Biomedical subjects

M Ando

Publications and source records attributed to M Ando.

At least 217 records · Page 12Linked to original sources

PubMed1999

Elongated pericyte-like cells connect discrete capillaries in the cochlear stria vascularis of gerbils and rats.

Bridging structures between discrete capillaries in the stria vascularis of the cochlea were studied morphologically in gerbils and rats. Serial thin sections for transmission electron microscopy revealed (1) that elongated cells surrounded by the basal lamina provided the structural basis for the bridging structure, (2) that the basal lamina surrounding the elongated cell extended to the basal lamina around the capillary endothelial cell, (3) that the electron density of the cytoplasm was similar to that of the pericytes around the capillaries, and (4) that the cell was attached to the capillaries at both ends only. Visualization of the basal lamina by immunofluorescent methods revealed (1) that capillaries were often bent at the site of attachment of the bridging cell, (2) that the bridging cell bifurcated occasionally, and (3) that the density of the bridging cell was much higher in the stria vascularis than in the underlying spiral ligament. Filamentous actin visualized by fluorescent phalloidin was not apparent in the bridging cell. We propose that the bridging cell provides mechanical strength to the tortuous capillary network in the stria vascularis and participates in the specific function of the stria vascularis in cooperation with other types of cells.

Animals↗

PubMed1999

Immunological identification of an inward rectifier K+ channel (Kir4.1) in the intermediate cell (melanocyte) of the cochlear stria vascularis of gerbils and rats.

The cochlear stria vascularis produces the positive endocochlear potential (EP) and the endolymph. Both the EP and the endolymph are essential for the physiological function of hair cells. The intermediate cell is one of several cell types constituting the stria vascularis. It is known that inward rectifier K+ channels can play a constitutive role in the determination of the resting membrane potential. Localization of a member of the inward rectifier K+ channel family, Kir4.1, in the stria vascularis of gerbils and rats was investigated by immunological methods. A polyclonal antibody specific to the C-terminus of the rat Kir4.1 channel was raised in rabbits. Immunostaining of dissociated cells revealed that the Kir4.1 channel was localized to the intermediate cell, but not to the epithelial marginal cell. Subcellular localization of the Kir4.1 channel to the plasma membrane of the intermediate cell was confirmed by immunoelectron microscopy. Immunostaining of whole-tissue preparations revealed a network-like structure composed of intermediate cells. It seems likely that the Kir4.1 channel mediates the inwardly rectifying K+ current in the intermediate cell as shown previously by electrophysiological methods, and that this channel plays key roles in the production of the EP and K+ transport in the stria vascularis.

Amino Acid Sequence↗

PubMed1999

Predictive factors for mortality and cerebral complications in arteriosclerotic aneurysm of the aortic arch.

BACKGROUND: The incidence of cerebral complications is high in patients with aortic arch aneurysm. METHODS: Between December 1977 and December 1995, 246 patients with arteriosclerotic arch aneurysm underwent operation. Thirty-nine patients had an aneurysm involving the entire arch, 193 had only distal arch aneurysm, and 14 had arch aneurysm extending to the descending aorta. Eighty-seven patients underwent replacement of the total arch, 85 had replacement of only the distal arch, 14 had simultaneous replacement of the descending aorta, 45 had patch repair, and 15 had thromboexclusion. Selective cerebral perfusion was used in 112 patients and partial bypass in 58 in the earlier series of patients, but deep hypothermic circulatory arrest with retrograde cerebral perfusion technique was exclusively applied in the most recent 76 patients. RESULTS: There were 50 (20%) early deaths and 37 (19%) late deaths. Postoperative stroke was found in 26 (11%) patients of which 13 (50%) died. Mutual predictive factors for postoperative mortality and stroke were earlier series, preoperative chronic renal failure, ruptured aneurysm, arch clamping during procedure, and using partial cardiopulmonary bypass. Among 129 patients operated on during the most recent 5 years, early mortality and incidence of stroke decreased to 14.7% and 6.9%, respectively. CONCLUSIONS: Results of operations for arteriosclerotic aneurysms of the transverse aortic arch in 246 patients during a period of 17 years have been improving but are still not satisfactory.

Adult↗

PubMed1999

A new method for the treatment of graft infection in the thoracic aorta: in situ preservation.

BACKGROUND: We have developed a new method to control graft infection by a combination of two procedures, extensive disinfection followed by tissue flap implantation, allowing preservation of the original graft. METHOD: Soon after the diagnosis of graft infection was confirmed, the wound was re-explored, and debridement, irrigation and packing with sponges soaked with 10% iodine solution were employed. This procedure was repeated every 8 hours for the first 48 hours. For the second step, tissue flaps using omentum or muscle were implanted around the graft as well as in dead space, and the wound was closed primarily. MATERIALS: A total of 6 patients were treated: 4 in the acute and 2 in the chronic phase of infection. The original procedures were a Bentall procedure + arch replacement (1), ascending aorta replacement + arch (3) and replacement of the descending aorta (2). In descending aorta cases, an extended thoracoplasty was concomitantly added to eliminate dead space in the pleural cavity. RESULTS: Graft infections were controlled in all 6 patients. One hospital death unrelated to infection was encountered. Five patients were discharged, but 1 died of a stent-graft complication. The follow-up period ranged from 4 months to 10 years. CONCLUSION: Our method of extensive disinfection followed by tissue flap coverage of the graft proved to be highly effective in controlling the serious complication of graft infection associated with surgery of the thoracic aorta.

Adult↗

PubMed1999

Surgical treatment of Behçet's disease involving aortic regurgitation.

BACKGROUND: Behçet's disease involving aortic regurgitation is rare, and prosthetic valve detachment after aortic valve replacement is one of the most serious complications reported. We investigated the surgical results in 10 patients with aortic regurgitation caused by Behçet's disease. METHODS: Between 1981 and 1997, 10 patients with aortic regurgitation secondary to Behçet's disease had surgery. There were 8 men and 2 women, and their ages ranged from 33 to 60 years (mean, 46+/-8 years). The surgical procedures for aortic regurgitation were aortic valve replacement in 6 patients and Bentall type operation in 4. RESULTS: No patient died during the hospital stay. The follow-up periods ranged from 11 to 185 months (mean, 87 months). Two patients died during the follow-up period. The acturial survival rate was 89% at 5 years and 67% at 10 years. Prosthetic valve detachment or suture detachment requiring redo operation occurred in 4 patients, 3 of whom had redo operations twice. Four patients had a composite graft replacement, and 1 patient died after the operation. No prosthetic valve detachment was noted in 64% of the patients at 5 years and in 43% at 10 years. CONCLUSIONS: The rate of prosthetic valve detachment was 40% (4 of 10 patients), with a higher incidence in patients with Behçet's disease than in those treated during the same period at the same hospital for aortitis caused by other diseases. Surgical techniques for treatment of this condition should be modified to improve the surgical outcome in these patients.

Adult↗

PubMed1999

Is distal anastomosis only to the true channel in chronic type B aortic dissection justified?

BACKGROUND: We investigated long-term outcomes of the distal false lumen of the aorta and aortic branches after distal anastomosis of the graft only to the true lumen in chronic type B aortic dissection. METHODS: From November 1979 until June 1998, we treated 98 patients without Marfan syndrome who had chronic type B aortic dissection and underwent replacement of the descending aorta, 79 of whom had distal anastomosis to the true lumen only. The celiac artery originated from the false lumen in 11 patients, superior mesenteric artery in 5, right renal artery in 19, and left renal artery in 16. RESULTS: There were 12 (15.1%) early deaths. Spinal cord ischemia was detected in 5 patients. Postoperative follow-up was achieved in 67 patients, and 13 patients died. Postoperative survival at 10 years was 67.6% +/- 7.1%. Eight patients had complete occlusion of the distal false lumen, 54 patients had occlusion of the false lumen down to the celiac artery, and 5 patients had a patent false lumen. Four patients required further replacement of the thoracoabdominal aorta. CONCLUSIONS: In non-Marfan patients with chronic type B aortic dissection, the false lumen distal to the graft anastomosis was likely to be thrombosed when the graft was anastomosed to the true lumen only. Postoperative visceral circulation was not compromised, but spinal cord ischemia is a problem that remains to be solved.

Adult↗

PubMed1999

Chronic hypersensitivity pneumonitis in Japan: a nationwide epidemiologic survey.

BACKGROUND: Pulmonary fibrosis inevitably develops in patients with chronic hypersensitivity pneumonitis (HP). OBJECTIVE: We conducted a nationwide epidemiologic study in Japan to evaluate the frequency and clinical characteristics of chronic HP. METHODS: This report is on 36 cases of chronic HP, including 10 patients with summer-type HP, 5 patients with home-related HP, 7 patients with bird fancier's lung, 5 patients with isocyanate-induced HP, 4 patients with farmer's lung, and 5 patients with other types of chronic HP. Chronic HP was further subgrouped into 2 types: one type of patients were first seen with chronic disease (9 patients), and the other type became chronic with fibrosis after repeated acute episodes (27 patients). RESULTS: The upper lung field was frequently involved in chronic HP (17%). Ground-glass opacities were observed in 57% and air space consolidation in 30% of the patients. Honeycombing was apparent in 37%. Twenty-six of 28 patients had antibodies to the presumptive antigens. Five of 8 patients with chronic HP were positive for antigen-induced lymphocyte proliferation. In 2 cases patients did not have detectable antibodies to causative antigens, although antigen-induced lymphocyte proliferation was detectable. The ratio of CD4 to CD8 in BAL lymphocytes was lowest in isocyanate-induced HP (mean 0.22) and tended to be high in farmer's lung and bird fancier's lung. Granulomas were observed in 39% and Masson bodies in 42% of specimens on histologic examination. Administration of prednisolone was effective in 58% of patients. CONCLUSIONS: The insidious form of chronic HP has probably been misdiagnosed as idiopathic pulmonary fibrosis when a good history was not taken and immunologic (especially antigen-induced lymphocyte proliferation) and BAL testing were not counted.

Aged↗

PubMed1999

Expression and hormonal regulation of rat ovarian interleukin-1beta converting enzyme, a putative apoptotic marker: endocrine- and paracrine-dependence.

It is the purpose of this paper to assess the expression, cellular localization, and hormonal regulation of rat ovarian interleukin (IL)-1beta converting enzyme (ICE), a putative apoptotic marker. In agreement with previous observations ICE transcripts were noted in relatively increased abundance in the thymus, lung, spleen and small intestine. Although ICE transcripts were barely expressed in the untreated, immature rat ovary, they were apparent throughout a simulated estrous cycle. The in vivo expression of ovarian ICE rose gradually from 6 h after ovulation triggering to a peak (1.74-fold increase versus control, P < 0.05) 24 h after human chorionic gonadotropin administration, a marked and significant decrease to baseline being noted 24 h later. To examine the effect of in vitro culture on ovarian ICE gene expression, whole ovarian dispersates from immature rats were cultured without treatment for 72 h. ICE gene expression significantly (P < 0.01) increased to a maximum 24 h post plating (2.55-fold increase as compared with time zero). Treatment with IL-1beta was associated with a small but statistically insignificant increase in ovarian ICE gene expression. Similarly, provision of IL-RA resulted in a modest, albeit statistically insignificant, decrease in ovarian ICE gene expression. Treatment with GnRH (but not FSH, LH or PMSG) significantly (P < 0.05) increased ovarian ICE gene expression (41.5% increase versus control). Treatment with dexamethasone (but not diethylstilbestrol, R5020 or R1881) produced a significant (P < 0.05) 42.3% decrease in ovarian ICE gene expression as compared with untreated controls. Treatment with TNF alpha (but not ET-1, TGF alpha, TGF beta, IGF-I or bFGF) produced a significant (P < 0.01) 2.5-fold increase in ovarian ICE gene expression as compared with untreated controls. Taken together, our present findings: (1) reaffirm the ovarian expression of the ICE gene, (2) document a periovulatory increase in ovarian ICE gene expression, (3) show the inhibitory effect of glucocorticoids in this regard, and (4) establish TNF alpha as an upregulator. Taken together, these findings suggest a role for ovarian ICE either in the context of apoptosis/atresia or in the context of the ovulatory process.

Animals↗

PubMed1999

Cytotoxic and porphyrinogenic effects of diphenyl ethers in cultured rat hepatocytes: chlornitrofen (CNP), CNP-amino, chlomethoxyfen and bifenox.

We studied the cytotoxic and porphyrinogenic effects of four diphenyl ethers (DPEs), chlornitrofen (CNP), CNP-amino, chlomethoxyfen and bifenox, in rat hepatocytes cultured on Matrigel. Cytotoxicity was determined as a decrease in viability measured by the release of lactate dehydrogenase. Of the DPEs examined. CNP-amino was the most cytotoxic, with an LC50 value of 0.36 mM (95% confidence interval, 0.33-0.40 mM). CNP also reduced the viability in a concentration-dependent manner at the concentrations of 0.50 mM or above. In contrast, no concentration-dependent decrease in viability was observed in the chlomethoxyfen- and bifenox-treated hepatocytes at the concentrations up to 1.0 mM. To identify the enzyme involved in the metabolic activation of CNP-amino, inhibition studies were carried out using SKF 525-A (0.050 mM) and methimazole (1.0 mM). SKF 525-A, a cytochrome P450 inhibitor. quickened the onset of cell killing by CNP-amino, while methimazole, an inhibitor of flavin-containing monooxygenase (FMO), partially suppressed the cytotoxicity of CNP-amino. These results suggest that FMO plays an important role in the cytotoxicity induced by CNP-amino, while cytochrome P450 participates in the detoxification, possibly via the ring-hydroxylation. The maximum porphyrin accumulation was observed at 0.13 mM for chlomethoxyfen (18-fold) and at 0.25 mM for CNP and bifenox (17- and 21-fold, respectively). In contrast to these DPEs, the porphyrinogenic effect of CNP-amino was weak, with the maximum accumulation at 0.13 mM (at least fivefold). The predominant species was protoporphyrin IX in all of the DPE-treated cultures. These results suggest that all of the DPEs examined, possibly including CNP-amino, inhibit protoporphyrinogen oxidase, resulting in the accumulation of protoporphyrin IX.

Animals↗

PubMed1999

Surgical treatment for aortic regurgitation caused by non-specific aortitis.

Aortic regurgitation caused by non-specific aortitis is relatively rare, and prosthetic valve detachment after aortic valve replacement has been reported to be one of the most serious complications. The authors investigated the surgical results in patients with aortic regurgitation caused by non-specific aortitis. Between 1978 and 1997, 90 patients with aortic regurgitation secondary to non-specific aortitis underwent surgery. There were 28 males and 62 females. The age of these patients ranged from 19 years to 70 years (mean, 48 years). Sixty-five patients were diagnosed to have Takayasu's arteritis, 10 had Behçet's disease and 15 had aortitis of unknown etiology. The surgical procedures for aortic regurgitation were aortic valve replacement in 62 patients, Bentall-type operation in 27 and remodeling in one. Five patients (5.6%) died during the hospital stay. The follow-up duration ranged from 1 month to 224 months (mean, 98 months). Twenty-one patients died during the follow-up period, and the actuarial survival rate was 83% at 5 years and 68% at 10 years. Prosthetic valve detachment occurred in 12 patients (13.3%). Two patients required a re-aortic valve replacement, eight had a composite graft replacement and two patients underwent a homograft reconstruction. Absence of prosthetic valve detachment was noted in 83% of the patients at 5 years and in 75% at 10 years. The incidence of prosthetic valve detachment was 40% (4/10) in patients with Behçet's disease, 33% (5/15) in aortitis of unknown etiology, 4.6% (3/65) in Takayasu's arteritis and 29% (8/28) in male patients. Surgical techniques for treatment of this condition should be modified for further improvement of the surgical outcome in these patients with Behçet's disease and aortitis of unknown etiology.

Adult↗

PubMed1999

The formation of two layers detectable by intraoperative echocardiography is a reliable predictor of late thrombosis within the false lumen of a dissected aorta.

The subjects consisted of one patient with chronic type A and three patients with chronic type B aortic dissection, who underwent replacement of an aorta obliterating distal false lumen. After the repair, the formation of two layers was detected by direct scanning echocardiography within the false lumen even during heparinization. In all cases, postoperative computed tomography confirmed complete thrombosis of the false lumen. The formation of two layers was considered to be a reliable predictor of late thrombosis.

Adult↗

PubMed1999

Early and long-term results of surgery for aneurysms of the thoracic aorta in septuagenarians and octogenarians.

OBJECTIVE: The purpose of this study was to demonstrate early and long-term results of surgery for thoracic aortic aneurysm in patients over 70 years of age compared with those of patients under 70 years and to clarify the clinical problems peculiar to this subset of patients. PATIENTS AND METHODS: Of 1157 patients who underwent surgery for thoracic aortic aneurysm from 1978 to December 1997, 261 who were 70 years or older were selected for analysis. Mean age at the time of surgery was 74.4 +/- 3.5 years. Aneurysms were atherosclerotic in 177 patients and aortic dissection in 84. Acute aortic dissection was found in 25 patients and ruptured aneurysm in 44. The control group consisted of 896 patients under 70 years. Preoperative complications such as AAA, peripheral arterial disease, emphysema, and old cerebral infraction were more common in the older group. Operative procedures consisted of replacement of the ascending aorta or hemiarch in 51 patients, total arch replacement in 75, distal arch replacement in 35, descending aorta replacement in 75, replacement of the thoracoabdominal aorta in 28, and extra-anatomical repair and others in 15. The technique of extracorporeal circulation was selective cerebral perfusion in 69 patients, deep hypothermic circulatory arrest in 90, femoro-femoral bypass in 39, left heart bypass in 12, and temporary aorto-arterial bypass in 30, and others in 21. RESULT: Early mortality was 21% (54 patients), which was greater than that of the control group (113 patients, 13%, P < 0.01). The incidence of postoperative stroke, transient brain dysfunction, and respiratory problems was higher in the study group (P < 0.01 in all). Mean duration in ICU among survivors was 9.3 +/- 20.2 days and that of the control group was 5.9 +/- 2.8 days (P < 0.01). In a recent series (from 1991 to 1997) postoperative mortality improved to 15.6% (30/192 patients) in the study group however this result was still inferior to that of the control group (8.6%, 39/452, P = 0.03) however mortality of emergency surgery during the same periods was still high (31%, 11/35 patients). Logistic regression analysis revealed that significant risk factors for postoperative hospital death were surgery before 1991, age over 70 years, preoperative cardiac problems, aneurysm rupture, postoperative stroke, low output syndrome, bleeding, and acute renal failure. Postoperative follow-up was obtained in 408 patients/year and the longest period was 10.2 years. Late deaths were documented in 31 patients. Five-year and 10-year survival were 61.2 +/- 5.7% and 31.3 +/- 16.4%, respectively. In the control group the 5-year and 10-year survival were 78.0 +/- 2.1% and 62.5 +/- 4.0%, respectively (P = 0.03). However, survival of the early survivors in the study group was similar with that of the age-matched normal population. Aortic reoperation was performed in 13 patients. Freedom from aortic reoperation was 86.7 +/- 4.2% at 5 years and 80.5 +/- 7.1% at 10 years in the study group and 83.4 +/- 1.8% at 5 years and 64.1 +/- 13.3% at 10 years in the control group (P = 0.27). CONCLUSION: Although recent advances have been achieved, early and long-term results of surgery for thoracic aortic aneurysm in patients older than 70 years were less satisfactory compared with those of patients under 70 years of age, especially in patients who required emergency surgery. Preoperative disorder of the vital organ systems was considered to be the main causative factor for high mortality, however, pertinent surgical strategies are necessary to improve the outcome of elderly patients.

Age Factors↗

PubMed1999

Interruption of the aortic arch associated with deletion of chromosome 22q11 is associated with a subarterial and doubly committed ventricular septal defect in Japanese patients.

OBJECTIVES: The purpose of this study was to clarify the clinical characteristics of interruption of the aortic arch associated with chromosome 22q11deletion. BACKGROUND: About half of patients with interruption of the aortic arch between the left common carotid and the left subclavian artery have deletion of chromosome 22q11. METHODS: In total, 20 patients with interruption of the aortic arch were studied with fluorescence in situ hybridization using peripheral lymphocytes and a DiGeorge syndrome chromosomal probe (Oncor N25). Cardiovascular anomalies in these patients were diagnosed by cross-sectional echocardiography and angiocardiography, and were confirmed at intracardiac repair. RESULTS: Of 13 patients with interruption between the left common carotid artery and the left subclavian artery, seven had the deletion. All 7 also showed thymic hypoplasia and hypocalcemia, together with a nasal voice and peculiar facies. Six of the seven patients had complete deficiency of the muscular outlet septum, with the defect extending to the perimembranous area. Such complete absence of the muscular outlet septum was not present in any of the patients without the deletion. CONCLUSIONS: Interruption of the aortic arch between the left common carotid and the left subclavian artery, absence of the thymus, and complete absence of the muscular outlet septum, were characteristic in Japanese patients with interruption of the aortic arch associated with deletion of chromosome 22q11.

Abnormalities, Multiple↗

PubMed1999

Unguarded mitral orifice, mirror-imaged atrial arrangement, and discordant atrioventricular connections.

We report two autopsy proven cases of unguarded mitral orifice associated with mirror-imaged atrial arrangement, discordant atrioventricular connections, double outlet right ventricle, pulmonary valvar stenosis or atresia, and atrialisation of the morphologically left ventricle. The morphologically left atrioventricular junction was devoid of valvar leaflets, and there was no tension apparatus within the ventricle. To the best of our knowledge, this is the first description of this rare cardiac malformation.

Abnormalities, Multiple↗

PubMed1999

Guaianolides as immunomodulators. Synthesis and biological activities of dehydrocostus lactone, mokko lactone, eremanthin, and their derivatives.

The naturally occurring guaianolides, namely mokko lactone (1), dehydrocostus lactone (2), eremanthin (3), and related guaianolides, 16, 17, 21, 22, 28-31, 33, 36, 37, and 39, have been synthesized starting from l-alpha-santonin in an effort to examine their structure-activity relationship as inhibitors of the killing function of cytotoxic T lymphocytes (CTL) and the induction of intercellular adhesion molecule-1 (ICAM-1). It was observed during the present study that the guaianolides possessing an alpha-methylene gamma-lactone moiety, i.e., 2, 3, 30, 33, 37, and 39, exhibited significant inhibitory activity toward the killing function of CTL and the induction of ICAM-1.

Adjuvants, Immunologic↗

PubMed1999

Clinical significance of MCP-1 levels in BALF and serum in patients with interstitial lung diseases.

It has previously been reported that the expression of monocyte chemoattractant protein-1 (MCP-1) in the lung tissues of patients with idiopathic pulmonary fibrosis (IPF) was different from that in the tissues of patients with other interstitial lung diseases (ILDs). The aim of this study was to determine whether this difference reflects the amount of MCP-1 in the bronchoalveolar lavage fluid (BALF) or serum of patients with ILD, and whether such a correlation, if it exists, is clinically useful. MCP-1 concentrations in the BALF and sera were evaluated in 86 patients with ILDs including IPF, acute interstitial pneumonia, interstitial pneumonia with collagen vascular disease (IP-CVD), chronic interstitial pneumonia (CIP), bronchiolitis obliterans-organizing pneumonia, sarcoidosis, hypersensitivity pneumonitis, and in 10 normal healthy volunteers who were controls (NC). BALF MCP-1 levels were significantly elevated in the IPF, IP-CVD, CIP and sarcoidosis groups compared with the NC group. The level in the IPF group was significantly higher than that in any other patient group. Serum MCP-1 levels in the IPF, IP-CVD, CIP and sarcoidosis groups were significantly higher than the NC group. No statistical difference was found in serum MCP-1 levels between the IPF, IP-CVD and CIP groups. BALF MCP-1 levels were significantly higher than serum MCP-1 levels in the IPF group and lower than in the IP-CVD and CIP groups. Serum MCP-1 levels correlated with the clinical course of ILD treated with corticosteroid therapy. These results show that measurement of monocyte chemoattractant protein-1 levels in both bronchoalveolar lavage fluid and serum may be helpful in discriminating idiopathic pulmonary fibrosis from other types of interstitial lung disease and that monitoring of serum monocyte chemoattractant protein-1 may be useful for predicting the clinical course of interstitial lung diseases.

Adrenal Cortex Hormones↗

PubMed1999

Elevated bronchoalveolar concentrations of MCP-1 in patients with pulmonary alveolar proteinosis.

Pulmonary alveolar proteinosis (PAP) is a rare disease of unknown aetiology characterized by accumulations of lipoproteinaceous material within the alveoli. The alveolar macrophages become increasingly foamy, and are thought to have a role in the pathogenesis of PAP. However, the mechanisms of macrophage recruitment are unclear. In the bronchoalveolar lavage fluid (BALF) of four patients with PAP and 20 normal control subjects, the following were examined: the monocyte chemotactic activity due to the chemokine monocyte chemoattractant protein (MCP)-1 with the use of a chemotactic chamber assay, the levels of MCP-1 by enzyme-linked immunosorbent assay, and the MCP-1 expression on lavage cells by immunocytochemistry and in situ hybridization. The monocyte chemotactic activity in the BALF of the PAP patients was markedly elevated, and the activity was completely absorbed by treatment with anti-MCP-1. The MCP-1 levels in the BALF were surprisingly high in the PAP group (25,100+/-472 pg x mL(-1)), whereas low levels of MCP-1 were detected in the normal control subjects (mean: never smokers 4.8; smokers 10.4 pg x mL(-1)). MCP-1 protein and messenger ribonucleic acid were expressed by macrophages from the PAP patients, and the expression was reduced according to foaming of the cells; there were monocyte-like macrophages with strong expression, small foamy cells with moderate expression, large foamy cells with a faint expression of MCP-1, and ghost cells with no expression. However, the increase of macrophage number in the PAP BALF was relatively small. These data suggest that monocyte chemoattractant protein(-1) expression by alveolar macrophages represents an amplification mechanism for the recruitment of additional macrophages to the alveoli in pulmonary alveolar proteinosis. It is possible that an ingestion of an excess of alveolar materials in pulmonary alveolar proteinosis may impair the macrophage function and the survival, resulting in the lack of a prominent increase in the macrophage number in bronchoalveolar lavage fluid.

Adult↗

PubMed1999

Dose escalation and pharmacokinetic study of a humanized anti-HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer.

We conducted a phase I pharmacokinetic dose escalation study of a recombinant humanized anti-p185HER2 monoclonal antibody (MKC-454) in 18 patients with metastatic breast cancer refractory to chemotherapy. Three or six patients at each dose level received 1, 2, 4 and 8 mg kg(-1) of MKC-454 as 90-min intravenous infusions. The first dose was followed in 3 weeks by nine weekly doses. Target trough serum concentration has been set at 10 microg ml(-1) based on in vitro observations. The mean value of minimum trough serum concentrations at each dose level were 3.58 +/- 0.63, 6.53 +/- 5.26, 40.2 +/- 7.12 and 87.9 +/- 23.5 microg ml(-1) respectively. At 2 mg kg(-1), although minimum trough serum concentrations were lower than the target trough concentration with a wide range of variation, trough concentrations increased and exceeded the target concentration, as administrations were repeated weekly. Finally 2 mg kg(-1) was considered to be sufficient to achieve the target trough concentration by the weekly dosing regimen. One patient receiving 1 mg kg(-1) had grade 3 fever, one at the 1 mg kg(-1) level had severe fatigue defined as grade 3, and one at 8 mg kg(-1) had severe bone pain of grade 3. No antibodies against MKC-454 were detected in any patients. Objective tumour responses were observed in two patients; one receiving 4 mg kg(-1) had a partial response in lung metastases and the other receiving 8 mg kg(-1) had a complete response in soft tissue metastases. These results indicate that MKC-454 is well tolerated and effective in patients with refractory metastatic breast cancers overexpressing the HER2 proto-oncogene. Further evaluation of this agent with 2-4 mg kg(-1) weekly intravenous infusion is warranted.

Antibodies, Monoclonal↗