Immunomodulatory effects of D-allose on cytokine production by plasmacytoid dendritic cells.

D-Allose is classified as a 'rare sugar,' i.e., part of the group of monosaccharides that are present in low quantities in the natural world. D-Allose has been demonstrated to exert many physiological functions. The effects of the rare sugars on immune responses are largely unexplored. Here, we investigated the physiological effects of D-allose on murine dendritic cells' cytokine production. When plasmacytoid dendritic cells (pDCs) were stimulated with a Toll-like receptor 7 (TLR7) ligand, a single-stranded RNA (ssRNA), or a TLR9 ligand, CpG DNA, in the medium containing D-allose, the productions of both interferon-alpha (IFN-α) and interleukin (IL)-12p40 were severely decreased. In contrast, a normal production of these cytokines was observed when pDCs were stimulated with other TLR7 ligands, an imidazoquinoline, or a guanosine analog. In contrast to the pDCs, conventional dendritic cells (cDCs) produced IL-12p40 and tumor necrosis factor-alpha (TNF-α) in response to an imidazoquinoline or CpG DNA even though D-allose was present in the medium. D-Allose did not induce pDC death, and not inhibit the endocytic uptake of fluorophore-labeled CpG DNA into pDCs. These results suggested that D-allose exerts its inhibitory effects after CpG DNA is internalized. We analyzed the TLR7/9 signal-induced activation of downstream signaling molecules in pDCs and observed that when pDCs were stimulated with a ssRNA or CpG DNA, the phosphorylation status of the MAPK family, which includes Erk1/2, JNK/SAPK, and p38 MAPK, was attenuated in the presence of D-allose compared to D-glucose controls. The stimulation of pDCs with an imidazoquinoline induced a strong phosphorylation of these MAPK family members even in the presence of D-allose. These findings reveal that D-allose can inhibit the cytokine production by pDCs stimulated with ssRNA or CpG DNA via an attenuation of the phosphorylation of MAPK family members.

Severe Functional Tricuspid Stenosis Due to Phosphoglyceride Crystal Deposition Disease in Right Atrium.

This case report concerns a 72-year-old-female with severe functional tricuspid stenosis due to phosphoglyceride crystal deposition disease and a history of atrial septum closure and tricuspid valvuloplasty. Phosphoglyceride crystal deposition disease is extremely rare, and percutaneous transcatheter biopsy under intracardiac echocardiographic guidance proved to be useful for its diagnosis. (Level of Difficulty: Advanced.).

Effect of hypertension on the optimal anthracycline cumulative dose for developing left ventricular dysfunction in patients with malignant lymphoma.

The most serious adverse effect of anthracycline chemotherapy is progressive dose-dependent left ventricular (LV) dysfunction, and a total cumulative doxorubicin dose ≥ 240 mg/m2 has been classified as putting patients at high risk for developing cardiac dysfunction. Hypertension is the single most important risk factor for heart failure and chemotherapy-induced LV dysfunction, but the effect of hypertension on the total cumulative doxorubicin dose to prevent the development of LV dysfunction in patients scheduled for anthracycline chemotherapy remains uncertain. The aim of this study was to investigate the effect of hypertension on the optimal total cumulative anthracycline dose to prevent the development of LV dysfunction in patients with malignant lymphoma. We retrospectively studied 92 patients with malignant lymphoma and preserved LV ejection fraction (LVEF) who underwent anthracycline chemotherapy. Echocardiography was performed before and 2 months after anthracycline chemotherapy. LV hypertrophy (LVH) was defined as concentric hypertrophy, and LV dysfunction after chemotherapy as a relative decrease in LVEF ≥ 5%. The cutoff value of the total cumulative doxorubicin dose for the development of LV dysfunction was lower for hypertensive patients (n = 23) than for non-hypertensive patients (n = 69) (259.3 mg/m2 vs. 358.9 mg/m2). Importantly, the cutoff value of the total cumulative doxorubicin dose to prevent the development of LV dysfunction in hypertensive patients with LVH was even lower at 40.1 mg/m2. A lower cumulative anthracycline dose can cause LV dysfunction in hypertensive patients with malignant lymphoma, especially when complicated by LVH. Our findings can thus be expected to have clinical implications for better management of such patients.

Characteristics of non-valvular atrial fibrillation with left atrial appendage thrombus who are undergoing appropriate oral anticoagulation therapy.

We investigated the characteristics of patients with non-valvular atrial fibrillation (NVAF) and left atrial (LA) appendage (LAA) thrombus who had been given appropriate oral anticoagulation therapy. We studied 737 NVAF patients who were scheduled for catheter ablation or electrical cardioversion. All patients received appropriate oral anticoagulation therapy for at least 3 weeks prior to echocardiography in accordance with the guidelines. Whether LAA thrombus was present or absent on transesophageal echocardiography (TEE) was determined by at least three senior echocardiologists. LAA thrombi were observed in 22 patients (3.0%). Multivariate logistic regression analysis showed that LAA flow and LA volume index were both independent predictors of LAA thrombus formation; however, LAA flow (≤ 18 cm/s) was indicated as a more powerful predictor. Moreover, the prevalence of LAA thrombus formation in patients with NVAF without LA enlargement (LA volume index ≤ 34 mL/m2) was extremely rare (0.4%). LAA thrombus formation in patients with a mildly dilated LA volume index of 34-49.9 mL/m2 and paroxysmal AF was also extremely rare (0.0%). LAA flow is strongly associated with LAA thrombus formation, even in NVAF patients treated with appropriate oral anticoagulation therapy. Augmented oral anticoagulation therapy or transcatheter or surgical LAA closure should be considered for such patients, especially for those with an LAA flow < 18 cm/s. Furthermore, TEE for evaluating LAA thrombus before catheter ablation or electrical cardioversion may be unnecessary for NVAF patients who are undergoing appropriate oral anticoagulation therapy, depending on LA size.

Easy-to-use preload stress echocardiography by using combined dynamic postural stress can identify high-risk patients with heart failure with reduced ejection fraction.

AIMS: Haemodynamic assessment during stress testing is not commonly performed in patients with heart failure with reduced ejection fraction (HFrEF) because of its invasiveness, lower feasibility, and safety concerns. This study aimed to assess the haemodynamic characteristics of patients with HFrEF in response to non-invasive preload stress during dynamic postural alterations achieved by combining both semi-sitting position and passive leg-lifting and to evaluate whether combined postural stress could be used for risk stratification in these patients. METHODS AND RESULTS: For this study, 101 patients with HFrEF and 35 age-matched and sex-matched healthy controls were prospectively recruited. After all standard echocardiographic measurements were obtained in the left decubitus position, all subjects underwent postural stress testing, which consisted of changing from semi-sitting position to passive leg-lifting. During a median follow-up period of 12.2 months, 21 (21%) patients developed adverse cardiovascular events. In patients without adverse cardiovascular events, the stroke volume index (SVi) significantly changed from 28 ± 8 to 35 ± 10 mL/m2 (P < 0.001) during combined postural stress. By contrast, ΔSVi during combined dynamic postural stress was significantly smaller in patients with cardiovascular events than in those without events (ΔSVi 3.4 ± 4.0 vs. 6.4 ± 3.8 mL/m2 , P = 0.002), which indicated severely diseased heart operated on a relatively flat portion of the Frank-Starling curve. In a multivariate Cox proportional hazard analysis, ΔSVi (hazard ratio 0.81, P = 0.02) was an independent predictor of future adverse cardiovascular events. CONCLUSIONS: The combined assessment of dynamic postural stress is a non-invasive, simple, quick, and easy-to-use clinical tool for assessing preload reserve and risk stratification in HFrEF patients.

"Accelerated aging" of the heart as heart failure with preserved ejection fraction-analysis using leg-positive pressure stress echocardiography.

The aging process is a significant risk factor for heart failure. The incidence of heart failure with preserved ejection fraction (HFpEF) dramatically increases with age. Although HFpEF occurs along a continuum of aging of the cardiovascular system, the pathophysiology that differentiates overt HFpEF from physiological aging is not fully understood. A total of 102 subjects were prospectively recruited: 25 patients with HFpEF and 77 healthy controls. Controls were stratified into three age-groups: young (n = 27, 20-40 years), middle aged (n = 25, 40-65 years), and elderly (n = 25, > 65 years). All participants underwent preload stress echocardiography using a leg-positive pressure (LPP) maneuver. With an increase in age, progressive concentric left ventricular (LV) remodeling was observed in healthy controls, resulting in the hemodynamic consequences of an age-dependent increase in the E/e' ratio (ANOVA, P < 0.001). During LPP stress, the E/e' ratio significantly increased in the middle-aged and elderly groups (from 8 ± 2 to 9 ± 3, from 10 ± 2 to 12 ± 3, P < 0.05, respectively), and this was more pronounced in patients with HFpEF (from 16 ± 5 to 17 ± 7, P < 0.05). Forward stroke volume (SV) significantly increased in each healthy group during LPP stress (all P < 0.001) but failed to increase in the HFpEF group (from 43 ± 13 to 44 ± 14 mL/m2, P = 0.65). In a multivariate analysis, LV mass index (odds ratio [OR] 1.051, P < 0.05), E/e' ratio (OR 1.480; P < 0.05), and change in SV (OR 0.780; P < 0.05) were independent parameters that differentiated HFpEF from physiological aging. Structural remodeling and impaired preload reserve may both be critical features that characterize the pathophysiology of HFpEF.

The World Ovarian Cancer Coalition Every Woman Study: identifying challenges and opportunities to improve survival and quality of life.

INTRODUCTION: With the global incidence of ovarian cancer set to rise by 55% to 371 000 per year by 2035, current 5-year survival rates below 50%, and 15% of women with ovarian cancer dying within 2 months of diagnosis, urgent action is required to improve survival and quality of life. OBJECTIVE: To deal with the evidence gap relating to the experience of women with the disease around the globe and identify opportunities to drive progress. METHODS: The study included a review of global trends in incidence, mortality, and survival (October 2017); qualitative interviews with women and clinicians in 16 countries (December 2017); and an online survey for women available in 15 different languages (open for 2 months, March to early May 2018). Women were eligible to participate if they had been diagnosed in the previous 5 years and were proficient in one of the 15 languages offered. RESULTS: A total of 1531 women from 44 countries took part in the analysis. On average, 69.1% of women were not aware of ovarian cancer before their own diagnosis, varying from 50.9% (Hungary) to 86.4% (Brazil). A total of 78.3% of symptomatic women sought medical help, varying from 62.8% (Japan) to 87.7% (UK). Fewer than half of the women visited a doctor within 1 month (46.3%) of experiencing symptoms, varying from 38.5% (USA) to 77.3% (Germany), and a quarter of women waited 3 months or more. On average, 43.2% of women were diagnosed within 1 month of visiting a doctor, ranging from 30% (UK) to 62.3% (Italy). The average estimated time from experiencing symptoms to diagnosis was 31 weeks, but this ranged from 21.3 (Germany) to 39.7 (Brazil). Rates of post-diagnosis genetic testing ranged from 5.0% (Japan) to 79.1% (USA). Clinicians indicated that access to specialist treatment in high-volume centers varies greatly by country and region. CONCLUSION: The findings of this study identify some of the major challenges and opportunities to improve the time to diagnosis and management of women with ovarian cancer. These problems vary widely by country, and reducing the variability is an important first step towards improving outcomes for women with ovarian cancer.

Association between clinical risk factors and left ventricular function in patients with breast cancer following chemotherapy.

The sequential or concurrent use of two different types of agents such as anthracyclines and trastuzumab may increase myocardial injury and cancer therapeutics-related cardiac dysfunction (CTRCD), which is often the result of the combined detrimental effect of the two therapies for breast cancer patients. However, the association between clinical risk factors and left ventricular (LV) function in such patients is currently unclear. We studied 86 breast cancer patients with preserved LV ejection fraction (LVEF) and treated with anthracyclines, trastuzumab, or both. Echocardiography was performed before and 16 days after chemotherapy. In accordance with the current position paper, clinical risk factors for CTRCD were defined as: cumulative dose of doxorubicin > 240 mg/m2, age > 65-year-old, body mass index > 30 kg/m2, previous radiation therapy, B-type natriuretic peptide > 100 pg/mL, previous history of cardiovascular disease, atrial fibrillation, hypertension, diabetes, and smoking. The relative decrease in LVEF after chemotherapy for patients with more than four risk factors was significantly greater than that for patients without (- 9.3 ± 10.8% vs. - 2.2 ± 10.2%; p = 0.02). However, this finding did not apply to patients with more than one, two or three risk factors. Patients with more than four risk factors also tended to show a higher prevalence of CTRCD than those without (14.3% vs. 2.8%; p = 0.12). Moreover, the relative decrease in LVEF became greater as the number of risk factors increased. This study found multiple risk factors were associated with LV dysfunction following chemotherapy. Our findings can thus be expected to have clinical implications for better management of patients with breast cancer referred for chemotherapy.

Impact of hypertension on left ventricular function in patients after anthracycline chemotherapy for malignant lymphoma.

BACKGROUND: Hypertension is considered an important risk factors for cancer therapeutics-related cardiac dysfunction (CTRCD) as well as heart failure. However, the impact of hypertension and left ventricular (LV) hypertrophy (LVH), which is associated with hypertension, on LV function in patients treated with anthracycline chemotherapy for malignant lymphoma remains uncertain. METHOD: We studied 92 patients with malignant lymphoma and with preserved LV ejection fraction (LVEF). Echocardiography was performed before and two-month after anthracycline chemotherapy. CTRCD was defined as the presence of an absolute decrease in LVEF ≥10% to a final value <53%. LVH was defined as concentric hypertrophy, which was determined as relative wall thickness ≥ 0.42 and LV mass index >95 g/m2 for females and > 115 g/m2 for males. RESULTS: Relative decrease in LVEF after anthracycline chemotherapy in patients with hypertension (n = 23) was significantly higher than that in patients without hypertension (n = 69) (-5.8% [-9.4, -1.3]) vs. (-1.1% [-4.1, 2.5]); P = .005). Moreover, the prevalence of CTRCD in patients with hypertension tended to be higher than in those without hypertension (17% vs. 5%, p = .09). A sequential logistic model for predicting CTRCD, based on baseline clinical variables including major clinical risk factors, was improved by the addition of the complication of hypertension (P = .049), and further improved by the addition of the presence of LVH (P = .023). CONCLUSIONS: Hypertension, especially when complicated by LVH, was found to be associated with LV dysfunction after anthracycline chemotherapy in patients with malignant lymphoma and preserved LVEF. Watchful observation or early therapeutic intervention may thus be needed for such patients by the addition of the presence of LVH.

COVID-19 pneumonia in a patient with adult T-cell leukemia-lymphoma.

Although some patients with COVID-19 develop only mild symptoms, fatal complications have been observed among those with comorbidities. As patients with cancer are immunocompromised, they are thought to have a high risk of severe illness associated with COVID-19. We report a COVID-19 patient with adult T-cell leukemia-lymphoma (ATL) who was treated using favipiravir. A 69-year-old woman with lymphoma-type ATL was treated using cyclophosphamide, doxorubicin, vincristine, prednisolone and mogamulizumab (M-CHOP) with substantial efficacy. However, in cycle 4 of M-CHOP therapy, she developed fever with mild cough. The patient was admitted to the hospital and CT revealed bilateral ground-glass opacities. SARS-CoV-2 was detected by RT-PCR and the patient was diagnosed with COVID-19. Considering severe immunosuppression caused by ATL, we initiated favipiravir therapy. Subsequently, the fever improved without antipyretics and her C-reactive protein level decreased rapidly. SARS-CoV-2 PCR tests were negative on days 17 and 18 of favipiravir therapy, and the patient was discharged without residual disease on the final CT. This is the first documented case of COVID-19 in a patient with ATL. Although severe immunosuppression caused by ATL was present, severe COVID-19 pneumonia did not develop. The immunosuppressed condition caused by hematological malignancy may not always be a risk factor for severe illness associated with COVID-19. Further accumulation of data regarding COVID-19 in patients with hematological malignancies is warranted to clarify the risk factors for severe illness, the best-in-class antiviral agent, and the optimal treatment strategy in this population.

The mechanism of action of Spi-B in the transcriptional activation of the interferon-α4 gene.

Plasmacytoid dendritic cells (pDCs) are characterized by an exclusive expression of nucleic acid sensing Toll-like receptor 7 (TLR7) and TLR9, and production of high amounts of type I interferon (IFN) in response to TLR7/9 signaling. This function is crucial for both antiviral immunity and the pathogenesis of autoimmune diseases. An Ets family transcription factor, i.e., Spi-B (which is highly expressed in pDCs) is required for TLR7/9 signal-induced type I IFN production and can transactivate IFN-α promoter in synergy with IFN regulatory factor-7 (IRF-7). Herein, we analyzed how Spi-B contributes to the transactivation of the Ifna4 promoter. We performed deletion and/or mutational analyses of the Ifna4 promoter and an electrophoretic mobility shift assay (EMSA) and observed an Spi-B binding site in close proximity to the IRF-7 binding site. The EMSA results also showed that the binding of Spi-B to the double-stranded DNA probe potentiated the recruitment of IRF-7 to its binding site. We also observed that the association of Spi-B with transcriptional coactivator p300 was required for the Spi-B-induced synergistic enhancement of the Ifna4 promoter activity by Spi-B. These results clarify the molecular mechanism of action of Spi-B in the transcriptional activation of the Ifna4 promoter.

Knowledge, fatigue, and cognitive factors as predictors of lymphoedema risk-reduction behaviours in women with cancer.

OBJECTIVE: To identify social-cognitive factors predicting lymphoedema risk-reduction behaviours (hereafter, self-care) after discharge among patients in Japan with breast or gynaecological cancers, using the extended model of the theory of planned behaviour. METHODS: A cross-sectional questionnaire study was conducted in an oncology hospital. Items measured were (1) knowledge about self-care; (2) the Cancer Fatigue Scale; (3) social-cognitive factors in the theory of planned behaviour (attitudes, subjective norms, and perceived behavioural control); (4) self-care (limb hygiene, observation, articular movement, recommended risk-reduction behaviours in daily life, and diet and weight control); and (5) demographics. Of 202 respondents, 147 who had not been diagnosed with lymphoedema were eligible for statistical analysis (65.3% with gynaecological cancer, 34.7% with breast cancer). RESULTS: Structural equation modelling was used to examine a hypothesised model based on the theory of planned behaviour. The results revealed that a longer time since surgery, higher levels of fatigue, less knowledge, higher expected efficacy of self-care, and lower perceived behavioural control directly and significantly predicted less self-care behaviour. CONCLUSIONS: Besides education about self-care behaviour, levels of fatigue and perceived behavioural control should be taken into account to encourage female patients with cancer to perform self-care after discharge. Continuous psycho-educational programmes after discharge may help to facilitate self-care behaviours among long-term female cancer survivors.

Information-seeking, information sources and ongoing support needs after discharge to prevent cancer-related lymphoedema.

OBJECTIVES: To compare gynaecological and breast cancer patients in their information-seeking behaviours, usefulness of information sources and ongoing care needs after discharge to prevent the onset of lymphoedema. METHODS: We conducted a consecutive cross-sectional survey in an oncology hospital. Adult patients with stage I, II or III gynaecological or breast cancer who had undergone lymph node dissection and had not been diagnosed with lymphoedema were eligible for inclusion. The survey explored physical health status, knowledge of self-care, information-seeking behaviours, information sources and need for ongoing care from an oncology hospital and/or community health centre. RESULTS: Among 254 patients recruited, 202 responded (79.5% response rate). In total, 147 patients were eligible for statistical analysis. Irrespective of cancer type, the most commonly sought information was lymph drainage. Information on preventing weight gain was sought more often by breast cancer patients than gynaecological cancer patients. Regardless of cancer type, the most common information sources were nurses at an oncology hospital. Gynaecological cancer patients perceived nurses at the oncology hospital as useful for understanding risks, symptoms and prevention of lymphoedema. Irrespective of cancer type, ongoing need for help with lymphoedema prevention was reported both from the oncology hospital and the community centre. Limb symptoms, poor health status and poor knowledge affected the ongoing needs of gynaecological cancer patients at the oncology hospital, whereas poor health status affected ongoing needs in community health centres among both types of cancer patients. CONCLUSIONS: Both gynaecological and breast cancer patients reported ongoing care needs, but that details of information-seeking behaviours differed.

The Possible Link between GABAergic Dysfunction and Cognitive Decline in a Patient with Idiopathic Hypoparathyroidism.

Idiopathic hypoparathyroidism (IHP) is accompanied by cognitive impairment. We report the case of a 70-year-old IHP patient with cognitive disturbance. Brain computed tomography showed bilateral calcification in basal ganglia, thalamus, and cerebellum. Neuropsychological assessment revealed low scores for intelligence, memory, and perseverative errors. Brain positron emission tomography showed a significant reduction in [(18)F]-Fludeoxyglucose (FDG) uptake in bilateral frontal, left temporal and parietal cortices, along with a marked reduction in [(11)C]-flumazenil binding in left frontal, temporal, parietal, and bilateral cerebellum. These findings suggest cognitive impairment in IHP may be ascribed to GABAergic dysfunction, thus leading to, or coexisting with, cerebral hypometabolism.

Cloning of a cDNA encoding the Gly m Bd 28K precursor and its vacuole transport in tobacco BY2 suspension-cultured cells.

Gly m Bd 28K (Gm28K), a soybean allergen, is formed as a preproprotein consisting of a predicted signal peptide, Gm28K, and the 23-kDa peptide (Gm23K). Gm28K and Gm23K are found in the protein-storage vacuoles (PSVs) of developing soybean seeds. However, the complete structure of Gm28K has not yet been identified and its processing and transport to the vacuoles has never been clarified. In the present study, we elucidated the 5'-nucleotide sequence of cDNA encoding the Gm28K precursor and identified a putative signal peptide (SP) with 24 N-terminal amino acid residues. We expressed peptides from the Gm28K precursor as fusion proteins with enhanced green fluorescent protein (EGFP) in tobacco BY2 suspension-cultured cells. BY2 cells transformed by an expression vector for SP-EGFP-Gm28-Gm23K (SP-EGFP-Gm28-Gm23K/BY2 cells) and SP-Gm28-Gm23K-EGFP/BY2 cells produced the EGFP fused-Gm28K precursor, and the EGFP-fluorescence in their vacuoles were recorded. In the experiments with SP-EGFP/BY2 and SP-EGFP-Gm28K/BY2 cells, large amounts of the EGFP segments were secreted into the medium. On the other hand, the fluorescence of EGFP in SP-EGFP-Gm23K/BY2 cells was shown to accumulate only in the endoplasmic reticulum without secretion into the medium. These findings show that the SP signals the precursor to enter the lumen of the endoplasmic reticulum and that both the Gm28K and Gm23K components may be involved in the transport from the endoplasmic reticulum (ER) lumen via the Golgi to the vacuoles in a proprotein form.

Activation of Notch1 promotes development of human CD8(+) single positive T cells in humanized mice.

Notch1 mutations are found in more than 50% of human T cell acute lymphoblastic leukemia (T-ALL) cells. However, the functions of Notch1 for human T cell development and leukemogenesis are not well understood. To examine the role of Notch1, human hematopoietic stem cells (HSCs), which had been transduced with a constitutively active form of Notch1 (ICN1), were transplanted into severely immunodeficient NOD/Shi-scid-IL2rγ(null) (NOG) mice. We found that the great majority of the ICN1-expressing hematopoietic cells in the bone marrow expressed surface markers for T cells, such as CD3, CD4, and CD8, and that this T cell development was independent of the thymus. Accordingly, phenotypically mature CD8(+) single positive (SP) T cells were observed in the spleen. Furthermore, T-ALL developed in one NOG recipient mouse out of 26 that had been secondary transferred with the T cells developed in the first NOG mice. These results indicate that Notch1 signaling in HSCs promotes CD8(+) SP T cell development, and that T cell leukemogenesis may require additional oncogenic factors other than Notch1 activation.

Neutralization of leukotriene C4 and D4 activity by monoclonal and single-chain antibodies.

BACKGROUND: Cysteinyl leukotrienes (LTs) are key mediators in inflammation. To explore the structure of the antigen-recognition site of a monoclonal antibody against LTC4 (mAbLTC), we previously isolated full-length cDNAs for heavy and light chains of the antibody and prepared a single-chain antibody comprising variable regions of these two chains (scFvLTC). METHODS: We examined whether mAbLTC and scFvLTC neutralized the biological activities of LTC4 and LTD4 by competing their binding to their receptors. RESULTS: mAbLTC and scFvLTC inhibited their binding of LTC4 or LTD4 to CysLT1 receptor (CysLT1R) and CysLT2 receptor (CysLT2R) overexpressed in Chinese hamster ovary cells. The induction by LTD4 of monocyte chemoattractant protein-1 and interleukin-8 mRNAs in human monocytic leukemia THP-1 cells expressing CysLT1R was dose-dependently suppressed not only by mAbLTC but also by scFvLTC. LTC4- and LTD4-induced aggregation of mouse platelets expressing CysLT2R was dose-dependently suppressed by either mAbLTC or scFvLTC. Administration of mAbLTC reduced pulmonary eosinophil infiltration and goblet cell hyperplasia observed in a murine model of asthma. Furthermore, mAbLTC bound to CysLT2R antagonists but not to CysLT1R antagonists. CONCLUSIONS: These results indicate that mAbLTC and scFvLTC neutralize the biological activities of LTs by competing their binding to CysLT1R and CysLT2R. Furthermore, the binding of cysteinyl LT receptor antagonists to mAbLTC suggests the structural resemblance of the LT-recognition site of the antibody to that of these receptors. GENERAL SIGNIFICANCE: mAbLTC can be used in the treatment of inflammatory diseases such as asthma.

[Supporting lymphedema patients by working together among different job categories].

Therapeutic methods and preventive education related to lymphedema are beginning to attract attention as a result of revisions to the associated medical treatment fees. Currently, fees for guidance on the prevention of lymphedema and the payment of medical expenses for compression garments after the onset of lymphedema are covered by insurance. However, complex treatments are not covered, and the response to the onset of lymphedema differs according to the treatment facility. Patients who develop lymphedema have to contend with it for long periods of time. In addition, the difference in the response noted between facilities delays the start of treatment and hampers continued treatment. Multidisciplinary collaboration is essential for patients to continue treatment without difficulty and face lymphedema with confidence. This study describes multidisciplinary collaboration methods to assist lymphedema patients as well as challenges for the future treatment of this disease.

An autopsy case of the Marburg variant of multiple sclerosis (acute multiple sclerosis).

We herein report an autopsy case of the Marburg variant of multiple sclerosis (MS). A 29-year-old woman developed acute and progressive neurological symptoms. A diagnosis of MS was suspected based on the patient's clinical background and brain MRI findings and the lack of evidence of malignancy on a brain biopsy. Despite the administration of typical treatment for MS, a fatal outcome occurred three months after disease onset. The autopsy revealed multiple inflammatory demyelinating lesions in the central nervous system. In addition, two noteworthy histopathological features were observed compared with prototypical MS. We evaluate the pathogenic differences between the Marburg type and prototypical MS by discussing the neuropathology and cerebrospinal fluid (CSF) findings of our case.

Development of a multi-step leukemogenesis model of MLL-rearranged leukemia using humanized mice.

Mixed-lineage-leukemia (MLL) fusion oncogenes are intimately involved in acute leukemia and secondary therapy-related acute leukemia. To understand MLL-rearranged leukemia, several murine models for this disease have been established. However, the mouse leukemia derived from mouse hematopoietic stem cells (HSCs) may not be fully comparable with human leukemia. Here we developed a humanized mouse model for human leukemia by transplanting human cord blood-derived HSCs transduced with an MLL-AF10 oncogene into a supra-immunodeficient mouse strain, NOD/Shi-scid, IL-2Rγ(-/-) (NOG) mice. Injection of the MLL-AF10-transduced HSCs into the liver of NOG mice enhanced multilineage hematopoiesis, but did not induce leukemia. Because active mutations in ras genes are often found in MLL-related leukemia, we next transduced the gene for a constitutively active form of K-ras along with the MLL-AF10 oncogene. Eight weeks after transplantation, all the recipient mice had developed acute monoblastic leukemia (the M5 phenotype in French-American-British classification). We thus successfully established a human MLL-rearranged leukemia that was derived in vivo from human HSCs. In addition, since the enforced expression of the mutant K-ras alone was insufficient to induce leukemia, the present model may also be a useful experimental platform for the multi-step leukemogenesis model of human leukemia.