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Among adult and pediatric patients, concern is growing in regard to toxic shock syndrome (TSS) resulting from methicillin-resistant Staphylococcus aureus (MRSA) nosocomial infection. We investigated the incidence and characteristics of this form of TSS in patients with burn injury who were admitted to our burn care units from January 2008 to December 2011. Of the 244 patients with nosocomial MRSA infection admitted during the study period, TSS occurred in 20 (8.2%) patients whose average age was 42.9 years, average total burn surface area (TBSA) was 31.7%, and average day of TSS appearance was 9.5 days after injury. There were no particular characteristics associated with age, TBSA or day of TSS appearance in these patients. All but 1 patient recovered from TSS within an average of 9.4 days. The incidence of TSS due to nosocomial MRSA infection in these burn patients was higher than expected. TSS due to nosocomial MRSA infection should be considered in burn care.

Lenalidomide (Len) and dexamethasone (dex) therapy is a standard therapy in patients with multiple myeloma. Elderly or unfit patients may reduce Len or dex doses to prevent toxicities that lead to treatment discontinuation. However, there have been few studies evaluating the efficacy and safety of lower doses of Len and dex. We conducted a phase II study of 1.5-year low-dose Len and dex therapy following melphalan and prednisolone (MP), the number of which cycles was determined by a response within 9 cycles. The Len dose was 10 mg daily and the dex dose was 20 mg weekly, which were continued for 1.5 years. Twenty-one patients were enrolled. The median number of cycles of MP was 3 (range, 2-9). The overall response rate was 81% and a very good partial response or better was achieved in 33.3% of patients. The median follow-up time for survivors was 70.5 months (range, 42-83 months), the median progression-free survival (PFS) was 27 months (95% CI, 21-33 months), and the median overall survival was not reached. Grade 3 or 4 adverse events were observed in 28.6% of patients. In conclusion, the low-dose Len and dex therapy safely achieved comparable efficacies to the standard-dose regimen in elderly patients with newly diagnosed multiple myeloma. UMIN000007889.

We report a case of crush syndrome that developed while the patient was squatting to use a Japanese-style toilet. The patient was a 61-year-old male with an obese body. He was sitting on the toilet and couldn't stand up, and after a few hours, the landlord found him and called the emergency services. On presentation, the patient was hyperkalemic and in shock, and his serum creatine kinase levels rose to a maximum of 287,600 U/L. He was diagnosed with postural crush syndrome in both lower extremities due to squatting position in a Japanese-style toilet. Subjective symptoms, physical examination, and blood tests were monitored and the patient was observed. As a result, the patient could be treated conservatively without fasciotomy. Dialysis was not necessary because the fluid infusion maintained adequate urine output and corrected the hyperkalemia. Magnetic resonance imaging of both lower extremities showed multiple high-signal areas in the muscles of the bilateral thighs and lower legs. This case suggested that if the wound is closed, the peripheral pulse is palpable, and the patient's symptoms have improved, a fasciotomy should not be performed. People who are too heavy to squat may need to be careful when using this kind of toilet.

Background Rapid decline in renal dysfunction due to primary renal lymphoma, or secondary renal lymphoma by infiltration from a primary origin, is extremely rare. There are notably few reports indicating infiltration of T-cell lymphoma into the kidney. Case presentation A 61-year-old woman with a sudden body rash and liver dysfunction was brought to our hospital presenting with a dull headache and blurred vision. Laboratory tests revealed rapidly progressive renal failure. Histological examination of the kidney and skin indicated infiltration of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). Infiltration of PTCL-NOS to the liver and spleen, and presence of Uveitis masquerade syndrome were suspected. Imaging showed that the lesion was limited to extralymphatic organs. Renal function was improved with administration of steroids, including pulse steroid therapy, before administering cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) therapy. Conclusions This is the first reported case of rapidly progressive renal failure caused by perivascular tubulointerstitial nephritis with the direct invasion of PTCL-NOS. In our case, a single steroid dose showed dramatic results with respect to renal symptoms.

Autosomal recessive cerebellar ataxias (ARCAs) are clinically and genetically heterogeneous neurological disorders. Through whole-exome sequencing of Japanese ARCA patients, we identified three index patients from unrelated families who had biallelic mutations in ERCC4. ERCC4 mutations have been known to cause xeroderma pigmentosum complementation group F (XP-F), Cockayne syndrome, and Fanconi anemia phenotypes. All of the patients described here showed very slowly progressive cerebellar ataxia and cognitive decline with choreiform involuntary movement, with young adolescent or midlife onset. Brain MRI demonstrated atrophy that included the cerebellum and brainstem. Of note, cutaneous symptoms were very mild: there was normal to very mild pigmentation of exposed skin areas and/or an equivocal history of pathological sunburn. However, an unscheduled DNA synthesis assay of fibroblasts from the patient revealed impairment of nucleotide excision repair. A similar phenotype was very recently recognized through genetic analysis of Caucasian cerebellar ataxia patients. Our results confirm that biallelic ERCC4 mutations cause a cerebellar ataxia-dominant phenotype with mild cutaneous symptoms, possibly accounting for a high proportion of the genetic causes of ARCA in Japan, where XP-F is prevalent.

Mesenchymal stromal cells (MSCs) are multipotent progenitor cells and there is much interest in how MSCs contribute to the regulation of the tumor microenvironment. Whether MSCs exert a supportive or suppressive effect on tumor progression is still controversial, but is likely dependent on a variety of factors that are tumor-type dependent. Multiple myeloma (MM) is characterized by growth of malignant plasma cells in the bone marrow. It has been shown that the progression of MM is governed by MSCs, which act as a stroma of the myeloma cells. Although stroma is created via mutual communication between myeloma cells and MSCs, the mechanism is poorly understood. Here we explored the role of lysophosphatidic acid (LPA) signaling in cellular events where MSCs were converted into either MM-supportive or MM-suppressive stroma. We found that myeloma cells stimulate MSCs to produce autotaxin, an indispensable enzyme for the biosynthesis of LPA, and LPA receptor 1 (LPA1) and 3 (LPA3) transduce opposite signals to MSCs to determine the fate of MSCs. LPA3-silenced MSCs (siLPA3-MSCs) exhibited cellular senescence-related phenotypes in vitro, and significantly promoted progression of MM and tumor-related angiogenesis in vivo. In contrast, siLPA1-MSCs showed resistance to cellular senescence in vitro, and efficiently delayed progression of MM and tumor-related angiogenesis in vivo. Consistently, anti-MM effects obtained by LPA1-silencing in MSCs were completely reproduced by systemic administration of Ki6425, an LPA1 antagonist. Collectively, our results indicate that LPA signaling determines the fate of MSCs and has potential as a therapeutic target in MM.

Toxic shock syndrome (TSS) caused by methicillin-resistant Staphylococcus aureus (MRSA) nosocomial infection is a growing concern in both adult and pediatric patients. The reason why TSS appears in only some patients with MRSA infection remains unclear. In this study, we analyzed serial TSS toxin-1 (TSST-1) antibody in patients with burn injury to investigate the mechanisms of TSS caused by MRSA nosocomial infection. This study comprised of patients with burn injury in our burn care unit from September, 2010 to August, 2011. Serum samples were collected serially on admission, at 48 to 72 hours after injury, on the day MRSA infection appeared, and on the day MRSA infection resolved. TSST-1 antibody was measured by enzyme-linked immunosorbent assay (ELISA). TSS was diagnosed according to the criteria of the Centers for Disease Control. Serial serum samples were collected from 24 patients and nosocomial MRSA infection was detected in 12 patients. In these 12 patients, TSS occurred in five patients (TSS+ group) but did not occur in the other seven patients (TSS- group). TSST-1 antibody level was significantly lower in the TSS+ group than TSS- group on admission and on the day MRSA infection appeared. All patients in the TSS+ group received intravenous immune globulin when TSS was diagnosed, and no patients died of TSS. Patients suffering from TSS had a lower level of TSST-1 antibody than patients not suffering from TSS. Testing for TSST-1 antibody in the clinical setting might help to predict and prevent the appearance of TSS caused by nosocomial MRSA infection.

The bone marrow microenvironment comprises multiple cell niches derived from bone marrow mesenchymal stem cells. However, the molecular mechanism of bone marrow mesenchymal stem cell differentiation is poorly understood. The transcription factor GATA2 is indispensable for hematopoietic stem cell function as well as other hematopoietic lineages, suggesting that it may maintain bone marrow mesenchymal stem cells in an immature state and also contribute to their differentiation. To explore this possibility, we established bone marrow mesenchymal stem cells from GATA2 conditional knockout mice. Differentiation of GATA2-deficient bone marrow mesenchymal stem cells into adipocytes induced accelerated oil-drop formation. Further, GATA2 loss- and gain-of-function analyses based on human bone marrow mesenchymal stem cells confirmed that decreased and increased GATA2 expression accelerated and suppressed bone marrow mesenchymal stem cell differentiation to adipocytes, respectively. Microarray analysis of GATA2 knockdowned human bone marrow mesenchymal stem cells revealed that 90 and 189 genes were upregulated or downregulated by a factor of 2, respectively. Moreover, gene ontology analysis revealed significant enrichment of genes involved in cell cycle regulation, and the number of G1/G0 cells increased after GATA2 knockdown. Concomitantly, cell proliferation was decreased by GATA2 knockdown. When GATA2 knockdowned bone marrow mesenchymal stem cells as well as adipocytes were cocultured with CD34-positive cells, hematopoietic stem cell frequency and colony formation decreased. We confirmed the existence of pathological signals that decrease and increase hematopoietic cell and adipocyte numbers, respectively, characteristic of aplastic anemia, and that suppress GATA2 expression in hematopoietic stem cells and bone marrow mesenchymal stem cells.

Aggressive natural killer cell leukemia (ANKL) is a highly aggressive lymphoproliferative disease. An appropriate therapeutic strategy for ANKL remains to be established, but a few case reports have suggested that allogeneic hematopoietic stem cell transplantation (allo-HCT) can be curative. Here, we report a young woman with ANKL showing central nervous system (CNS) invasion, who has been in complete remission for more than a year after allo-HCT following two courses of intravenous chemotherapy and several rounds of intrathecal chemotherapy. Intensive remission induction chemotherapy followed by conventional myeloablative allo-HCT is a promising approach for long-term remission in cases of this aggressive malignancy.

Acquired hemophilia A is a rare and potentially fatal condition of coagulopathy caused by autoantibodies against clotting factor VIII (factor VIII inhibitor). We report a case of a 63-year-old woman, who presented with a sudden onset of severe hemorrhagic tendency with exclusively prolonged activated partial thromboplastin time (APTT). She was diagnosed with acquired hemophilia A due to a decrease in factor VIII activity and a high titer of factor VIII inhibitor. Hemorrhage was well controlled by recombinant activated factor VII. Although the level of factor VIII inhibitor did not decline with prednisolone and cyclophosphamide, it became undetectable with rituximab. In parallel with controlling hemorrhage, malignancy, which may cause acquired hemophilia A, was searched for and sigmoid colon cancer was found. After the eradication of factor VIII inhibitor, surgical resection was performed uneventfully. Thereafter, acquired hemophilia A has been in complete remission without any additional therapy. The present case suggests the efficacy of rituximab for refractory acquired hemophilia A and the importance of the identification of underlying diseases that can cause acquired hemophilia A.

Abstract 1825 Multiple myeloma (MM) is a B-cell neoplasm characterized by clonal proliferation of malignant plasma cells in the bone marrow (BM). The development of new drugs has increased survival time, but the disease is still incurable. Recently, the BM microenvironment has been reported to play an important role in proliferation and survival of MM cells, suggesting that clarification of the interaction between BM stromal cells and MM cells may provide insights to allow the development of novel treatment strategies for MM. As the signal between MM cells and the BM microenvironment should be bidirectional, it is possible that MM cells produce signals that alter the BM microenvironment to one appropriate for their survival. To validate this hypothesis, we examined the changes in gene expression profile in human BM-derived mesenchymal stem cells (MSC) by co-culture with MM cell line OPM-2. cDNA array analysis indicated that 2 days of co-culture with OPM-2 induced multiple factors in MSC, which are known to have positive effects on survival of MM cells, such as interleukin-6, insulin-like growth factor-1, stromal cell-derived factor 1, vascular cell adhesion molecule 1 (VCAM1), and intercellular adhesion molecule 1 (ICAM1). Other than known factors, thymic stromal lymphopoietin (TSLP), which is a cytokine involved in progression of pancreatic and breast cancer through induction of T helper 2 cell responses, was found to be upregulated by co-culture (ratio 2.22). To confirm the results of cDNA array analysis, MSC co-cultured with OPM-2 or KMS-34 were tested for expression and secretion of TSLP by real-time PCR and ELISA. Real-time PCR revealed that the expression of TSLP in co-cultured MSC was two to three times higher than that in MSC monocultures. Significantly elevated levels of TSLP secretion from MSC after stimulation with PMA/ionomycin were observed by co-culture with OPM-2 or KMS-34 compared with monoculture (201.3 ± 5.0 pg/ml, 176.1 ± 13.3 pg/ml, and 96.6 ± 5.5 pg/ml, respectively; P < 0.01) as measured by ELISA. TSLP did not exhibit any effect on proliferation or drug resistance of MM cells independent of the level of TSLP receptor expression, therefore we evaluated the immunomodulatory effects of TSLP secreted by MSC. Monocyte-derived dendritic cells (MDDC) were first treated with the supernatant of either MSC or MSC co-cultured with KMS-34. Then, allogeneic naïve CD4+ T cells were co-cultured with pretreated MDDC. MDDC treated with the supernatant of co-cultured MSCs expanded IL-13+ CD4+ T cells to a greater extent than MDDC treated with the supernatant of MSC monocultures (10.3 ± 3.7 %, 5.9 ± 4.2 %, respectively; P = 0.02), and addition of anti-TSLP neutralizing antibodies to the supernatant decreased the expansion of IL-13+ CD4+ T cells (10.3 ± 3.7 %, 7.1 ± 2.6 %, respectively; P = 0.04). These results suggested that MM cells act to form more advantageous BM microenvironment for their survival through induction of pleiotropic molecules in MSC involved in not only proliferation and survival of MM cells, but also modifying immunological status. Disclosures: No relevant conflicts of interest to declare.

We report four patients with a new type of familial parkinsonism and dementia consisting of an autosomal dominant inheritance, dopa-responsive parkinsonism, severe dementia, variable myoclonus and autonomic disturbances. Autopsy of two patients revealed symmetrical cerebral atrophy with fronto-temporal dominant distribution, and marked depigmentation in the substantia nigra and locus ceruleus. Neuronal loss and gliosis were observed in the deep cerebral cortex and amygdala as well as in the areas vulnerable to Parkinson's disease. In the cerebral cortex, swollen neurons with frequent granulovacuolar changes were observed, consisting of ballooned neurons and those with argyrophilic intracytoplasmic inclusions, in addition to neuropil threads. Atypical neurofibrillary tangles, which barely stained with tau antibodies, were numerous in the upper cortical layers, consisting of 15-nm straight tubules. In addition, tau-negative astrocytic fibrillary tangles were also frequent. Electron microscopically, the ballooned neurons and argyrophilic neuronal inclusions contained filamentous structures coated with fuzzy electron-dense deposits. The inclusions showed immunohistochemical features different from those of cortical Lewy bodies and Pick bodies. Occasional Lewy bodies were present in the brain stem lesions of both patients. In two of our patients, the pathology in the brain stem was similar to that of Parkinson's disease, whereas their cerebral pathology was unusual and has not been reported previously.

A 43-year-old male developed rapidly progressing anemia and a bone marrow examination revealed pure red cell aplasia (PRCA). He was diagnosed as having myasthenia gravis (MG) and invasive thymoma, and achieved complete remission by radiation and chemotherapy six years ago. Despite increased doses of oral prednisolone from 7.5 mg/day to 60 mg/day, a diagnosis of T-cell acute lymphoblastic leukemia (T-ALL) was made one month later based on findings of 37.2% abnormal lymphoblasts and positive surface markers for CD2, CD3 and CD7 T-cells. Cases of PRCA associated with MG and thymoma have been reported in the literature, however such a case followed by T-ALL is very rare.

A 27-year-old-woman with paramyotonia congenita was reported. She began to suffer from myotonia since infancy. Myotonia was aggravated by cold, but with intense cooling myotonia did not change to flaccid paralysis. Four generations of her family showed the same symptoms that suggested autosomal dominant inheritance. Neurological examinations revealed no impairments of mental function, cranial nerves and sensory system. Muscular atrophy or hypertrophy was not observed. Percussion myotonia of the tongue and thenar muscles could be elicited at room temperature. Myotonia was aggravated by cold. An oral intake of potassium chloride (7 grammes) did not provoke any muscle weakness or flaccid paralysis. Routine laboratory data and findings of head CT scan, cerebrospinal fluid and electroencephalogram were normal. The nosological distinction between paramyotonia congenita and hyperkalemic periodic paralysis has been debated since 1956. Paralysis induced by cold is thought to be a feature of paramyotonia congenita, thus raising a possible relationships to hyperkalemic periodic paralysis. In our case cold paralysis never occurred spontaneously and could not be provoked by immersion in ice water or by potassium loading. This finding confirms the existence of paramyotonia congenita without cold paralysis and may provide a nosological distinction between paramyotonia congenita and hyperkalemic periodic paralysis.

The neutron shielding structure of a vacuum vessel consisting of low activation materials as Al or Ti alloy are studied for the super-upgrade of the JT-60 (JT-60SU) design. A 25–40 cm thick water tank-type vacuum vessel using Ti6Al4V and boron (1% of 10 B) doped water are shown to be the best choice. This design concept gave results consistent with the design requirements: the one-turn resistivity of the vacuum vessel is ∼ 50 μω , and the dose rate inside the vessel is ∼ 15 mrem/h a year after shutdown. The total nuclear heating of the whole TF-coil can be reduced to ∼ 11 kW for a DD fusion neutron rate of 1 × 10 18 /s.

We studied influences of low-intensity argon laser irradiation at various wavelengths on mitochondrial respiration in vitro. Isolated guinea pig liver mitochondria were suspended in an isotonic buffer solution (pH 7.4,37°C). The mitochondrial suspension was introduced into a constant temperature reaction chamber in which an irradiation fiber, a thermocouple, an oxygen electrode, and a stirrer were installed. Under respiratory conditions of state 4, state 3, and uncoupled respiration, mitochondrial oxygen consumption was measured during low-intensity argon laser irradiations at 351nm, 458 nm, and 514.5 nm. The 351 nm and the 458 nm irradiations at 200 mW inhibited uncoupled respiration by 19% and 11%, respectively, and the irradiation at 351 nm inhibited state 3 respiration as well by 10%. In contrast, the 514.5 nm irradiation enhanced both state 3 and uncoupled respiration by 6–7%. Temperature reference experiments indicated that the thermal effect alone could not account for the effects of laser irradiation on mitochondrial oxygen consumption. These results suggest that the 351 nm and the 458 nm laser irradiation may injure the mitochondrial inner membrane, while the 514.5 nm laser irradiation may slightly promote the rate of ATP synthesis. © 1994 Wiley-Liss, Inc.

A stereo-divergent synthesis of L-threo- and L-erythro-[2,3-2H2]-phenylalanine by a catalytic deuteriation of (Z)-dehydrophenylalanine included in a chiral diketopiperazine ring is accomplished simply by changing the substituents on the nitrogen atoms in the diketopiperazine ring.

Megadolicho-Basilar Artery例の経過中に解離性動脈瘤を生じ, 右前下小脳動脈症候群を呈した症例を報告した.症例は64歳の男性で眩量, 強度の右耳鳴から入院となった.神経学的には, 構音障害, 注視方向性の眼振, 右末梢性顔面神経麻痺, 左伝音性難聴, 右聴力消失と耳鳴, 右軟口蓋麻痺, 舌の左側偏位, 不全四肢麻痺, 顔面を含む左側での全知覚低下を認めた.X線CTでは脳底動脈が拡張, 蛇行し, 橋を圧迫している解離前の所見に加え, 解離後のCTでは脳底動脈壁に器質化した壁在血栓を認めた.MRIでは解離後にT2強調像にて高信号で示される右前下小脳動脈領域の梗塞を認めた.脳血管撮影では左椎骨動脈i撮影の静脈相にて脳底動脈に造影剤の貯留を認めた.Megadolicho-Basilar Arteryと解離性動脈瘤は両者とも動脈硬化が基盤にあると考えられるが, 両者の合併は未だ報告がなく, 貴重な症例と思われた.

胞状奇胎の摘出後に脳静脈洞血栓症を引き起こした一女性例を報告する.不正性器出血と下腹部腫瘤を自覚し, 胞状奇胎と診断され子宮内容除去術を施行された.術後5日目より頭痛, 右上肢麻痺, 随意眼球運動の制限, 意識障害, 痙攣が出現。検査では, 凝固系, 線溶系, 血小板機能の亢進を認めた.また血中胎盤絨毛性ゴナドトロピンは胞状奇胎摘出の前後で大きく変化した (200,000から20,000IU/L).MRI, CT, 脳血管造影で上矢状洞前半部・左横静脈洞血栓症を認めた.抗凝固・血栓溶解療法が奏効し, 検査値上, 凝固機能亢進も正常化した.類妊娠状態といえる胞状奇胎に脳静脈洞血栓症を合併したとの報告はなく, 脳静脈洞血栓症の成因を考える上で興味ある症例と考えられた.

Significant improvement of Takayasu arteritis after cord blood transplantation in a patient with myelodysplastic syndrome

Hyperhomocysteinemia results from an impaired methionine metabolism. Sulfite oxidase, which is an important enzyme in methionine metabolism, contains molybdenum. In contrast, tungsten has a molybdenum-antagonistic effect. Thus, we hypothesized that dietary tungsten may decrease plasma homocysteine levels and influence methionine metabolism. Male New Zealand White rabbits (n=15) were fed a low-cholesterol basal diet and then placed on three different diets: 0.1% cholesterol (Chol), Chol plus 1% methionine (Met), and Chol plus Met plus 0.1% tungsten (W). The animals received these diets for 20 weeks. Biochemical tests of blood and urine were performed. Plasma homocysteine levels were significantly lower in the Chol+Met+W group than in the Chol+Met group. Plasma levels of total cholesterol, triglyceride, lipid peroxide, and urinary 24-h taurine concentrations were higher in the Chol + Met + W group than in the Chol + Met group. In comparison, concentrations of 2, 3-diphosphoglycerate (2, 3-DPG), reduced glutathione (GSH) in erythrocytes, and urinary 24-h SO4(2) were lower in the Chol+Met+W group than in the Chol+Met group. From these results, tungsten could be expected to exhibit an antiatherogenic effect. Conversely, it may have effects on atherogenic factors. Thus, tungsten may play a number of roles in the methionine metabolism.