A case of immune complex type hemolytic anemia induced by initial micafungin administration.

We report the first case of immune complex type hemolytic anemia by initial micafungin administration that was given as prophylaxis to a 42-year-old Japanese man receiving chemotherapy for primary amyloidosis. The few cases found in the literature were associated with secondary administration causing immune hemolytic attacks. Despite its rarity, the present case calls for increased awareness of micafungin-induced hemolytic anemia upon initial administration.

The experience of being a spouse of a person with dementia in respect to their marital relationship in Japan.

BACKGROUND AND PURPOSE: While the marital relationship with partners with dementia has an impact on spousal carers' well-being, the spousal understandings or expectations of their marital relationship have not been fully identified. As the marital relationship is formed by individual backgrounds including society, culture and psychological status, the aim of this study was to identify the experience of being the spouse of a person with dementia in the context of their marital relationship. The study was conducted in Japan. RESEARCH DESIGN: To identify spousal experience of being, Heideggerian perspectives of interpretive phenomenology were applied. STUDY SAMPLE: Seven couples aged over 65 years, each comprising one partner with dementia who received home nursing, and their spouse participated in this study. DATA COLLECTION: The couples were observed, and semi-structured interviews were conducted. DATA ANALYSIS: Interpretive data analysis based on the Hermeneutic circle of Heideggerian perspectives was applied. RESULTS: In the findings, the experience of being a spouse, contextualised by spousal understandings of marital relationship, was formed through seven themes. The main context for spousal understanding of their marital relationship was helping each other as husband and wife, and this relationship was seen as natural and unchanging. It reflected on spousal potentiality of being, that is, living together indefinitely as before. Spouses tried to provide suitable care for their partners using memories while preserving a sense of identity, maintaining external relationships and accepting unanticipated internal responsibility. CONCLUSIONS: In conclusion, fulfilling unmet needs could help spouses to ease intense care load, which re-acknowledges their own and their partner's identity, and their relationship by reminiscing their past.

Epidemiological study of gastroenteropancreatic neuroendocrine tumors in Japan.

BACKGROUND: There have been few epidemiological studies on gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in Japan. METHODS: We examined the epidemiology of GEP-NETs [pancreatic endocrine tumors (PETs) and gastrointestinal neuroendocrine tumors (GI-NETs)] in Japan in 2005 using a nationwide stratified random sampling method. RESULTS: A total of 2,845 individuals received treatment for PETs. Prevalence was estimated as 2.23/100,000 with an annual onset incidence of 1.01/100,000. Non-functioning tumor (NF)-PET constituted 47.4%, followed by insulinoma (38.2%) and gastrinoma (7.9%). Distant metastases were reported in 21% patients with NF-PETs and occurred more frequently as tumor size increased (>2 cm). Multiple endocrine neoplasia type 1 (MEN-1) was detected in 10% of PETs but only in 6.1% of NF-PETs. NF-PETs were detected incidentally by physical examination in 24% patients. In 2005, an estimated 4,406 patients received treatment for GI-NETs. Prevalence was estimated as 3.45/100,000, with an annual onset incidence of 2.10/100,000. The locations of GI-NETs varied: foregut, 30.4%; midgut, 9.6%; and hindgut, 60.0%. Distant metastases were observed in 6%. Lymph node metastases occurred more frequently as tumor size increased (>1 cm). The frequency of MEN-1 complications was 1%. Physical examination revealed GI-NETs in 44% patients. The frequency of symptomatic GI-NETs was 3.4%. Interestingly, 77.1% of patients with foregut GI-NETs had type A gastritis. CONCLUSION: Our results show there are large differences in GEP-NETs between Japan and Western nations, primarily due to differences in the presence of MEN-1 in NF-PETs and the location, symptomatic status, and prevalence of malignancy in GI-NETs.

Diabetic mastopathy of bilateral breasts in an elderly Japanese woman with type 2 diabetes: a case report and a review of the literature in Japan.

We report a case of diabetic mastopathy in an elderly woman with type 2 diabetes. The patient was a 69-year-old woman diagnosed with type 2 diabetes at the age of 33 years. She had been treated with insulin for 25 years, however, her blood glucose had been poorly controlled. She noticed bilateral breast lumps in September 2002. Mammography of the breast showed increased density in the glandular pattern and architectural distortion without focal mass and microcalcification. Ultrasonography of the breast showed an irregular-shaped hypoechoic mass with an acoustic shadow. As malignancy needed to be excluded, core needle biopsy was performed in the left breast and diabetic mastopathy was confirmed pathologically. Diabetic mastopathy is usually a complication of pre-menopausal type 1 diabetes and develops in a unilateral breast. This case developed in bilateral breasts in an elderly type 2 diabetic patient.

Preliminary results of a Japanese nationwide survey of neuroendocrine gastrointestinal tumors.

BACKGROUND: We conducted a nationwide survey to estimate the incidence of neuroendocrine gastrointestinal tumors (NETs) newly diagnosed in Japan from 2002 through 2004. METHODS: Data on 1541 patients, 514 pancreatic endocrine tumors (PETs) and 1027 gastrointestinal carcinoids (GICs), were collected and analyzed. RESULTS: Nonfunctioning tumors (NF-PET) constituted 47.7% of PETs. Next in frequency were insulinoma (31.7%) and gastrinoma (8.6%). Malignancy was frequent in NF-PETs (46.1%) and gastrinomas (45.5%), but only 7.4% of insulinomas were malignant. The incidence of multiple endocrine neoplasia type-1 associated with PETs was 7.4%. The incidence of GICs was 28.8%, 5.2%, and 66.0% in foregut, midgut, and hindgut, respectively. Carcinoid syndrome and metastases were observed in only 1.7% and 5.6% of GICs, respectively. CONCLUSIONS: The incidence of NETs in Japan was clarified by this preliminary study. Comparatively large differences in GICs between Japan and Western nations were present with regard to the location, symptomatic status, and prevalence of malignancy.

Muscle afferent contributions to tibial nerve somatosensory evoked potentials investigated using knee stimulations.

OBJECTIVE: To investigate the contribution of muscle afferents to tibial nerve somatosensory evoked potentials (SEPs). METHODS: The left tibial nerve was stimulated at the knee and ankle in eight normal subjects. We tried to selectively stimulate Ia fibers from the calf muscles at the popliteal fossa by subtly changing the stimulation site while monitoring the H-waves of the calf muscles and sensory events. RESULTS: Selective or predominant Ia stimulation at the knee was achieved in seven subjects, and evoked a significantly smaller first cortical component (labeled as P38 for both ankle and knee stimulations) than that evoked by ankle stimulation or by mixed stimulation of the foot branch and muscle afferents at the knee. The P38 following mixed stimulation at the knee was smaller than that following ankle stimulation in six out of eight subjects, which must be due to a partial gating mechanism and also indicates that calf Ia afferent SEPs are not extremely large. CONCLUSIONS: Physiologically important muscle afferents from the large calf muscles evoked rather small cortical components. SIGNIFICANCE: It seems reasonable to infer that the contribution of muscle afferents from the small intrinsic foot muscles to routine tibial nerve SEPs following ankle stimulation is even smaller.

Acute liver dysfunction complicated with uncontrollable glycemia due to insulin antibody: successful treatment with glucocorticoid and lispro insulin.

Here, we report a case of acute liver dysfunction complicated with uncontrollable glycemia due to insulin antibody. The patient was admitted to our hospital due to diabetic ketoacidosis. He was administered insulin immediately, however, his fasting plasma glucose level remained unstable despite the insulin treatment. Blood biochemistry revealed severe liver dysfunction, although no markers including hepatitis virus or autoantibodies associated with autoimmune liver diseases were detected. The 125I-insulin binding rate was high (54%). The characteristics of insulin antibody in this patient were similar to the antibodies of IAS patients, therefore we administered oral glucocorticoid against insulin antibody. The reduction in the 125I-insulin binding rate and the binding capacity of the high affinity site of insulin antibodies were balanced after oral glucocorticoid therapy. In addition, preprandial subcutaneous regular insulin was switched to lispro insulin. Postprandial plasma glucose levels were relatively improved by lispro insulin. The etiology of acute liver dysfunction was unknown, however, we believe that the combination of oral glucocorticoid and lispro insulin was suitable and useful for preventing recurrent liver dysfunction in this patient.

Primary hyperparathyroidism associatiated with aldosterone-producing adrenocortical adenoma and breast cancer: relation to MEN1 gene.

A rare case of primary hyperparathyroidism associated with primary aldosteronism and breast cancer is reported. A 44-year-old woman was admitted to our hospital to undergo surgical removal of breast cancer. She had hypertension with low serum potassium, and slightly but significantly elevated serum calcium levels. Further studies demonstrated an enlarged left superior parathyroid gland and a left aldosterone-producing adrenocortical adenoma. Blood pressure was controlled with spironolactone and nifedipine, and left mastectomy was done for breast cancer. The pathological diagnosis was scirrhous breast carcinoma. Although the postoperative course was uneventful, her serum calcium gradually and progressively rose to higher levels. Left superior parathyroidectomy and left adrenalectomy were then performed simultaneously. The pathological diagnoses of the resected parathyroid gland and adrenal gland were parathyroid chief cell adenoma and adrenocortical adenoma with hyperplasia of zona glomerulosa, respectively. To clarify if the occurence of these tumors may be related to MEN1 gene mutations, we analyzed MEN1 gene in this patient, and found a loss of heterozygosity of the MEN1 locus in the parathyroid adenoma and breast cancer. Thus, we conclude that an alteration of the MEN1 gene and/or another tumor suppressor gene located at the MEN1 locus on chromosome 11q13 may be responsible for the development of parathyroid adenoma and breast cancer in our patient suggesting that the clinical spectrum of MEN1 might include breast cancer. In addition, serum calcium should be interpreted with caution in primary aldosteronism, because hypercalcemia may be masked in the presence of aldosterone excess.

[The diagnosis and treatment of insulinoma and gastrinoma].

The gastroenteropancreatic endocrine tumor is relatively rare tumor that originate from pancreas, duodenum, and a variety of neuroendocrine cells. The differential diagnosis and preoperative localization of the tumor are important, because surgical resection of the tumor is the first choice of treatment. Of these tumors, insulinomas and gastrinomas are usually small in size (less than 2.0 cm), and methods of preoperative localization such as ultrasonography, computed tomography or magnetic resonance imaging often fail to identify them. These tumors often malignant, and tumors as small as 1 to 2 mm might develop lymph node metastases especially in gastrinomas. Recent studies have shown that selective arterial calcium stimulation test and hepatic venous sampling using intraarterial calcium injection as the insulin secretagogue are useful for detection of small insulinomas, and the selective intraarterial injection of secretin test combined with venous sampling (Imamura technique), for detection of small gastrinomas. In addition, somatostatin-receptor scintigraphy is widely used in Western countries. Moreover, detection of the tumor during operation using ultrasonography delivered much better results than preoperative diagnoses. These tumors may be associated with multiple endocrine neoplasia type 1, and MEN1 gene mutation analysis is necessary in those patients.

Frequency and significance of anti-glutathione S-transferase autoantibody (anti-GST A1-1) in autoimmune hepatitis.

Several phase I and phase II multi-drug metabolizing enzymes, such as CYP2D6, 3A4, and UGTA1, were reported to act as immunotargets in a subset of autoimmune hepatitis and hepatic autoimmunity. However, it is uncertain whether glutathione S-transferase (GST) A1-1, one of the phase II multi-drug metabolizing enzymes, is also an immunotarget in autoimmune hepatitis. So, in the present study, we investigated the frequency and significance of anti-GST A1-1 in sera from patients with autoimmune hepatitis. A total of 74 serum samples from patients with autoimmune hepatitis were examined in the present study. As controls, 20 serum samples from patients with primary biliary cirrhosis, 10 serum samples from patients with primary sclerosing cholangitis, 40 serum samples from patients with liver cirrhosis type B and C, 32 serum samples from patients with systemic lupus erythematosus, and 20 serum samples from normal controls were used. Anti-GST A1-1 antibody was determined by immunoblotting using the recombinant full-length GST A1-1 protein as the antigen. The immunofluorescent staining pattern of anti-GST A1-1 was investigated using rat liver and kidney sections. We compared clinicopathologic findings between anti-GST A1-1-positive and -negative autoimmune hepatitis patients. Anti-GST A1-1 was detected in 12 (16%) of 74 patients with autoimmune hepatitis, however, it was not detected in any control serum samples except for two patients with primary biliary cirrhosis. The immunofluorescence staining pattern of anti-GST A1-1 was found to be unique and different from those of anti-mitochondrial antibody or anti-liver-kidney microsome type 1 antibody. Anti-GST A1-1 coexisted with other autoantibodies such as anti-nuclear or anti-smooth muscle antibodies, but did not coexist with anti-soluble liver antigen/liver pancreas. Anti-GST A1-1-positive autoimmune hepatitis patients had severe clinical features and a poor prognosis compared with anti-GST A1-1-negative patients. These findings suggested that despite the low frequency, anti-GST A1-1 might be the marker of an early progression in autoimmune hepatitis.

[Phase III additional clinical study of 111In-pentetreotide (MP-1727): diagnosis of gastrointestinal hormone producing tumors based on the presence of somatostatin receptors].

Additional phase III multicenter clinical study was performed to investigate the efficacy, safety, and usefulness of somatostatin receptor scintigraphy using 111In-pentetreotide (MP-1727), which binds to somatostatin receptors. Forty patients were included in the study; Group A: 18 patients, gastrointestinal hormone producing tumors had been detected with conventional imaging modalities, Group B: 22 patients, no tumors had been detected with conventional imaging modalities in spite of high serum hormone levels. By comparing the results of the octreotide suppression test, 12/16 cases (75.0%) of Group A and 11/19 cases (57.9%) of Group B were assessed as "effective." By comparing the results of immunohistological examination, 5/9 cases (55.6%) of Group A and 2/4 cases (50.0%) of Group B were assessed as "effective." Severe adverse events were not observed in any of the evaluable 35 cases. MP-1727 was judged as clinically useful in 11/16 cases (68.8%) of Group A and 5/19 cases (26.3%) of group B. These results suggest that MP-1727 scintigraphy is very useful for the diagnosis and decision of the therapeutic strategy of gastrointestinal hormone producing tumors.

Immunoreactivity to pyruvate dehydrogenase complex-E2 in well-defined patients with autoimmune hepatitis: Western blot analysis.

Anti-mitochondrial antibodies (AMA) are frequently detected in sera from patients with primary biliary cirrhosis (PBC). Major autoantigens for AMA have been identified as members of the 2-oxoacid dehydrogenase enzyme complex family, with pyruvate dehydrogenase complex (PDC)-E2 showing strongest reactivity to AMA in PBC patients. Recently, anti-PDC-E2 has been found in patients with other diseases. Since frequency and significance of anti-PDC-E2 in patients with autoimmune hepatitis (AIH) remain obscure, we measured anti-PDC-E2 in sera from well-defined AIH cases by Western blotting using bovine heart mitochondrial protein and recombinant PDC-E2 protein as antigen sources. All 55 enrolled patients fulfilled the international diagnostic criteria for definite or probable AIH. Anti-PDC-E2 positivity showed concordance between native and recombinant antigens. Anti-PDC-E2 was detected in nine of 55 sera from AIH patients (16%). Variables including alkaline phosphatase (ALP) and IgM concentrations, effects of prednisolone, and pathologic findings concerning bile ducts showed no significant differences between anti-PDC-E2-positive and anti-PDC-E2-negative AIH patients. These data indicate that detection of anti-PDC-E2 is not rare in defined AIH, but anti-PDC-E2-positive AIH does not represent an intermediate entity in a clinical spectrum between AIH and PBC.

Appearance of human plasma cells following differentiation of human B cells in NOD/SCID mouse spleen.

Relatively little is known for the differentiation and maturation process of human B cells to plasma cells. This is particularly important in reconstitution work involving transfer of autoantibodies. To address this issue, we transplanted human peripheral blood mononuclear cells (PBMC) directly into the spleen of irradiated NOD/SCID mice depleted of natural killer cell activity. Within 6 weeks, naive B cells differentiated into memory B cells and, importantly, the numbers of human CD138+ plasma cells in spleen increased by 100 fold after transplantation. Plasma cell numbers correlated with the detection of human IgM and IgG in serum, indicating that human B cells had differentiated into mature plasma cells in the murine spleen. In addition to CD19+ plasma cells, a distinct CD19- plasma cell population was detected, suggesting that downregulation of CD19 associated with maturation of plasma cells occurred. When purified human B cells were transplanted, those findings were not observed. Our results indicate that differentiation and maturation of human B cells and plasma cells can be investigated by transplantation of human PBMC into the spleen of NOD/SCID mice. The model will be useful for studying the differentiation of human B cells and generation of plasma cells.

Intestinal cryptosporidiosis as an initial manifestation in a previously healthy Japanese patient with AIDS.

BACKGROUND: Cryptosporidium parvum infection has been recognized as one of the pathogens causing severe and persistent diarrhea in immunodeficient patients, such as those with AIDS, worldwide. However, in Japan, the frequency of this infection has been rare, except for environmental contamination through the water supply. In this communication, we describe a Japanese patient with AIDS presenting with intestinal Cryptosporidiosis as an initial manifestation. METHODS: The oocysts of Cryptosporidium parvum in his stool were detected by the Ziehl-Neelsen method and electron microscopy. The antigen-specificity was proved by immunostaining, using a fluorescein isothiocyanate (FITC)-labeled monoclonal antibody and enzyme-linked immunosorbent assay (ELISA), using Cryptosporidium-specific antibody. RESULTS: A 28-year-old Japanese homosexual man was admitted to our hospital because of severe watery diarrhea of 1-week duration. Numerous oocysts of Cryptosporidium parvum were observed in his stool. Cryptosporidium parvum antigen was detected in stool samples. Serological examinations revealed that anti-HIV-1 antibody was positive, and HIV RNA was positive at a high level. He was diagnosed as having AIDS associated with intestinal Cryptosporidiosis. The circulating CD4+ T-cell count was 152/microl. His diarrhea was not alleviated by administration of loperamide and an ordinary antibiotic agent, but ultimately resolved by the administration of the macrolide antibiotic agent, clarithromycin. CONCLUSIONS: We emphasize that the presence of Cryptosporidium parvum infection should be kept in mind in searching for pathogens causative of severe diarrhea in AIDS patients.