Isolated Central Nervous System Involvement after Brentuximab Vedotin Treatment for HIV-Positive ALK-Negative Anaplastic Large Cell Lymphoma.

Human immunodeficiency virus (HIV)-associated lymphoma poses a high mortality risk despite antiretroviral therapy (ART). Although intermediate- or high-grade B-cell lymphomas are common, anaplastic large-cell lymphomas (ALCLs) are rare and seldom affect the central nervous system (CNS). Herein, we present a case of HIV-associated ALCL with isolated CNS involvement that occurred following the discontinuation of ART that was administered after treatment with brentuximab vedotin (BV)-which does not cross the blood-brain barrier. At the time of CNS recurrence, the patient's CD4 count was 9 cells/mm3. This is the first report of CNS recurrence in HIV-associated ALCL. Considering the high risk of CNS relapse, we suggest initiating CNS prophylaxis in cases of HIV-associated ALCL, particularly in patients receiving CNS-impermeable agents such as BV.

New evidence for the antiquity of Desmostylus (Desmostylia) from the Skooner Gulch Formation of California.

Desmostylus is an extinct marine mammal genus that belongs to Desmostylia, a clade of extinct herbivorous mammals. While desmostylian remains are widely reported from Paleogene and Neogene marine strata of the North Pacific Rim, occurrences of the genus Desmostylus are almost entirely limited to middle Miocene strata, with only a few early Miocene records from Japan. Here we report a Desmostylus tooth from the earliest Miocene (Aquitanian) Skooner Gulch Formation in northern California, USA. This specimen exhibits cuspules around the crown, a primitive trait of the subfamily Desmostylidae, as seen in more basal branching desmostylid taxa such as Cornwallius and Ounalashkastylus, but with a high tooth crown and thickened enamel. The specimen is also diagnostically different from all other desmostylid genera, such as Cornwallius, and Ounalashklastylus. The Aquitanian age of the Skooner Gulch Formation implies that the distinctive tooth morphology of Desmostylus has persisted, largely unchanged, for more than 15 million years and that desmostylids possibly originated in western North America.

SNARE-binding protein synaptosomal-associated protein of 29 kDa (SNAP29) regulates the intracellular sequestration of glucose transporter 4 (GLUT4) vesicles in adipocytes.

AIMS/INTRODUCTION: Insulin stimulates translocation of glucose transporter 4 (GLUT4) from the perinuclear location to the plasma membrane. In the unstimulated state, intracellular vesicles containing GLUT4 are sequestered into specialized storage vesicles that have come to be known as the insulin-responsive compartment (IRC). The IRC is a functional compartment in the perinuclear region that is a target of the insulin signaling cascade, although its precise nature is unclear. Here, we report a novel molecular mechanism facilitating formation of the IRC. MATERIALS AND METHODS: We determined synaptosomal-associated protein of 29 kDa (SNAP29) by mass spectrometry to be an EH domain-containing protein 1 (EHD1)-binding protein. Then, its expression was confirmed by western blotting. Subcellular localization of SNAP29 was determined by immunofluorescent microscopy. Interactions between SNAP29 and syntaxins were determined by immunoprecipitation. We measured glucose uptake and GLUT4 translocation in 3T3-L1 adipocyte expressing SNAP29 or silencing SNAP29. RESULTS: We found SNAP29 to be localized in the perinuclear region and to show partial co-localization with GLUT4 under basal conditions. We also found that SNAP29 binds to syntaxin6, a Qc-SNARE, in adipocytes. In SNAP29-expressing cells, vesicles containing GLUT4 were observed to aggregate around the perinuclear region. In contrast, when SNAP29 was silenced, perinuclear GLUT4 vesicles were dispersed throughout the cytosol. Insulin-stimulated glucose uptake was inhibited in both SNAP29-expressing and SNAP29-silenced cells. CONCLUSIONS: These data suggest that SNAP29 sequesters and anchors GLUT4-containing vesicles in the perinuclear region, and might have a role in the biogenesis of the perinuclear IRC.

New data from the first discovered paleoparadoxiid (Desmostylia) specimen shed light into the morphological variation of the genus Neoparadoxia.

Desmostylia is an extinct clade of marine mammals with two major sub-clades, Desmostylidae and Paleoparadoxiidae, known from Oligocene to Miocene strata of the North Pacific coastline. Within Paleoparadoxiidae, three genera have been identified: Archaeoparadoxia, Paleoparadoxia, and Neoparadoxia. The latter taxon is the geochronologically youngest palaeoparadoxiid and Neoparadoxia is characterized by a comparatively larger body size, although it is known only from a few specimens within a short temporal and geographic range. Here we report the discovery of an isolated tooth, which we identify as Neoparadoxia cf. N. cecilialina, constituting only the second individual specimen of Neoparadoxia with preserved dentition yet reported. This specimen was collected near Corona, California, USA, and we attribute it to the "Topanga" Formation, extending the geographic range of this taxon in Southern California. While the exact geographic locality was not recorded when it was collected in 1913, we establish two potential localities based on associated hand-written museum label and new stratigraphic information. Although initially identified as Desmostylus hesperus, this specimen of Neoparadoxia was collected 10 years before the first named paleoparadoxiid from Japan. We expect that description of more complete desmostylian material from elsewhere in Southern California will clarify the taxonomic richness and paleoecological role of this clade in Cenozoic marine mammal assemblages.

A "Mammalian-like" Pycnodont Fish: Independent Acquisition of Thecodont Implantation, True Vertical Replacement, and Carnassial Dentitions in Carnivorous Mammals and a Peculiar Group of Pycnodont Fish.

Vertebrates developed tooth replacement over 400 million years ago. Then, 200 million years later, the combination of vertical tooth replacement with the thecodont implantation (teeth in bone sockets) appeared a key morphological innovation in mammalian evolution. However, we discovered that an extinct fish taxon, Serrasalmimus secans, showed the same innovation in the lineage Serrasalmimidae, which survived the end Cretaceous mass extinction event. The carnassial teeth are known in both mammals and pycnodont fish, but these teeth do not share the same tissues or developmental processes. Therefore, this serrasalmimid pycnodont fish might have independently acquired mammal-like tooth replacement and implantation, indicating that the fish and mammals convergently evolved the carnassial dental morphologies at about the same time, approximately 60 My ago, in separate ecosystems.

Pathological Characteristics of a Patient with Severe Fever with Thrombocytopenia Syndrome (SFTS) Infected with SFTS Virus through a Sick Cat's Bite.

A woman in her fifties showed symptoms of fever, loss of appetite, vomiting, and general fatigue 2 days after she was bitten by a sick cat, which had later died, in Yamaguchi prefecture, western Japan, in June 2016. She subsequently died of multiorgan failure, and an autopsy was performed to determine the cause of death. However, the etiological pathogens were not quickly identified. The pathological features of the patient were retrospectively re-examined, and the pathology of the regional lymph node at the site of the cat bite was found to show necrotizing lymphadenitis with hemophagocytosis. The pathological features were noted to be similar to those of patients reported to have severe fever with thrombocytopenia syndrome (SFTS). Therefore, the lymph node section was retrospectively tested immunohistochemically, revealing the presence of the SFTS virus (SFTSV) antigen. The sick cat showed similar symptoms and laboratory findings similar to those shown in human SFTS cases. The patient had no history of tick bites, and did not have skin lesions suggestive of these. She had not undertaken any outdoor activities. It is highly possible that the patient was infected with SFTSV through the sick cat's bite. If a patient gets sick in an SFTS-endemic region after being bitten by a cat, SFTS should be considered in the differential diagnosis.

The phylogeny of desmostylians revisited: proposal of new clades based on robust phylogenetic hypotheses.

BACKGROUND: Desmostylia is a clade of extinct aquatic mammals with no living members. Today, this clade is considered belonging to either Afrotheria or Perissodactyla. In the currently-accepted taxonomic scheme, Desmostylia includes two families, 10 to 12 genera, and 13-14 species. There have been relatively few phylogenetic analyses published on desmostylian interrelationship compared to other vertebrate taxa, and two main, alternative phylogenetic hypotheses have been proposed in previous studies. One major problem with those previous studies is that the numbers of characters and OTUs were small. METHODS: In this study, we analyzed the phylogenetic interrelationship of Desmostylia based on a new data matrix that includes larger numbers of characters and taxa than in any previous studies. The new data matrix was compiled mainly based on data matrices of previous studies and included three outgroups and 13 desmostylian ingroup taxa. Analyses were carried out using five kinds of parsimonious methods. RESULTS: Strict consensus trees of the most parsimonious topologies obtained in all analyses supported the monophyly of Desmostylidae and paraphyly of traditional Paleoparadoxiidae. Based on these results, we propose phylogenetic definitions of the clades Desmostylidae and Paleoparadoxiidae based on common ancestry.

Protein kinase C iota facilitates insulin-induced glucose transport by phosphorylation of soluble nSF attachment protein receptor regulator (SNARE) double C2 domain protein b.

AIMS/INTRODUCTION: Double C2 domain protein b (DOC2b), one of the synaptotagmins, has been shown to translocate to the plasma membrane, and to initiate membrane-fusion processes of vesicles containing glucose transporter 4 proteins on insulin stimulation. However, the mechanism by which DOC2b is regulated remains unclear. Herein, we identified the upstream regulatory factors of DOC2b in insulin signal transduction. We also examined the role of DOC2b on systemic homeostasis using DOC2b knockout (KO) mice. MATERIALS AND METHODS: We first identified DOC2b binding proteins by immunoprecipitation and mutagenesis experiments. Then, DOC2b KO mice were generated by disrupting the first exon of the DOC2b gene. In addition to the histological examination, glucose metabolism was assessed by measuring parameters on glucose/insulin tolerance tests. Insulin-stimulated glucose uptake was also measured using isolated soleus muscle and epididymal adipose tissue. RESULTS: We identified an isoform of atypical protein kinase C (protein kinase C iota) that can bind to DOC2b and phosphorylates one of the serine residues of DOC2b (S34). This phosphorylation is essential for DOC2b translocation. DOC2b KO mice showed insulin resistance and impaired oral glucose tolerance on insulin and glucose tolerance tests, respectively. Insulin-stimulated glucose uptake was impaired in isolated soleus muscle and epididymal adipose tissues from DOC2b KO mice. CONCLUSIONS: We propose a novel insulin signaling mechanism by which protein kinase C iota phosphorylates DOC2b, leading to glucose transporter 4 vesicle translocation, fusion and facilitation of glucose uptake in response to insulin. The present results also showed DOC2b to play important roles in systemic glucose homeostasis.

A long-forgotten 'dinosaur' bone from a museum cabinet, uncovered to be a Japan's iconic extinct mammal, Paleoparadoxia (Desmostylia, Mammalia).

Here, we report a new 'discovery' of a desmostylian fossil in the geological collection at a national university in Japan. This fossil was unearthed over 60 years ago and donated to the university. Owing to the original hand-written note kept with the fossil in combination with interview investigation, we were able to reach two equally possible fossil sites in the town of Tsuchiyu Onsen, Fukushima. Through the interviews, we learned that the fossil was discovered during construction of a debris flow barrier and that it was recognized as a 'dinosaur' bone among the locals and displayed in the Village Hall before/until the town experienced a fire disaster in 1954. As scientific findings, the fossil was identified to be a right femur of Paleoparadoxia (Desmostylia), which shows well-preserved muscle scars on the surface. The age was estimated to be 15.9 Ma or younger in zircon-dating. This study shows an excellent case that historical and scientific significances could be extracted from long-forgotten uncatalogued specimens as long as the original information is retained with the specimens.

How can we reliably identify a taxon based on humeral morphology? Comparative morphology of desmostylian humeri.

Desmostylia is a clade of marine mammals belonging to either Tethytheria or Perissodactyla. Rich fossil records of Desmostylia were found in the Oligocene to Miocene strata of the Northern Pacific Rim, especially in the northwestern region, which includes the Japanese archipelago. Fossils in many shapes and forms, including whole or partial skeletons, skulls, teeth, and fragmentary bones have been discovered from this region. Despite the prevalent availability of fossil records, detailed taxonomic identification based on fragmentary postcranial materials has been difficult owing to to our limited knowledge of the postcranial diagnostic features of many desmostylian taxa. In this study, I propose the utilization of diagnostic characters found in the humerus to identify desmostylian genus. These characters can be used to identify isolated desmostylian humeri at the genus level, contributing to a better understanding of the stratigraphic and geographic distributions of each genus.

Recurrent extramedullary relapse of acute myelogenous leukemia after allogeneic hematopoietic stem cell transplantation in a patient with the chromosomal abnormality t(8;21) and CD56-positivity.

Isolated extramedullary (EM) relapse of acute myelogenous leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is rare. Predisposing factors include CD56 expression and the chromosomal abnormality t(8;21). We describe an AML patient showing the chromosomal abnormality t(8;21) and CD56 expression who experienced a unique EM relapse after allo-HSCT. Approximately 10 months after allo-HSCT, he experienced relapse involving the femur and lumbar vertebrae and, subsequently, an EM relapse of the stomach. Although we administered only local radiotherapy and not systemic chemotherapy, he showed no bone marrow relapse on long-term follow-up after achieving complete hematological remission. These findings suggest that the graft-versus-leukemia effect may preferentially maintain marrow remission rather than prevent EM relapse. In addition, our findings show that extended survival is possible after EM relapse following allo-HSCT in patients with marrow hematopoiesis of donor origin, and that augmentation of the graft-versus-leukemia effect may be useful.

Angioimmunoblastic T cell lymphoma associated with reversible myelofibrosis.

A 56-year-old man complained of fever, anemia, thrombocytopenia and lymph node swelling. Biopsy of the lymph node demonstrated angioimmunoblastic T cell lymphoma (AITL) with the loss of normal architecture, proliferation of neoplastic T cells, small vessels mixed with eosinophils and plasma cells. Aspiration of bone marrow was dry tap, and biopsy demonstrated myelofibrosis with increased proliferation of reticulin fiber. Markedly elevated plasma levels of transforming growth factor beta1 (TGF-beta1) and soluble interleukin-2 receptor (sIL-2R) were observed, and that of platelet growth factor (PDGF) AB was slightly elevated. After chemotherapy, remission of lymphoma was achieved. The aspiration of bone marrow became possible, and the level of TGF-beta1 and PDGF AB showed normalization; thus, myelofibrosis was reversible.

A case of factor X (FX) deficiency due to novel mutation V196M, FX Hofu.

The patient, a 20-year-old male, was found to have a slightly prolonged prothrombin time (PT). No episodes of bleeding were noted. The measurement of coagulation factors revealed that the level of factor X (FX) activity was solely deficient, 51% (normal range: 70-130% ), and that of FX antigen was 100%. Analysis of the entire FX gene revealed the novel missense mutation of GTG to ATG, resulting in the substitution of the 196th amino acid valine --> methionine. The mother and younger brother had a normal PT time and expressed no episode of bleeding. The mother exhibited a normal level of FX activity and antigen; however the younger brother showed a slight decrease in both the parameters. This mutation was not observed in the mother and younger brother. Polymorphism is not observed at this point in healthy persons. The present novel FX mutation was named FX Hofu.

Sarcoidosis acutely involving the musculoskeletal system.

A 69-year-old man complained of knee pain, subsequent polyarthralgia, and pains of the muscles of the pelvic girdle and thighs. At the same time, erythema of the face and hands appeared. Biopsy of the skin and muscle revealed non-caseating granuloma of epithelioid cells. The level of serum angiotensin-converting enzyme was normal, but that of lysozyme was elevated. Chest X-ray and CT did not show bilateral hilar lymphadenopathy (BHL) but revealed infiltrative ground glass appearance-like shadows of both lungs, and a Ga scintigram disclosed accumulation in the right hilar region, but not in the muscles. These complaints were quickly ameliorated by the administration of prednisolone. The present patient represented a rare case of acute musculoskeletal system involvement in sarcoidosis not typical of Löfgren's syndrome.

Acute myeloblastic leukemia in a patient with hereditary protein C deficiency.

The patient had been diagnosed with hereditary protein C deficiency. She recently developed acute myeloblastic leukemia (AML). Chemotherapy for AML by cytosine arabinoside, aclarubicin followed by granulocyte colony-stimulating factor (CAG) was started. Disseminated intravascular coagulation (DIC) was observed, however thromboembolic complication was not observed during the hospital course. Hematological remission was not obtained, and the patient died of pseudomembranous pancolitis. Whether the development of these rare disorders of hereditary protein C and AML are coincidental, or involve a causal relationship remains unknown.

T-gamma delta large granular lymphocyte leukemia preceded by pure red cell aplasia and complicated with hemophagocytic syndrome caused by Epstein-Barr virus infection.

A 51-year-old man developed anemia, and was diagnosed with pure red cell aplasia through the absence of erythroid progenitors. Initially, he was treated with cyclosporine and prednisolone for 6 months but they were ineffective. Large granular lymphocyte (LGL) leukemia with the T-cell gamma delta phenotype evolved after 6 months showing CD2+, CD3+, CD8- and CD56- with the T-cell receptor beta gene rearrangement, clonalities of gamma and delta genes and complex chromosome abnormality simultaneously with hemophagocytic syndrome (HPS). Epstein-Barr virus (EBV) genomic DNA was detected in the bone marrow cells. Administration of bolus methylprednisolone was ineffective, and the patient died one month later. In the present patient, it seemed that lymphoproliferative disease of large granular lymphocytes (LDGL) manifested initially as PRCA, gammadelta LGL leukemia evolved, and finally fatal HPS become complicated, presumably caused by the EBV reactivation in the immunodeficiency state with the administration of immunosuppressants.

A breast cancer patient with myelodysplastic syndrome postoperatively treated by radiation and tamoxifen administration--a case report.

A 72-year-old female developed pancytopenia 4 years after breast cancer surgery. She had received regional radiation postoperatively, and tamoxifen for 4 years. Bone marrow examination demonstrated immature myeloblasts and dysplastic cells. Myelodysplastic syndrome (MDS) of refractory anemia with excess blasts (RAEB) was diagnosed, and the patient died of cerebral hemorrhage 4 months after the diagnosis of RAEB. Radiation and the administration of tamoxifen were suspected to have played a role in the development of secondary MDS.

A family with hemoglobin Hirosaki.

A 48-year-old man had a 30-year history of hemolytic anemia of undetermined cause. Spherocytes were not observed, osmotic fragility was normal, and red cell enzyme activities were normal. His brother and daughter also had hemolytic anemia. The brother had previously undergone splenectomy, and the anemia had been ameliorated. In the proband and daughter, no abnormal hemoglobin was apparent in the results of isoelectric focusing and DEAE anion-exchange high-performance liquid chromatography analyses. On evaluation with the isopropanol test, unstable hemoglobin was not observed in the proband but was detected in the daughter. There was also a decreased ratio of 3 globin/3 globin chain production. Analysis of the 32 gene demonstrated the presence of a mutation (alpha43 [CE1] Phe --> Leu), hemoglobin Hirosaki.