Population pharmacokinetic analysis of meropenem in Japanese adult patients.

WHAT IS KNOWN AND OBJECTIVE: Meropenem is frequently employed as an empirical treatment for serious infections, but there has been no report on its population pharmacokinetic parameters for Japanese patients. Our aim is to undertake a population pharmacokinetic analysis of meropenem using non-linear mixed effects model (NONMEM). METHODS: Data from 68 patients were analysed via NONMEM with the first-order method. The participants' covariates, including gender, age, actual body weight, serum creatinine, serum albumin, serum total protein and creatinine clearance, were analyzed by the forward inclusion and backward elimination method to identify their potential influence on meropenem pharmacokinetics. The adequacy of the constructed model was assessed by goodness-of-fit plots and the precision of the parameter estimated at each step of the model development. To assess the robustness of the estimated parameter, bootstrap analysis was performed. RESULTS AND DISCUSSION: The data were best described by a one-compartment model. The serum creatinine values modified by the below normal limit in our hospital (mSCR) were an influential covariate for clearance (CL): CL (L/h) = 11·1 × (mSCR/0·7)(-1). The volume of distribution was estimated as 33·6 L. The coefficient of variation of the inter-individual variability of CL and the residual variability were 52·1% and 0·827% µg/mL, respectively. A comparison of the population pharmacokinetic parameters of meropenem in the final model estimated in NONMEM with original data, and 1000 bootstrap samples shows that both sets of estimates were comparable, thereby indicating the robustness of the proposed model. WHAT IS NEW AND CONCLUSION: A population pharmacokinetic model that satisfactorily described the disposition and variability of meropenem in our Japanese population is described. NONMEM analysis showed that the clearance of meropenem depended on modified serum creatinine. The results of this study should help Japanese patients on meropenem by improving the prediction accuracy of dosing using the Bayesian method.

Prevention of graft-versus-host disease by intrabone marrow injection of donor T cells: involvement of bone marrow stromal cells.

We have developed a new and effective method for bone marrow transplantation (BMT): bone marrow cells (BMCs) are injected directly into the bone marrow (BM) cavity of recipient mice. The intrabone marrow injection of BMCs (IBM-BMT) greatly facilitates the engraftment of donor-derived cells, and IBM-BMT can attenuate graft-versus-host reaction (GVHR), in contrast to conventional intravenous BMT (i.v.-BMT). Here, we examine the mechanisms underlying the inhibitory effects of IBM-BMT on GVHR using animal models where GVHR is elicited. Recipient mice (C57BL/6) were irradiated and splenic T cells (as donor lymphocyte infusion: DLI) from major histocompatibility complex-disparate donors (BALB/c) were injected directly into the BM cavity (IBM-DLI) or injected intravenously (i.v.-DLI) along with IBM-BMT. The BM stromal cells (BMSCs) from these recipients were collected and related cytokines were examined. The recipient mice that had been treated with IBM-BMT + i.v.-DLI showed severe graft-versus-host disease (GVHD), in contrast to those treated with IBM-BMT + IBM-DLI. The suppressive activity of BMSCs in this GVHD model was determined. The cultured BMSCs from the recipients treated with IBM-BMT + IBM-DLI suppressed the proliferation of responder T cells remarkably when compared with those from the recipients of IBM-BMT + i.v.-DLI in mixed leucocyte reaction. Furthermore, the level of transforming growth factor-beta and hepatocyte growth factor in cultured BMSCs from IBM-BMT + IBM-DLI increased significantly when compared with those from the recipients of IBM-BMT + i.v.-DLI. Thus, the prevention of GVHD observed in the recipients of IBM-BMT + IBM-DLI was attributable to the increased production of immunosuppressive cytokines from BMSCs after interaction with host reactive T cells (in DLI).

Transplantation of newborn thymus plus hematopoietic stem cells can rescue supralethally irradiated mice.

We attempted to rescue supralethally irradiated (SLI) mice by transplantation of hematopoietic stem cells (HSCs) plus thymus from variously aged donors (fetus, newborn and adult). Although the transplantations of these kinds of HSCs alone showed a very short survival, newborn liver cells (NLCs) (as the source of HSCs) plus newborn thymus (NT) transplantation markedly improved the survival rate. The transplantation attenuated severe damage in the small intestine, which is one of the major causes of death by SLI. In addition, the donor-derived CD4(+) T cells significantly increased with additional NT transplantation. The production of interleukin (IL)-7 and keratinocyte growth factor, which plays a crucial role in protection against radiation injury in the intestine, was the highest in NT. Finally, SLI mice that had received NLC plus IL-7(-/-) NT transplantation plus IL-7 injection showed improved survival, weight recovery and an elevated number of CD4(+) T cells compared with the mice that had received NLC plus IL-7(-/-) NT or plus IL-7 injection alone. These findings suggest that NLCs plus NT transplantation can rescue SLI mice most effectively, and that high production of IL-7 in NT plays a crucial role with induction of CD4(+) T cells.

Relationship of p53, Bcl-2, Ki-67 index and E-cadherin expression in early invasive breast cancers with comedonecrosis as an accelerated apoptosis.

AIMS: To study the relationship between comedonecrosis formation and morphology, apoptosis, and p53, Bcl-2, Ki-67 index and E-cadherin expression in early invasive breast cancer. EXPERIMENTAL DESIGN: Early invasive breast cancers were first divided into two groups according to the presence (CN+ tumours) or absence (CN- tumours) of comedonecrosis. The histological grade, apoptosis, and expression of E-cadherin, Ki-67, p53 and Bcl-2 in the cancer-affected area, and in normal ducts from the specimen, were then examined. RESULTS: Less tubule and gland formation was seen in CN+ tumours than in CN- tumours, although the histological grade between the groups was not different. During early comedonecrosis, cells undergo apoptosis and subsequent necrosis. p53 was higher in CN+ tumours than in CN- tumours and normal ducts, whereas Bcl-2 was lower in CN+ tumours than in CN- tumours and normal ducts. Both tumours had higher Ki-67 than in normal ducts, but no difference was evident between the tumours. CN+ tumours had slightly higher E-cadherin than that in CN- tumours, but lower than that in normal ducts. The level of comedonecrosis was positively correlated with p53, but inversely correlated with Bcl-2 in all tumours, and p53 and Bcl-2 were inversely correlated with each other. Furthermore, comedonecrosis and p53 were correlated with Ki-67 in CN+ tumours, and Bcl-2 was correlated with Ki-67 in CN- tumours. CONCLUSION: Comedonecrosis may be actively regulated through an apoptotic procedure in massive cancers for their survival and progression, and the above proteins may be associated cooperatively in this process. CN+ and CN- tumours may have opposite proliferative systems under the p53-Bcl-2 pathway.

[Extralobar pulmonary sequestration with aberrant lobulation of the lower lobe; report of a case].

An adult case of extralobar pulmonary sequestration with aberrant lobulation of the right lower lobe is reported. A 32-year-old woman admitted to our hospital with a right intrathoracic tumor in the chest computed tomography (CT). Chest CT showed a mass lesion on the right diaphragm of a diameter 5 cm and abnormal fissure of the right lower lobe. Under the diagnosis of pulmonary sequestration without clearly thick vessels, video-assisted thoracoscopic surgery was performed. The mass existed between the right diaphragm and posterior lower lobe with a thin stalk, and the lower lobe had aberrant lobulation. The resected mass was histopathologically diagnosed as extralobar pulmonary sequestration.

[Clinicopathologic study of thymic epithelial tumors].

OBJECTIVE: We analyzed clinicopathologic characters and long-term results of 11 thymic epithelial tumors. METHODS: Five cases of thymic carcinoma and 6 cases of thymoma treated in our hospital from September 1991 to June 2002 were retrospectively analyzed. RESULTS: The histological subtypes of thymic carcinoma were basaloid carcinoma in 2 cases, epidermoid non-keratinizing carcinoma in 1 case, undifferentiated carcinoma in 1 case and sarcomatoid carcinoma in 1 case. Four cases underwent chemotherapy and radiotherapy. Three cases underwent midsternal thoracotomy, 1 had total resection and 2 had exploratory thoracotomy due to tumor invasion of the right upper lobe and cardiac sac. Two cases of basaloid carcinoma had been alive more than 10 years since the operation. The histological subtypes of thymoma were 1, 2, 1, 1 and 1 cases with type A, AB, B 1, B 2 and B 3. All cases underwent midsternal thoracotomy, 4 cases had thymothymectomy and 2 cases had extended thymothymectomy. Five cases have been alive since the operation. Strong immunoreactivity for bcl-2 and p 53 expression of epidermoid non-keratinizing carcinoma and undifferentiated carcinoma were seen. ki-67 labeling index of epidermoid non-keratinizing carcinoma and undifferentiated carcinoma and type B 3 thymoma were higher than those of the other carcinomas and thymomas.

Auto-MHC class II-reactive T cell line obtained from MRL/+ mice suffering from lpr-GVHD. II. Analyses of functional characteristics of T cell line by in vivo administration.

Functional characteristics of an autoreactive (I-Ek-restricted) T cell line (l/+ T1), previously established from MRL/M(p-)+/+(MRL/+) mice with lpr-GVHD, were analyzed in vivo. Intravenous injection of l/+ T1 cells to non-irradiated H-2k (MRL/+ or AKR) mice (but not H-2d mice) induced enhanced spontaneous proliferation of recipient spleen cells; this was also I-Ek self-restricted. This augmented self-reactivity seemed to be mediated by recipient L3T4+ T cells, since few l/+ T1 cells were detected in the spleen cells of l/+ T1-injected AKR mice by cell surface marker analyses, and the treatment of the spleen cells with anti-Thy-1.1 antibody (Ab) or anti-L3T4 Ab plus complement abolished this enhanced spontaneous proliferation. The production of IgM rheumatoid factor (RF) in AKR mice and IgG RF in MRL/+ mice increased, although no enhancement of anti-ssDNA Ab production was observed. Judging from both spleen B cell proportion and serum Ig levels, autoantibody induction by the injection of l/+ T1 cells was not associated with polyclonal B cell activation. When lethally irradiated B10 congenic mice were used as recipients, B10. BR mice showed elevated levels of IgM anti-ssDNA and IgM RF 1 wk after l/+ T1 cell injection; it is likely that lethal irradiation causes autoantigens, particularly DNA, to be exposed. These findings suggest that the autoreactivity of l/+ T1 cells can be transferred to recipient L3T4+ T cells via T-T interaction or the immunological network, and that increased autoreactivity induces autoantibody production in the presence of autoantigen stimulation. In contrast to the stimulatory effects observed in AKR and MRL/+ mice, MRL/Mp-lpr/lpr(MRL/lpr) mice showed a different response to the injection of l/+ T1 cells; spontaneous proliferation of spleen cells and autoantibody production were not enhanced, and suppression of the mitogen responses was observed. It is discussed that lpr-GVHD may be due to these unusual features of MRL/lpr mice.

Analyses of lpr-GVHD by adoptive transfer experiments using MRL/lpr-Thy-1.1 congenic mice.

When MRL/Mp- +/+ (MRL/+) mice are lethally irradiated and then reconstituted with MRL/Mp-lpr/lpr (MRL/lpr) spleen and/or bone marrow cells (BMCs), the mice develop a graft-versus-host disease (GVHD)-like syndrome which is known as lpr-GVHD. We analyzed lpr-GVHD by adoptive transfer experiments using congenic MRL/lpr-Thy-1.1 mice to distinguish the donor and recipient cells. MRL/+ mice were lethally (9.5 Gy) irradiated and then reconstituted with BMCs of MRL/lpr-Thy-1.1 mice treated with anti-Thy-1.1 monoclonal antibody (mAb) plus complement (C). The mice were sacrificed 5 to 6 weeks after bone marrow transplantation (BMT), and the spleen cells were transferred to second recipients. The second recipients (MRL/+ or MRL/lpr mice) were non-irradiated, sublethally (6 Gy) irradiated or lethally (9.5 Gy) irradiated. The lethally irradiated mice were also injected with syngeneic BMCs treated with anti-Thy-1.2 mAb plus C. When whole spleen cells (1 x 10(8) were injected into lethally irradiated MRL/+ mice, the mice showed short survival (1.2-1.5 months) and severe histological changes in the spleen (atrophy and fibrosis), liver (lymphoid infiltration in the Glisson's sheath) and lung (lymphoid infiltration around the bronchus and vessel). The sublethally irradiated MRL/+ mice at 2 months after transfer showed histological changes similar to the lethally irradiated MRL/+ recipients, although the former survived more than 3 months, suggesting that histological changes do not reflect on mortality. These GVH-like diseases were not transferable to MRL/lpr mice; they developed autoimmune diseases.(ABSTRACT TRUNCATED AT 250 WORDS)

A new view of the so-called adenoma malignum of the uterine cervix.

Adenoma malignum of the uterine cervix (mucinous type of minimal deviation adenocarcinoma, mucinous MDA), is a unique neoplasm that is difficult to diagnose owing to the deceptively benign appearance of the tumour cells. The present study was undertaken to explore the phenotypic expression of this tumour compared with those of non-neoplastic cervical tissues and of cervical carcinomas of various types. Ten cases of mucinous MDA, 50 cases with non-neoplastic cervical tissues, 13 of cervical adenocarcinoma including the mucinous (endocervical or intestinal type) and endometrioid types, and 2 of mucoepidermoid carcinoma were examined by various histochemical staining methods, including those for gastric mucins, pepsinogen, lysozyme, chromogranin A and carcinoembryonic antigen. The results revealed that mucinous MDA characteristically exhibited gastric phenotypes. The presence of gastric metaplasia was also demonstrated in 9 cases of mucinous MDA and in 5 of the other cases examined. The 7 endocervical-type adenocarcinomas also included 4 that expressed gastric phenotypes, and 2 of the 3 intestinal-type adenocarcinomas showed the same properties focally. These results indicate the presence of a group of lesions expressing gastric phenotypes in the uterine cervix and suggest a close relationship between these lesions. Cervical adenocarcinomas expressing gastric phenotypes are probably derived from MDA.

Potential flow of alpha activity in the human electroencephalogram.

The movement of potential field of alpha activity was investigated with a potential flow technique, alpha activity was divided into slow, medium and fast subbands. The peak-to-peak amplitude and source density distribution of each subband was also constructed. The potential flow of medium alpha was from medial to lateral in the anterior region, and from lateral to medial in the posterior region. The flow patterns of slow and fast alpha were more complicated. Similar flow directions formed a group. Different groups met or diverged at discontinuous grid points around the local maxima of potential distribution. The discontinuous points of medium alpha were centered in the parieto-occipital region, and those of slow and fast alpha were more equally distributed over the scalp. Against potential gradients, several groups of similar flow directions participated in the formation of potential field. The generation of potential field was assumed to be controlled widely for medium alpha and locally for slow and fast alpha.

Immunoblastic lymphadenopathy-like T-cell lymphoma complicated by multiple gastrointestinal involvement.

We report a rare case of immunoblastic lymphadenopathy (IBL)-like T-cell lymphoma complicated by multiple gastrointestinal involvement, which appeared to be ameliorated by chemotherapy but resulted in perforative peritonitis. A 66-year-old Japanese woman who had generalized lymphadenopathy and eruptions was admitted to our hospital because of bloody stool. Colonoscopic examination revealed hemorrhagic ulcers in the terminal ileum and a saucer-like ulcer in the cecum. Gastrointestinal endoscopy revealed several ulcerative or elevated lesions in stomach and duodenum. Biopsy specimens of these lesions and of a lymph node showed characteristic histological features of IBL-like T-cell lymphoma. The initial treatment with prednisolone (PSL) and cyclophosphamide (CPA) was effective. Six months after the treatment, however, she developed bloody stool again caused by multiple ulcerative lesions in the large intestine. The recurrence of the disease was determined histologically, and four courses of CPA, PSL, vinblastine sulfate and doxorubicin hydrochloride (CHOP) therapy were administered. One month after completing the CHOP therapy, she developed intestinal obstruction and then acute peritonitis resulting from perforation at an ulcer scar in the jejunum. Surgical treatment was successful, and histological examination demonstrated no lymphoma cells in the resected specimen. A gastrointestinal perforation should be recognized as a potential complication of IBL-like T-cell lymphoma, even during remission.

Correlation of immunohistochemical p53 labeling index with inhibition rate in chemosensitivity test in gastric and colon cancer.

To determine whether the expression of p53, p21, bcl-2 or Ki-67 in cancer cells is predictive of chemosensitivity, immunohistochemical examination of these factors and chemosensitivity assays were performed on colon and gastric cancer specimens. Chemosensitivity tests were performed using CDDP, 5-FU, MMC, or ADR and inhibition rate (IR) was calculated by MTT assay. Before exposure to anticancer drugs, the samples were investigated immunohistochemically for expression of the above factors and after anticancer drug exposure by TUNNEL staining, for the presence of apoptotic cells. With 5-FU and MMC, the apoptotic index was well correlated with IR, so their effects were related to apoptosis. Moreover, with these two agents, the p53 labeling index (LI) was inversely correlated with IR and p21-LI showed a good correlation with IR. We therefore concluded that immunohistochemical studies for p53 and p21 were useful for predicting the chemosensitivities of colon and gastric cancer to MMC and 5-FU.

Induction of immune-mediated hearing loss in SCID mice by injection of MRL/lpr mouse spleen cells.

Induction of immune-mediated hearing loss in SCID mice by injection of MRL/lpr mouse spleen cells The MRL/lpr mouse, which has a mutation in the Fas gene encoding a cell-surface receptor for apoptosis, shows an accumulation of abnormal immunocompetent cells and SLE-like disease. It has recently been reported that this mouse also manifests sensorineural hearing loss (SHL) with cochlear pathology at 20 weeks of age. We examined the effects of injecting MRL/lpr spleen cells on the development of SHL in severe combined immunodeficient (SCID) mice, which originally develop neither SHL nor cochlear pathology. Immune-mediated SHL and cochlear pathology were, indeed, transferred to the SCID mice by the injection of spleen cells from the MRL/lpr mice. These findings suggest that cell-mediated immunity is involved in the development of SHL and cochlear pathology.

A case report of FSH-producing nasal ectopic pituitary adenoma extending to the frontal cranial fossa.

We report the first case of an ectopic pituitary adenoma in the nasal cavity that produced follicle-stimulating hormone (FSH). A 60-year-old man complaining of left nasal bleeding had a polypoid tumor in the left nasal cavity. Findings of computed tomographic scanning and magnetic resonance imaging showed that the tumor originated from the olfactory cleft, occupied the nasal cavity, and extended to the frontal cranial fossa. Results of histologic examination suggested ectopic pituitary adenoma. Magnetic resonance imaging results showed the pituitary gland to be normal. Electron microscopy findings demonstrated a large number of secretory granules in the tumor cells that were positive for FSH on immunohistochemical analyses. Serum gonadotropin levels were normal, and no clinical signs of hypersecretory syndrome were noted. The above findings led us to establish the diagnosis of FSH-producing ectopic pituitary adenoma. The patient underwent craniofacial resection of the tumor followed by an uneventful recovery. The pathologic findings and clinical course of the case were comparable to those of FSH-producing adenomas arising from the pituitary gland.

Hepatocarcinogenesis inhibition by caffeine in ACI rats treated with 2-acetylaminofluorene.

The inhibitory effects of caffeine have been demonstrated on the development of various organs in animals. The purpose of the present study was to examine the inhibitory effect of caffeine on hepatocarcinogenesis and to determine the responsive dose of caffeine on hepatocarcinogenesis in young male ACI rats. Animals given a diet containing 2-acetylaminofluorene (2-AAF) for 12 weeks and then a basal diet and tap water containing caffeine for 18 weeks showed statistically significant decreases in the incidence, multiplicity (the number of hepatic tumors per rat) and histological grade compared with rats fed a diet containing carcinogen for 12 weeks followed by tap water alone. Dose-dependent inhibition of hepatocarcinogenesis by caffeine was also seen. The inhibitory effect of caffeine on hepatocarcinogenesis in rats was found when caffeine was administered during the initiation phase.

[Clinical laboratory data and reference intervals standardized in Fukuoka].

In Fukuoka whose population is approximately five million inhabitants, surveys on the accuracy of laboratory data have been performed by the Fukuoka Prefecture Medical Association for the last 30 years. We have been attempting to evaluate the data for routine use since 1988, and it has become possible to share laboratory data between all institutions in Fukuoka prefectures. As a result, reference intervals for 23 clinical chemistry analytes were established in 1995, to which were added in 1996 five serum protein constituents that have been utilized for clinical examinations. Methods for documentations and monitorings the data obtained in the prefecture were also established, standardization of the above analytes extended to 97% of the institutions in the prefecture. Results for 14 of the 23 clinical chemistry analytes have become highly reliable and clinically useful as differences between institutions in terms of results have narrowed. Standardization of other analytes is now in progress.

[A case of thymoma with pure red cell aplasia].

A 71-year-old man was admitted to the hospital because of general fatigue. There were few reticulocytes in the peripheral blood and no erythroblasts in the bone marrow. Chest CT revealed an anterior mediastinal tumor. Under a diagnosis of thymoma with PRCA, extended thymothymectomy was performed. Histological diagnosis was mixed type thymoma with no invasive growth beyond the capsule. Administration of predonisolone following surgery was not effective for PRCA. Otherwise, peripheral blood counts were significantly improved following occasional onset of acute bronchitis.

[Ventricular pseudo-false aneurysm after myocardial infarction; report of a case].

A 72-year-old man was admitted to our hospital with chest discomfort and syncope. The echocardiography showed the left ventricular aneurysm. The coronary arteriography revealed a complete occlusion at distal portion of the right coronary artery and anterior aneurysm of the left ventricle was demonstrated. We diagnosed that it was false aneurysm because of communicating with the left ventricle through a small orifice. Surgical repair was carried out after resection of the aneurysm of the left ventricle. The postoperative course was uneventful and discharged on the 33rd day after surgery. Pseudo-false ventricular aneurysm of the left ventricle was diagnosed by histological examination.

[A case report of patient with advanced stomach carcinoma of linitis plastica type responding to multi-immunotherapy and chemotherapy].

Multiple-drug (OK-432, PSK and SPG) immunotherapy and chemotherapy provided remission of symptoms for 36 months in a patient aged 21 years suffering scirrhous gastric carcinoma associated with carcinomatous peritonitis in which direct infiltration to the pancreas, retroperitoneum and the left colon was observed. A remarkable improvement with time was observed by endoscopic and roentgenographic observation, and a substantial improvement was also observed in the NK-cell ratios of lymphocyte subsets of the OKT series in relation to immunologic parameters. A tumor necrosis factor [TNF]-like substance was thought to have been induced by multiimmunotherapy in this case.