-chromosome evolution predicts that, as recombination is suppressed along sex chromosomes, gametologs will progressively differentiate, eventually becoming heteromorphic. However, there are numerous examples of homomorphic sex chromosomes across the tree of life. This homomorphy has been suggested to result from frequent sex-chromosome turnovers, yet we know little about which forces drive them. Here, we describe an extremely fast rate of turnover among 28 species of Ranidae. Transitions are not random, but converge on several chromosomes, potentially due to genes they harbour. Transitions also preserve the ancestral pattern of male heterogamety, in line with the ‘hot-potato’ model of sex-chromosome transitions, suggesting a key role for mutation-load accumulation in non-recombining genomic regions. The importance of mutation-load selection in frogs might result from the extreme heterochiasmy they exhibit, making frog sex chromosomes differentiate immediately from emergence and across their entire length.

De novo CD5 ؉ diffuse large B-cell lymphoma (CD5 ؉ DLBCL) is known to have phenotypically and genotypically different characteristics than CD5 ؊ DLBCL and mantle cell lymphoma (MCL). To further characterize CD5 ؉ DLBCL, 109 patients with CD5 ؉ DLBCL were reviewed, and the results were compared with those of 384 CD5 ؊ DLBCL and 128 cyclin D1 ؉ MCL patients. Patients with CD5 ؉ DLBCL showed a higher age distribution (median, 66 years; P ‫؍‬ .0083) and a female predominance (male-female ratio, 49:60, P ‫؍‬ .011) compared with those with CD5 ؊ DLBCL. CD5 ؉ DLBCL was more closely associated with many aggressive clinical features or parameters than CD5 ؊ DLBCL: 69% older than 60 years (P ‫؍‬ .039), 34% with performance status greater than 1 (P ‫؍‬ .0016), 69% with serum lactate dehydrogenase level higher than normal (P < .0001), 62% with stage III/IV disease at diagnosis (P ‫؍‬ .0023), 35% with more than one extranodal site (P ‫؍‬ .023), and 40% with B symptoms (P ‫؍‬ .0031). The overall International Prognostic Index score was thus significantly higher for the patients with CD5 ؉ DLBCL than for those with CD5 ؊ DLBCL (P ‫؍‬ .00005). The most frequent site of extranodal involvement was bone marrow (28%), a higher frequency than that for CD5 ؊ DLBCL (P < .0001) but lower than that for cyclin D1 ؉ MCL (P ‫؍‬ .0015). Histopathologically, CD5 ؉ DLBCL showed centroblastic morphology except for 3 patients with immunoblastic disease, and interfollicular growth pattern (7%) and intravascular or intrasinusoidal infiltration (19%) were observed. Immunophenotypically, CD5 ؉ DLBCL was characterized by a CD5 ؉ CD10 ؊ CD19 ؉ CD20 ؉ CD21 ؊ CD23 ؊ cyclin D1 ؊ phenotype and a predominance of surface IgM. Of particular interest is that CD5 ؉ DLBCL was characterized by a survival curve significantly inferior to that for patients with CD5 ؊ DLBCL (P ‫؍‬ .0026). These findings suggest that CD5 ؉ DLBCL may constitute a unique subgroup of DLBCL.

The bearded dragon, Pogona vitticeps (Agamidae: Reptilia) is an agamid lizard endemic to Australia. Like crocodilians and many turtles, temperature-dependent sex determination (TSD) is common in agamid lizards, although many species have genotypic sex determination (GSD). P. vitticeps is reported to have GSD, but no detectable sex chromosomes. Here we used molecular cytogenetic and differential banding techniques to reveal sex chromosomes in this species. Comparative genomic hybridization (CGH), GTG- and C-banding identified a highly heterochromatic microchromosome specific to females, demonstrating female heterogamety (ZZ/ZW) in this species. We isolated the P. vitticeps W chromosome by microdissection, re-amplified the DNA and used it to paint the W. No unpaired bivalents were detected in male synaptonemal complexes at meiotic pachytene, confirming male homogamety. We conclude that P. vitticeps has differentiated previously unidentifable W and Z micro-sex chromosomes, the first to be demonstrated in an agamid lizard. Our finding implies that heterochromatinization of the heterogametic chromosome occurred during sex chromosome differentiation in this species, as is the case in some lizards and many snakes, as well as in birds and mammals. Many GSD reptiles with cryptic sex chromosomes may also prove to have micro-sex chromosomes. Reptile microchromosomes, long dismissed as non-functional minutiae and often omitted from karyotypes, therefore deserve closer scrutiny with new and more sensitive techniques.

Diffuse large B-cell lymphoma (DLBCL) having both t(14;18) and 8q24 translocations is rare. We evaluated the clinical characteristics and prognoses of patients with DLBCL carrying both t(14;18) and 8q24 translocations. A total of 1972 patients with non-Hodgkin's lymphoma were treated in the Adult Lymphoma Treatment Study Group (ALTSG) from 1998 to 2007. Nineteen cases of de novo DLBCL with the dual translocation were identified. The dual translocation was observed in 19 of 394 patients with DLBCL (10 males and 9 females, with a median age of 61 years). The dual translocation was observed significantly more frequently among patients with high lactate dehydrogenase levels, B symptoms, bone marrow involvement and advanced stage. Immunophenotyping was performed and showed DLBCL with a germinal center type in the majority of cases. Progression-free survival and overall survival rates were significantly lower in patients with the dual translocation than in those with other translocation. DLBCL patients with concurrent t(14;18) and 8q24 translocations have very poor prognosis. Even if patients had a complete response to chemotherapy, they subsequently suffered early relapse. In this study, only a few patients received rituximab, and its usefulness could not be assessed. Future studies with larger numbers of patients are required.

BackgroundLymphoid neoplasm with 18q21.3/BCL2 and 8q24/MYC translocation to immunoglobulin (IG) genes as dual-hit lymphoma/leukemia is very rare and known to have a poor clinical outcome. Design and MethodsTo clarify the clinicopathological characteristics of this malignancy, we analyzed 27 cases of cytogenetically proven dual-hit lymphoma/leukemia. ResultsDual-hit lymphoma/leukemia was diagnosed at presentation in 22 cases and at relapse or disease progression in 5 cases. At the time of diagnosis of dual-hit lymphoma/leukemia, extranodal involvement was found in 25 cases (93%) and central nervous system involvement occurred in 15 cases (56%). The median survival and 1-year survival rate of the 27 cases were only 6 months and 22%, respectively, after diagnosis of the dual-hit lymphoma/leukemia. Seven cases of triple-hit lymphoma/leukemia (dual-hit lymphoma/leukemia with 3q27/BCL6 translocation) were included; the median survival of these patients was only 4 months from the diagnosis of the dual-hit lymphoma/leukemia. The duration of survival of the patients with a triple-hit malignancy was shorter than that of the other 20 cases of dual-hit lymphoma/leukemia (p=0.02). The translocation partner of MYC subdivided the dual-hit cases into two groups; 14 cases of IGH and 13 cases of IGK/L. The MIB-1 index was investigated in 14 cases with aggressive B-cell lymphoma, and was higher in the group with MYC-IGH translocation (n=7) than in the MYC-IGK/L group (n=7) (p=0.02). Overall survival was not different between the MYC-IGH translocation group (n=14) and the MYC-IGK or MYC-IGL translocation group (n=13). ConclusionsDual-hit lymphoma/leukemia is a rare but distinct mature B-cell neoplasm with an extremely poor prognosis characterized by frequent extranodal involvement and central nervous system progression with either of the translocation partners of MYC.