Tunable Josephson Diode Effect on the Surface of Topological Insulators.

The Josephson rectification effect, where the resistance is finite in one direction while zero in the other, has been recently realized experimentally. The resulting Josephson diode has many potential applications on superconducting devices, including quantum computers. Here, we theoretically show that a superconductor-normal metal-superconductor Josephson junction diode on the two-dimensional surface of a topological insulator has large tunability. The magnitude and sign of the diode quality factor strongly depend on the external magnetic field, gate voltage, and the length of the junction. Such rich properties stem from the interplay between different current-phase relations for the multiple transverse transport channels, and can be used for designing realistic superconducting diode devices.

Anomalous Nonlocal Conductance as a Fingerprint of Chiral Majorana Edge States.

A chiral p-wave superconductor is the primary example of topological systems hosting chiral Majorana edge states. Although candidate materials exist, the conclusive signature of chiral Majorana edge states has not yet been observed in experiments. Here, we propose a smoking-gun experiment to detect the chiral Majorana edge states on the basis of theoretical results for the nonlocal conductance in a device consisting of a chiral p-wave superconductor and two ferromagnetic leads. The chiral nature of Majorana edge states causes an anomalously long-range and chirality-sensitive nonlocal transport in these junctions. These two drastic features enable us to identify the moving direction of chiral Majorana edge states in the single experimental setup.

3A Comparison between R-THP-COP and R-CHOP Regimens for the Treatment of Diffuse Large B-cell Lymphoma in Old Patients: A Single-institution Analysis.

Objective We retrospectively compared the clinical efficacy and toxicity of rituximab (R)-THP-COP (pirarubicin, cyclophosphamide, vincristine, and prednisolone) with that of R-CHOP (rituximab, adriamicin, cyclophosphamide, vincristine, and prednisolone) in previously untreated old patients with diffuse large B-cell lymphoma (DLBCL). Patients and Methods Patients admitted to our institution between 2004 and 2013 were examined. The patients received either R (375 mg/m2, day 1)-THP-COP (pirarubicin 50 mg/m2 day 1, cyclophosphamide 750 mg/m2 day 1, vincristine 1.4 mg/m2 day 1, and prednisolone 100 mg day 1-5) or R-CHOP (adriamicin 50 mg/m2 day 1, cyclophosphamide 750 mg/m2 day 1, vincristine 1.4 mg/m2 day 1, and prednisolone 100 mg day 1-5). The doses of chemotherapeutic agents were adjusted depending on the patient's age and associated complications. The treatment was performed for 6 to 8 cycles. Results Among 74 patients with DLBCL (median 76, range 65-90 years; male 39, female 35), 29 received R-THP-COP, while 45 received R-CHOP. The overall response rates were 94.6% (complete response 86.4%, partial response 8.1%). The 2-year overall and progression-free survival rates were 77.6% and 68.5% for the R-THP-COP regimen and 79.2% and 78.9% for R-CHOP, respectively. No significant differences were found between these two regimens regarding the clinical efficacies. The most frequent adverse event was neutropenia (72.4% for the R-THP-COP regimen, 88.9% for the R-CHOP regimen). The cardiac function as evaluated by ejection fraction values was not impaired in either regimen. Conclusion R-THP-COP was effective and safe as an alternative to R-CHOP.

Clinical and pathological aspects of human immunodeficiency virus-associated plasmablastic lymphoma: analysis of 24 cases.

Plasmablastic lymphoma (PBL) is a rare AIDS-related malignancy with a poor prognosis. Little is known about this entity, and no standard treatment regimen has been defined. To establish an adequate treatment strategy, we investigated 24 cases of PBL arising in human immunodeficiency virus-positive individuals. Most of the patients were in the AIDS stage, with a median CD4 count of 67.5/µL. Lymph nodes (58 %), gastrointestinal tract (42 %), bone marrow (39 %), oral cavity (38 %), and CNS (18 %) were the most commonly involved sites. Histology findings for the following were positive at varying rates, as follows: CD10 (56 %); CD30 (39 %); CD38 (87 %); MUM-1 (91 %); CD138 (79 %); EBER (91 %); and LMP-1 (18 %). There was a marked increase in patients in 2011-12, and the cases found in that period appeared to be more aggressive, showing a higher rate of advanced-stage PBL. Fourteen cases were treated with CHOP, while the others were treated with more intensive regimens, including bortezomib and hematopoietic stem cell transplantation. The overall median survival time was 15 months. A CD4 count of >100/µL at diagnosis and attaining complete remission in the first-line chemotherapy were associated with better outcomes (P = 0.027 and 0.0016, respectively). Host immune status and chemosensitivity are associated with improved prognosis in PBL.

Reduced administration of rasburicase for tumor lysis syndrome: A single-institution experience.

In the present study, the dosage and duration of rasburicase administration were retrospectively evaluated for the ability to control the serum uric acid (S-UA) level in 13 patients diagnosed with hematological malignancies and tumor lysis syndrome (TLS), or those at risk of developing TLS, at the University of Fukui Hospital. At the time of diagnosis, seven patients already exhibited laboratory TLS, and three demonstrated clinical TLS. All patients received rasburicase in addition to chemotherapy agents. The median dose was 0.19 mg/kg (range, 0.13-0.25 mg/kg), and the median duration was four days (range, 1-7 days). Six patients sequentially received a xanthine oxidase inhibitor, allopurinol or febuxostat. The primary estimate was the normalization of the S-UA level at the end of rasburicase treatment and on treatment day seven. The average S-UA level prior to treatment was 10.4±4.5 mg/dl (mean ±standard deviation), and 11 out of 13 patients demonstrated a S-UA level >7 mg/dl. The S-UA level at the end of rasburicase administration was 0.5±1.5 mg/dl and the S-UA level at day seven was 1.4±1.5 mg/dl. All the patients achieved normalization of the S-UA level. On day seven subsequent to the initiation of treatment, the patients receiving rasburicase for a maximum of three days exhibited an S-UA level of 1.9±1.8 mg/dl, while the patients receiving rasburicase for longer than three days demonstrated an S-UA level of 1.0±1.3 mg/dl (P=0.20; Mann-Whitney test). The administration of 0.13 mg/kg and 0.22 mg/kg resulted in comparable UA level reductions. The administration of allopurinol or febuxostat following rasburicase administration suppressed the re-increase in S-UA level. Therefore, it was concluded that reduced administration of rasburicase successfully controlled the S-UA level in TLS.

Prognostic effect of peripheral blood cell counts in advanced diffuse large B-cell lymphoma treated with R-CHOP-like chemotherapy: A single institution analysis.

The primary objective of the present study was to correlate blood cell counts (lymphocyte, monocyte and platelet counts) with early disease relapse following the attainment of complete remission (CR) by the rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP)-like regimen in patients with advanced diffuse large B-cell lymphoma (DLBCL). In total, 30 patients were evaluated, with a median follow-up period of 43 months. All the participating patients attained CR. In total, eight patients experienced relapse within two years of the diagnosis, and the three-year overall survival rate was recorded as 77%. The peripheral counts for lymphocytes, monocytes and platelets, and the lymphocyte-monocyte ratio, all of which have been reported to be prognostic in DLBCL, were assessed. None of these parameters were correlated with the incidence of early relapse or with the prognosis. The lymphocyte count was higher in the patients with durable remission than in those who relapsed, however, no significant differences were identified. Thus, the present study concluded that early disease relapse was not predicted by peripheral blood cell counts in advanced DLBCL that reached CR using the R-CHOP-like regimen.

Evaluation of staging and early response to chemotherapy with whole-body diffusion-weighted MRI in malignant lymphoma patients: A comparison with FDG-PET/CT.

BACKGROUND: To examine the utility of diffusion-weighted MRI (DW-MRI) for staging and early response to chemotherapy assessment in lymphoma patients as compared with fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT). METHODS: Twenty-eight patients with histologically confirmed malignant lymphoma underwent both MRI and FDG-PET/CT before (pretreatment) and after two courses of chemotherapy (mid-treatment). Staging with MRI (DW-MRI alone and with T2-weighted images) and FDG-PET was compared visually, and the concordance rate (kappa value, κ) was calculated. To evaluate early response to chemotherapy, patients were divided into two groups, lesion-positive (LP) and lesion-negative (LN), based on a proposed original criterion. Progression-free survival (PFS) was compared between the groups using the Kaplan-Meier method. RESULTS: The stage diagnosed with DW-MRI alone and with FDG-PET/CT was concordant in 22 patients (κ = 0.71; P < 0.05), and by adding T2-weighted images, the number of concordant patients increased to 26 (κ = 0.90; P < 0.05). On mid-treatment imaging, 19 patients were diagnosed as LN from both modalities. PFS differed significantly between LP and LN on both DW-MRI (P = 0.0013) and FDG-PET/CT (P = 0.037). CONCLUSION: DW-MRI is a promising tool for staging and evaluation of early response to chemotherapy in patients with lymphoma.

The response to induction therapy is crucial for the treatment outcomes of elderly patients with acute myeloid leukemia: single-institution experience.

BACKGROUND/AIM: The prognosis of acute myeloid leukemia (AML) in elderly patients remains poor due to their poor general condition and the intrinsic chemotherapy-resistant nature of their leukemia cells. The present retrospective study evaluated the clinical background as well as the response to treatment, of an unselected group of elderly patients with AML who were admitted to our Institution over a period of six years. PATIENTS AND METHODS: Patients aged 65 years or older with AML admitted to our Institution between January 2005 and May 2011 were evaluated retrospectively. RESULTS: Forty-six patients were admitted to our Institution, among whom 41 received remission induction chemotherapy. Twenty-four patients received intensive chemotherapy, while 13 received low-dose cytarabine-based chemotherapy. Other modalities were used in four patients. Complete remission was obtained in 20 patients (48.8%). The complete remission rate (50.0%) tended to be higher in patients receiving intensive chemotherapy than in those receiving low-dose cytarabine-based regimens (30.7%; p=0.25). The median survival time for the whole patient group was 12 months and the 2-year overall survival was 18%. The median survival times for patients with complete remission and for non-responding patients were 14 months and 7 months, respectively. The 2-year overall survival in patients with complete remission was 32%, while that of non-responding patients was 6% (p=0.0025, log-rank test). CONCLUSION: The present study suggests the necessity of achieving complete remission for obtaining better survival for elderly patients with AML.

Clinical effect of a multidisciplinary team approach to the initial treatment of patients with hospital-acquired bloodstream infections at a Japanese university hospital.

BACKGROUND: Hospital-acquired bloodstream infections (BSIs) are significant causes of mortality, and strategies to improve outcomes are needed. We aimed to evaluate the clinical efficacy of a multidisciplinary infection control team (ICT) approach to the initial treatment of patients with hospital-acquired BSI. METHODS: A before-after quasiexperimental study of patients with hospital-acquired BSI was performed in a Japanese university hospital. The ICT provided immediate recommendations to the attending physician about appropriate antimicrobial therapy and management after reviewing blood cultures, Gram's stain, final organism, and antimicrobial susceptibility results. RESULTS: The sample included 469 patients with hospital-acquired BSI (n = 210, preintervention group; n = 259, postintervention group). There were no significant differences between the groups in background or microbiologic characteristics. The 30-day mortality was significantly lower and significantly more patients received appropriate antimicrobial therapy in the postintervention group (22.9% vs 14.3%; P = .02 and 86.5% vs 69.0%; P < .001, respectively). Multivariate analysis confirmed that the ICT intervention was significantly associated with appropriate antimicrobial therapy (odds ratio, 2.22; 95% confidence interval, 1.27-3.89) and 30-day mortality (odds ratio, 0.49; 95% confidence interval, 0.25-0.95). CONCLUSIONS: A timely multidisciplinary team approach decreases the delay of appropriate antimicrobial treatment and may improve HABSI patient outcomes.

Significantly higher cytokine and chemokine levels in patients with Japanese spotted fever than in those with Tsutsugamushi disease.

Tetracyclines are administered to cure Japanese spotted fever (JSF) and tsutsugamushi disease (TD). It is generally said that the clinical course of JSF is worse than that of TD despite antibiotic treatment. The precise mechanism underlying the more severe clinical course of JSF is not fully understood. We therefore examined whether the differential cytokine profile between these two infectious diseases contributes to the difference in clinical severity. The serum concentrations of various cytokines (tumor necrosis factor alpha [TNF-α], interleukin-6 [IL-6], and gamma interferon [IFN-γ]) and chemokines (IL-8, interferon-inducible protein 10 [IP-10], monocyte chemoattractant protein 1 [MCP-1], macrophage inflammatory protein 1α [MIP-1α], MIP-1ß, and eotaxin) were measured in 32 TD and 21 JSF patients. The results showed that serum levels of TNF-α in the acute phases of TD and JSF were significantly increased, with a higher concentration of TNF-α in patients with JSF (mean, 39.9 pg/ml) than in those with TD (mean, 13.8 pg/ml). Comparatively higher levels of other cytokines and chemokines (IL-6, IFN-γ, IL-8, IP-10, MCP-1, MIP-1α, and MIP-1ß) were also observed in the acute phase of JSF. The clinical severity score (3.67 ± 1.71) of JSF patients was higher than that of TD patients (1.47 ± 0.77). Our findings revealed that the cytokine and chemokine levels in the acute phase of JSF were significantly higher than those in the acute phase of TD. The differential cytokine levels may be related to the difference in clinical severity between JSF and TD.

A high serum uric acid level is associated with poor prognosis in patients with acute myeloid leukemia.

Uric acid in serum (S-UA) is produced by the breakdown of the cellular nucleic acids of leukemia cells, and may be a marker of disease aggressiveness. S-UA levels were examined for association with clinical outcomes in patients with acute myeloid leukemia (AML). Fifty-six patients with AML admitted to our Institution were evaluated retrospectively. The median S-UA level at diagnosis was 5.0 mg/dl (range 2-13.8 mg/dl). The S-UA levels did not correlate with peripheral lactate dehydrogenase, peripheral white blood cell counts, or peripheral blast counts, and were not proportional to bone marrow blast counts or marrow cellularity. The S-UA levels in the patients who achieved complete remission were slightly lower than those in those who did not. S-UA levels less than, or equal to the median (5.0 mg/dl) were significantly associated with better prognoses, compared with S-UA levels greater than 5.0 mg/dl. Thus, the S-UA level may predict the prognosis of AML, and is a versatile and cost-effective test for such a purpose.

Detectable Wilms' tumor-1 transcription at treatment completion is associated with poor prognosis of acute myeloid leukemia: a single institution's experience.

BACKGROUND/AIM: The present retrospective study was conducted to measure Wilms' tumor-1 (WT1) mRNA levels in the peripheral blood of patients with acute myeloid leukemia (AML) in order to examine any association with the clinical outcomes. PATIENTS AND METHODS: A total of 58 AML patients were evaluated retrospectively in our institution. WT1 transcripts were determined by real-time reverse transcriptase-polymerase chain reaction in peripheral blood samples. RESULTS: WT1 levels at diagnosis did not vary according to response of induction treatments, and the levels were comparable between the patients with durable remission and the patients with relapse of disease. WT1 levels at the completion of the treatment were higher in the group with relapse of disease than in the group with sustained remission. Detectable WT1 transcripts after the completion of chemotherapy courses were associated with poor prognoses. CONCLUSION: WT1 mRNA levels at treatment completion may predict for prognosis of AML.

Tsutsugamushi disease caused by Shimokoshi-type Orientia tsutsugamushi: the first report in Western Japan.

An 85-year-old female farmer was admitted to our hospital for fever, general fatigue, and skin rash. Cephalosporin was not effective and minocycline was dramatically effective. An eschar was discovered on her inguinal region after the defervescence. Laboratory examination of serum taken 12 days after onset of the illness showed elevated titers of antibodies against the Shimokoshi strain of Orientia tsutsugamushi. The gene sequence analysis of specimen from the patient's eschar revealed high similarity to the Shimokoshi strain by nested polymerase chain reaction. Therefore, this patient was diagnosed as a case of Shimokoshi-type tsutsugamushi disease, which has not previously been reported in Western Japan. Recently, cases of this type have also been confirmed in northeastern Japan, suggesting the need for further epidemiological studies.

Minocycline modulates cytokine and chemokine production in lipopolysaccharide-stimulated THP-1 monocytic cells by inhibiting IκB kinase α/ß phosphorylation.

Minocycline, which is a member of the broad-spectrum bacteriostatic tetracycline antibiotics group, has also recently been shown to have additional effects that are separate from their antimicrobial function; however, the detailed mechanisms involved remain unknown. We examined the effects of minocycline on cytokine and chemokine production and the expression levels of intracellular phosphorylated proteins in a lipopolysaccharide (LPS)-induced cytokine response model in vitro. In the present study, 3 cytokines (tumor necrosis factor [TNF]-α, interleukin [IL]-6, and interferon [IFN]-γ) and 7 chemokines (IL-8, interferon inducible protein [IP]-10, monocyte chemoattractant protein [MCP]-1, macrophage inflammatory protein [MIP]-1α, MIP-1ß, regulated upon activation normal T-cell expressed secreted [RANTES], and eotaxin) were suppressed by minocycline in a dose-dependent manner. Moreover, the phosphorylation of inhibitor of nuclear factor-κB alpha (IκBα) and IκB kinase (IKK)α/ß, which is located upstream from IκBα, was significantly suppressed by minocycline, whereas the phosphorylation of extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK), p38, and TGF-ß-activated kinase (TAK)1 were not affected. Thus, minocycline appears to inhibit the signaling pathway at the level of IKKα/ß phosphorylation. In conclusion, minocycline was found to reduce the production of multiple cytokines and chemokines by inhibiting LPS-induced IKKα/ß phosphorylation. That is, minocycline appears to be a potent inhibitor of IKKα/ß phosphorylation. From a clinical and translational significance point-of view, these findings suggest that the use of minocycline offers the advantage of providing both antimicrobial and anti-inflammatory effects, which may be key in treating certain types of infectious diseases, particularly those that lead to hypercytokinemia and chronic inflammatory disorders.

Utility of PCR amplification and DNA microarray hybridization of 16S rDNA for rapid diagnosis of bacteremia associated with hematological diseases.

OBJECTIVES: The rapid diagnosis of bacteremia is crucial for patient management including the choice of antimicrobial therapy, especially in cases of hematological disease, because neutropenia occurs frequently during antineoplastic chemotherapy or disease progression. We describe a rapid detection and identification system that uses universal PCR primers to amplify a variable region of bacterial 16S ribosomal DNA (rDNA), followed by DNA microarray hybridization. METHODS: Probes for 72 microorganisms including most causal clinical pathogens were spotted onto a microarray plate. The DNA microarray and conventional methods of identification were applied to 335 cultures from patients with hematological diseases. RESULTS: Forty-one samples (12.2%) tested positive by conventional blood culture test in a few days, while 40 cases (11.9%) were identified by the new method within 24 h. The sensitivity and specificity of this new method were 93% and 99%, respectively, compared with conventional blood culture testing. CONCLUSIONS: PCR combined with a DNA microarray is useful for the management of febrile patients with hematological diseases.

Early relapse is associated with high serum soluble interleukin-2 receptor after the sixth cycle of R-CHOP chemotherapy in patients with advanced diffuse large B-cell lymphoma.

The clinical significance of serum soluble interleukin-2 receptor (sIL2R) levels was retrospectively assessed in patients with advanced diffuse large B-cell lymphoma (DLBCL). Twenty-one patients, who were newly-diagnosed with advanced DLBCL (stage III and IV) between 2006 and 2009, were evaluated. The median follow-up period was 37 months. All patients received 6-8 cycles of chemotherapy with rituximab in combination with doxorubicin, cyclophosphamide, vincristine, and prednisolone (CHOP)-like regimens and attained complete remission. Although all patients reached complete remission, six patients experienced disease relapse within 1 year after treatment completion. The overall survival was significantly poorer in patients with relapse than in patients with durable remission. The sIL2R levels after the sixth cycle of treatment were significantly higher in the relapse group than in the non-relapse group. Thus, the present study suggests sIL2R levels to be a valuable predictor for the prognosis of patients with advanced DLBCL.

Wilms' tumor-1 transcript in peripheral blood helps diagnose acute myeloid leukemia and myelodysplastic syndrome in patients with pancytopenia.

BACKGROUND/AIM: Pancytopenia is caused by acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), aplastic anemia (AA), or by non-hematological diseases. Because Wilms' tumor-1 (WT1) is overexpressed in patients with AML and MDS, its expression level may be helpful for diagnosing these hematological malignancies. PATIENTS AND METHODS: We retrospectively investigated the WT1 transcripts in peripheral blood (PB) from 47 patients with decreased blood cell counts. RESULTS: The final diagnoses included AML, MDS, AA, drug poisoning, and non-hematological diseases. PB WT1 mRNA was overexpressed in AML and MDS, whereas the patients with other diseases mostly tested negatively for the transcript. The patients with MDS with higher marrow blast counts had higher PB WT1 mRNA levels. The sensitivity of the PB WT1 transcript in detecting AML and MDS was 78%, and the specificity was 90%. CONCLUSION: The WT1 mRNA level in PB may help diagnose AML and MDS in patients with pancytopenia.

Induction of DNA strand breaks is critical to predict the cytotoxicity of gemtuzumab ozogamicin against leukemic cells.

Gemtuzumab ozogamicin (GO) consists of the CD33 antibody linked to calicheamicin. The binding of GO to the CD33 antigen on leukemic cells results in internalization followed by the release of calicheamicin, thereby inducing DNA strand breaks. We hypothesized that the induction of DNA strand breaks would be a surrogate marker of GO cytotoxcity. Here, two GO-resistant variants (HL/GO-CSA [225-fold], HL/GO [200-fold]) were established by serially incubating human leukemia HL-60 cells with GO with or without a P-glycoprotein (P-gp) inhibitor, cyclosporine A, respectively. The CD33 positivity was reduced in both variants. The HL/GO-CSA cells showed an increased multidrug resistance protein-1 (MRP1) transcript, and an MRP1 inhibitor partially reversed GO resistance. The HL/GO cells had neither P-gp nor MRP1 overexpression. Microarray analysis and Western blotting indicated elevated levels of DNA repair-associated proteins in both variants. Two other leukemic subclones, showing either P-gp or MRP1 overexpression, were also GO-resistant. Using single cell gel electrophoresis analysis, it was determined that GO-induced DNA strand breaks increased dose-dependently in HL-60 cells, whereas the number of breaks was reduced in the GO-resistant cell lines. The induction of DNA strand breaks was correlated with GO sensitivity among these cell lines. The CD33 positivity and the expression levels of transporters were not proportional to drug sensitivity. Using primary leukemic cells, the induction of DNA strand breaks appeared to be associated with GO sensitivity. Thus, GO-induced DNA strand breaks as the final output of the mechanism of action would be critical to predict GO cytotoxicity.

Fulminant candidemia diagnosed by prompt detection of pseudohyphae in a peripheral blood smear.

A 77-year-old man treated with prednisolone for pemphigus developed severe sepsis by Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus. Several antibiotics were administered. A peripheral blood smear showed growth of a large number of yeast extending pseudohyphae which could be seen both inside and outside of leucocytes. Antifungal agents were added immediately; however, he did not recover. Several days later, blood culture showed Candida albicans septicemia. The autopsy revealed microabscesses in the lung, heart, liver and kidney. A large amount of neutrophil invasion and yeast with pseudohyphae were also detected.

[Clinical significance of coagulase-negative Staphylococci isolated from blood culture samples of patients with hematological disorders; true bacteremia or contamination].

In recent years, findings of coagulase-negative Staphylococci (CNS) have been increasing on blood culture tests taken from patients with hematological disorders; however, the diagnosis of true bacteremia is often very difficult because CNS is an indigenous bacterium of the skin. We investigated the relationship between the time from obtaining the blood specimen to the detection of positive culture tests as well as the significance of the pathogen detected. Twenty-three inpatients demonstrated CNS-positive blood culture tests. It was judged that six patients (26%) had contamination, while 17 patients (74%) had true bacteremia. The mean interval until positive culture was 45.3 and 13.9 hours, respectively (p<0.005). The cut-off value for predicting true bacteremia was assumed to be 24 h; sensitivity was 94% and specificity was 83%. The interval until blood culture becomes positive will be a useful marker for accurately diagnosing true bacteremia.