A Self-Check Program Targeting Quality Improvement in a Hospital-Based Palliative Care Consultation Team, Japanese Society for Palliative Medicine: Issues Regarding Team Activities Identified through the Plan-Do-Check-Act Cycle.

Background: The number of hospital-based palliative care consultation teams (PCCTs) has increased in Japan, and quality improvement (QI) of PCCTs is an issue. The Japanese Society for Palliative Medicine is building a framework for continuous QI of PCCT activities. Objective: The objective of this study was to develop a program to support QI for PCCTs, and to describe the initial experience with the program. Design: The report details the development of a self-check program, followed by a one-year follow-up observational survey. Methods: We developed a self-check program using the concept of the Plan-Do-Check-Act (PDCA) cycle and a multidisciplinary expert panel. A total of 114 PCCTs entered the program in the first year. Results: We developed three forms for the CHECK, ACT-PLAN, and DO phases aligned with the PDCA cycle. The forms consisted of 34 items across 8 domains. A total of 83 PCCTs (729 members) returned the CHECK, ACT-PLAN forms, and 41 PCCTs returned the DO forms after one year. Overall, 213 high priority issues were identified in the ACT phase. The issues of many PCCTs were "Sharing goals of care is inadequate within the PCCT (33%)" and "Sharing goals of care is inadequate between patient/family or primary team and the PCCT (28%)." Improvements in identified issues were: "achieved" 23% and "almost achieved" 48% after one year. Conclusions: We developed a self-check program to support QI efforts for hospital-based PCCTs. The priority issues among PCCTs and improvement goals with examples were identified. These results will support ongoing efforts to develop a continuous improvement model for QI of PCCTs.

[Medroxyprogesterone Acetate as Part of Palliative Care for Terminal-Stage Breast Cancer Patients--A Report of Two Cases].

Various effective strategies have recently been described in the treatment of breast cancer, including endocrine therapy, chemotherapy, and molecular-targeted therapy, providing long-term survival benefits even after cancer recurrence. However, terminal-stage patients experience side effects and worse quality of life (QOL), in addition to deterioration of their general condition caused by the progression of the disease itself. When providing the best supportive care, use of anti-cancer drugs is not taboo and can represent a good option as long as physical, social, psychological, and spiritual supports are provided to both the patients and their families. Medroxyprogesterone acetate (MPA) is an endocrine therapeutic drug. In Japan, MPA is used only as a late-line endocrine therapy for breast cancer recurrence because many other endocrine therapy drugs are much more effective and MPA increases the risk of thrombosis and obesity. Here, we report 2 patients with breast cancer who reached terminal stage more than 10 years after the first diagnosis. MPA was administered as the final-line treatment. During that time, their appetite and QOL improved and the patients became more active than when they had been undergoing aggressive anticancer treatment. Both patients spent quality time with their families until their death. MPA may be a good option as part of palliative care of breast cancer patients in terminal stage.

Amphotericin B induces glial cell line-derived neurotrophic factor in the rat brain.

Amphotericin B (AmB) is a polyene antifungal drug and is reported to be one of a few reagents having therapeutic effects on prion diseases, that is, a delay in the appearance of clinical signs and prolongation of the survival time in an animal model. In prion diseases, glial cells have been suggested to play important roles; however, the therapeutic mechanism of AmB on prion diseases remains elusive. We have previously reported that AmB changed the expression of neurotrophic factors in microglia and astrocytes (Motoyoshi et al., 2008, Neurochem. Int. 52, 1290-1296; Motoyoshi-Yamashiro et al., 2013, ibid. 63, 93-100). These results suggested that neurotrophic factors derived from glial cells might be involved in the therapeutic mechanism of AmB. In the present study, we examined immunohistochemically the effects of AmB on the expression of neurotrophic factors in the rat brain. We found that direct injection of AmB into the striatum significantly enhanced the expression of glial cell line-derived neurotrophic factor protein. Amphotericin B also increased the expressions of CD11b and glial fibrillary acidic protein, markers of microglia and astrocytes, respectively. Moreover, expressions of the two neurotrophic factors by AmB were co-localized with the expression of CD11b or glial fibrillary acidic protein. These results suggest that AmB in vivo might also activate glial cells and induce the production of neurotrophic factors protecting neurons in prion diseases.

Activation of cultured astrocytes by amphotericin B: stimulation of NO and cytokines production and changes in neurotrophic factors production.

Amphotericin B (AmB) is a polyene antibiotic and reported to be one of a few reagents having therapeutic effects on prion diseases, such as the delay in the appearing of the clinical signs and the prolongation of the survival time. In prion diseases, glial cells have been suggested to play important roles by proliferating and producing various factors such as nitric oxide, proinflammatory cytokines, and neurotrophic factors. However, the therapeutic mechanism of AmB on prion diseases remains elusive. We have previously reported that AmB changed the expression of neurotoxic and neurotrophic factors in microglia (Motoyoshi et al., 2008, Neurochem. Int. 52, 1290-1296). In the present study, we examined the effects of AmB on cellular functions of rat cultured astrocytes. We found that AmB could activate astrocytes to produce nitric oxide via inducible nitric oxide synthase induction. AmB also induced mRNA expression of interleukin-1ß and tumor necrosis factor-α, and productions of their proteins in astrocytes. Moreover, AmB changed levels of neurotrophic factor mRNAs and proteins. Among three neurotrophic factors examined here, neurotrophin-3 mRNA expression and its protein production in the cells were down-regulated by AmB stimulation. On the other hand, AmB significantly enhanced the amounts of glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor proteins in the cells and the medium. These results suggest that AmB might show therapeutic effects on prion diseases by controlling the expression and production of such mediators in astrocytes.

Successful treatment of γ-heavy-chain disease with rituximab and fludarabine.

An 84-year-old Japanese man was admitted because of pancytopenia. The bone marrow was hypoplastic with a predominance of abnormal small lymphocytes and grape cells, which were positive for CD19 and CD20, and partially for the surface ĸ-light chain. Systemic CT scanning showed neither lymph node swelling nor hepatosplenomegaly. Serum immunoelectrophoresis and rocket immunoselection assays showed the presence of monoclonal IgG protein without a corresponding light chain and faint IgMĸ monoclonal protein. Histologic analysis of the clot preparation of the bone marrow aspirate facilitated a diagnosis of lymphoplasmacytic lymphoma (LPL). PCR analysis of the marrow cells demonstrated a clonal rearrangement of the immunoglobulin heavy-chain gene. From these results, we made a final diagnosis of γ-heavy-chain disease (γ-HCD) with underlying LPL localized in the bone marrow. We performed only a single course of immunochemotherapy (rituximab and fludarabine) in view of severely impaired hematopoiesis, which resulted in marked reduction of lymphoma cells and improvement of hematopoiesis. This report suggests the efficacy of rituximab plus fludarabine therapy for LPL-associated γ-HCD.

Extracellular superoxide dismutase in cultured astrocytes: decrease in cell-surface activity and increase in medium activity by lipopolysaccharide-stimulation.

Under pathological conditions such as ischemia/reperfusion, a large amount of superoxide anion (O(2) (-)) is produced and released in brain. Among three isozymes of superoxide dismutase (SOD), extracellular (EC)-SOD, known to be excreted outside cells and bound to extracellular matrix, should play a role to detoxify O(2) (-) in extracellular space; however, a little is known about EC-SOD in brain. In order to evaluate the SOD activity in extracellular space of CNS as direct as possible, we attempted to measure the cell-surface SOD activity on primary cultured rat brain cells by the inhibition of color development of a water-soluble tetrazolium due to O(2) (-) generation by xanthine oxidase/hypoxanthine added into extracellular medium of intact cells. The cell-surface SOD activity on cultured neuron and microglia was below the detection limit; however, that on cultured astrocyte was high enough to measure. By means of RT-PCR, all mRNA of three isozymes of SOD could be detected in the three types of the cells examined; however, the semi-quantitative analysis revealed that the level of EC-SOD mRNA in astrocytes was significantly higher than that in neurons and microglia. When astrocytes were stimulated with lipopolysaccharide (LPS) for 12-24 h, the cell-surface SOD activity decreased to a half, whereas the activity recovered after 36-48 h. The decrease in the activity was dependent on the LPS concentration. On the other hand, the SOD activity in the medium increased by the LPS-stimulation in a dose dependent manner; suggesting that the SOD protein localized on cell-surface, probably EC-SOD, was released into the medium. These results suggest that EC-SOD of astrocyte play a role for detoxification of extracellular O(2) (-) and the regulation of EC-SOD in astrocytes may contribute to the defensive mechanism against oxidative stress in brain.

[Amylase-producing multiple myeloma: a case report].

A 80-year-old man was admitted because of acute-onset thrombocytopenia and renal failure. He was diagnosed with Bence Jones (lambda) -type multiple myeloma associated with sepsis with methicillin-resistant Staphylococcus aureus. On admission, serum amylase activity was elevated to 1,814 IU/l (98% salivary type; S-amylase). Several days after admission, he developed bilateral myelomatous pleuritis. The activity of S-amylase in the effusion was 5,495 IU/l. Myeloma cells in the pleural effusion were positive for cytoplasmic amylase with an antibody against human amylase. High S-amylase activity was detected in the supernatant of cultured myeloma cells in the effusion. Furthermore, S-amylase gene expression was detected by RT-PCR. A diagnosis of amylase-producing multiple myeloma was made. The patient died of renal insufficiency complicated by severe DIC. We report a rare case of amylase-producing myeloma confirmed by immunocytochemistry, culture method, and gene expression.

[Two year investigation of glycosylation profiles in serum IgG from a patient with multiple myeloma].

Although abnormalities of glycosylation profile in serum IgG have been demonstrated in a variety of inflammatory autoimmune diseases such as rheumatoid arthritis, there are only a few reports describing long term monitoring of N-glycosylation profiles in such patients. Here we report the serial finding of N-glycosylation profiles of IgG-kappa M-protein in a patient with multiple myeloma monitored for two years. In this patient, serum formed a gel precipitation upon exposure to air. The HPLC mapping method demonstrated that IgG M-protein in the patient exhibited a significant decrease in the ratio of fucosyl to afucosyl N-glycans compared with that in a healthy control. With remission, the IgG M-protein showed an increase in this ratio, becoming closer to that in the healthy control. However, the gel-precipitation persisted. This finding suggested that this unique property of serum may not be related to the glycosylation profile of the M-protein.

In silico diagnosis of inherently inhibited gene expression focusing on initial codon combinations.

The translation start site, immediately downstream from the start codon, is a dominant factor for gene expression in Escherichia coli. At present, no method exists to improve the expression level of cloned genes, since it remains difficult to find the best codon combination within the region. We determined the expression parameters that correspond to all sense codons within the first four codons using GFPuv which encodes a derivative of green fluorescent protein. Using a genetic algorithm (GA)-based computer program, these parameters were incorporated in a simple, static model for the prediction of translation efficiency, and optimized to the expression level for 137 randomly isolated GFPuv genes. The calculated initial translation index (ITI), also proven for the DsRed2 gene that encodes a red fluorescent protein, should provide a solution to overcome the gene expression problem in cloned genes whose expression is often inherently blocked at the translation process. The proposed method facilitates heterologous protein production in E. coli, the most commonly used host in biological and industrial fields.

[Simultaneous presence of macroamylase and macrolipase in a patient with celiac disease].

Celiac disease is a permanent intolerance to ingested gluten that results in immunologically mediated inflammatory damage of the small intestinal mucosa. Here we report the case of a patient with Celiac disease demonstrating simultaneous macroamylasemia and macrolipasemia. The patient showed persistently elevated levels of serum amylase and lipase. Amylase and lipase in normal serum were eluted from a Superdex-200 column after the 4S protein. These enzymes in the serum from this patient were eluted in the 19S protein. This finding indicated that these enzymes from this patient had a molecular weight greater than that of normal amylase and lipase. Immunoprecipitation assay showed that amylase was bound to polyclonal IgG and IgA, whereas lipase was bound to polyclonal IgA. To our knowledge, the simultaneous presence of macroamylase and macrolipase in the same patient has been previously reported in only four cases. Interestingly, two of those patients had Celiac disease. If macroamylase and macrolipase are present, the possibility of Celiac disease should be considered.

[Immunochemical properties of free mu-chain protein in a patient with mu-heavy chain disease].

We report a case of mu-heavy chain disease. A 56-year-old woman presented with anemia and hemorrhagic diathesis. The serum of the patient was found to have free mu-heavy chain. The patient also had a kappa type-Bence Jones protein in serum and urine. Immunoelectrophoresis showed an abnormal precipitin line in the alpha 2-globulin region which reacted with antiserum to mu-chain but not with antiserum for light chains. The molecular weight of the monomer of the patient's mu-heavy chain protein was approximately 67,000 daltons less than that of the normal mu-heavy chain protein.

[A case with multiple myeloma in which serum forms gel precipitation upon exposure to air].

We present the case of a 69-years-old man who was admitted to hospital with multiple myeloma. IgG-kappa type monoclonal protein was detected in the serum. When we separated the serum obtained from blood sample of the patient and the lid of the collecting tube was opened, the patient's serum became gelled immediately. When the lid of the collecting tube remained closed, the patient's serum did not become gelled even at 4 degrees C. Moreover, the gelled serum of the patient did not resolve at 56 degrees C. Taken together, these results indicated that gel formation of the patient's serum may not be due to cryoglobulin. It was found that the pH of the patient's serum elevated to pH 8.0 quickly after exposed to air. It was also found that the patient's serum, but not the sera of other IgG-kappa multiple myeloma patients, became gelled as soon as PBS of pH 8.0 was added. These results highly suggest that the patient's serum becomes gelled at pH 8.0. However, the isoelectric focusing of isolated precipitation in the patient showed fractions around the pH 8.5-8.7 zone, which was different from the pH at which the precipitation began to form. We think that this may be the first report of a multiple myeloma patient whose serum becomes gelled after exposed to air.