[Evaluation of a combination chemotherapy with nedaplatin and 5-FU for oral cancers].

Nedaplatin (cis-diammine-glycolato platinum: CDGP) is a platinum compound with a molecular weight of 303.18 that was recently developed in Japan. There have been reports of the antineoplastic effects of Nedaplatin on cancers in the cranio-cervical region, lung, esophagus, urinary bladder, testis, ovary, and uterus. In this study, we performed combined therapy of CDGP and fluorouracil (5-FU) for 8 patients with oral cancers, and evaluated the results to elucidate the clinical effect and adverse side effects. The subjects were 8 patients with squamous cell carcinoma (5 males and 3 females aged 33-65 years). The primary carcinoma regions were the tongue in 5 patients, oral floor in 2 patients, and mandibular gingiva in 1 patient. The T-classification was T2 in 6 patients and T4 in 2 patients, and the clinical staging was Stage II in 5 patients, Stage III in 1 patient and Stage IV in 2 patients. We first administered 700 mg/m2 5-FU per day from day 1 to day 5 (total dose 3,500 mg/m2), then 90 mg/m2 CDGP on day 5. The clinical effect was evaluated as a partial response in all cases, showing a 100% success rate. The histopathological findings of resected tumors were evaluated by Ohboshi and Shimozato's classification. One patient was Grade IIA, 5 patients Grade IIB, and 2 patients Grade III. The adverse side effects were slight myelotoxicity, gagging, nausea, alopecia, and stomatitis less than Grade II. Although the oral cancers in this study were extroverted superficial ulcerative cancers, and the number of patients was low at 8, this combined therapy is considered useful and worth evaluating in further accumulated cases.

Suppression of experimental membranous glomerulonephritis in rats by an anti-MHC class II antibody.

BACKGROUND: We previously reported that idiopathic membranous nephropathy (IMN) strongly correlated with HLA-DRB1*1501-DRB5*0101-DQAI*0102-DQB1* 0602, a specific haplotype of human major histocompatibility complex (MHC), in Japanese patients. To investigate the role of MHC in the development of rat Heymann nephritis (HN), an animal model of membranous nephropathy, a monoclonal antibody (mAb) specific to rat MHC class II antigen (RT1B) was administered, and its effectiveness in inhibiting HN was assessed. METHODS: Active HN was induced in HN-sensitive Lewis rats by administering brush border proteins of rat proximal uriniferous tubules (FX1A). Rats were divided into four groups: rats treated with 1,000 micorg anti-rat MHC class II mAb, rats treated with 100 microg anti-rat MHC class II mAb, rats treated with murine myeloma IgG, and rats that did not receive either FX1A or any other mAb. We examined the differences in 24-hour urinary protein excretion and serum alloantibody titers against FX1A between groups at different time intervals, and the histologic features of kidneys at the end of the study. RESULTS: HN was induced in Lewis rats by inoculation with FX1A antigen. Administration of anti-MHC class II mAb successfully lowered urinary proteins, production of anti-FX1A alloantibodies, and the development of glomerular lesions in a dose-dependent manner. CONCLUSION: The present results demonstrated that the MHC class II molecule itself is directly involved in the pathogenesis of HN, and suggest that this therapy would be any better (or less toxic) than nonselective immunosuppressants in the treatment of IMN.

Relationship between fluctuation pattern of blood pressure during hemodialysis treatment and cardiovascular morphology: an autopsy study of 53 cases.

BACKGROUND: Cardiovascular morphological changes are often conspicuous in autopsy examination of chronic hemodialysis (HD) patients. On the other hand, the fluctuation pattern in blood pressure (BP) during HD treatment varies from one patient to another. Cardiovascular changes may correlate with clinical findings including BP fluctuation patterns during HD, although no autopsy studies have previously examined this issue. METHODS: In this study, 53 autopsies of patients who had been on chronic HD were reviewed. We determined the relationship between BP fluctuation during HD treatment along with stable and cardiovascular morphology, including heart weight, ventricular wall thickness, circumferences of the valves and the severity of aortic arteriosclerosis and coronary stenosis. Patients were divided into 4 groups according to the pattern of BP fluctuation during HD treatment at about 6 months before death: group 1 (n = 13), symptomatic hypotension and/or decline pattern during HD; group 2 (n = 11), continuously high BP during HD treatment; group 3 (n = 17), continuous normal BP during HD treatment, and group 4 (n = 12), continuously low BP without symptomatic hypotension during HD treatment. RESULTS: Heart weight and ventricular wall thickness were greatest in group 2. The scores for aortic arteriosclerosis in groups 1 and 2 were higher than in groups 3 and 4. The coronary stenosis index was significantly higher in group 1 than in the other groups, and that in group 2 was higher than in group 4. Multiple regression analysis showed that age, HD duration and pulse pressure were independent variables for the score of arteriosclerosis, and the decline pattern of BP fluctuation during HD and pulse pressure were independent variables for coronary stenosis index. CONCLUSIONS: Our results suggest that certain clinical parameters including BP during HD may reflect cardiovascular morphological changes in stable HD patients, although further examination, such as 24-hour blood pressure measurement is recommended to elucidate the pathophysiology of cardiovascular diseases in HD patients.

Effects of 16 weeks of treatment with tibolone on bone mass and bone mechanical and histomorphometric indices in mature ovariectomized rats with established osteopenia on a low-calcium diet.

Tibolone is a synthetic steroid with tissue-specific estrogenic, progestogenic, and androgenic properties. The therapeutic effects of tibolone on bone mass and strength, bone metabolic markers, and indices of histomorphometry were investigated in ovariectomized (ovx) rats on a low (0.1%)-calcium diet in comparison with 17alpha-ethynylestradiol (EE) or 1alpha-hydroxyvitamin D3 [1alpha(OH)D3]. Tibolone (0.1-3 mg/kg/day), EE (0.1 mg/kg/day), or 1alpha(OH)D3 (0.5 microg/kg/day) was administered orally once a day for 16 weeks, starting 12 weeks after ovariectomy, when the bone mineral density (BMD) of lumbar vertebrae (L4-5) and femur (global, proximal, and distal regions) had already been decreased by the combination of ovariectomy and low dietary calcium. The BMD of the lumbar vertebrae and the femur were higher in the groups treated with tibolone, EE, or 1alpha(OH)D3 than in the ovx control group. The BMD of the mid-diaphysial regions of femur and tibia, which consist mainly of cortical bone, were decreased 28 weeks after ovariectomy in the ovx control group. The BMD of the mid-diaphysial femur was higher in the groups treated with 1alpha-(OH)D3, and the BMD of mid-diaphysial tibia was higher in the groups treated with tibolone or 1alpha(OH)D3 than in the ovx control group. Like BMD, the compressive strength of the vertebral body of L2, corrected for the volume of each individual vertebra tested, was higher in the groups treated with tibolone, EE, or 1alpha(OH)D3 than in the ovx control group. Trabecular bone volume and trabecular number were reduced 12 and 28 weeks after ovariectomy but there was no change in trabecular thickness. These reduced indices were increased in the groups treated with tibolone, EE, or 1alpha(OH)D3 when compared with the ovx control group. Tibolone or EE decreased serum levels of osteocalcin and bone alkaline phosphatase and urinary levels of deoxypyridinoline and pyridinoline compared with the ovx control group. Furthermore, tibolone or EE decreased the mineralizing surface and bone formation rate as well as the osteoclast surface and osteoclast numbers. 1Alpha(OH)D3, however, did not affect these serum and urinary parameters. These data suggest that tibolone suppresses the accelerated bone turnover induced by a combination of ovariectomy and low dietary calcium, and indicate that tibolone may be a potentially useful drug for the treatment of postmenopausal osteoporosis.

Methodological issues of an epidemiological study: from the results of a study on psychological problems seen in outpatients visiting the internal medicine departments of general hospitals.

The frequency and type of psychological problems of outpatients in general healthcare settings, the recognition and management of those problems by physicians, and the course of the problems were investigated using a two-stage sampling design method. The subjects were outpatients visiting the department of internal medicine of two general hospitals in Nagasaki prefecture. For the first-stage investigation, the General Health Questionnaire 12-item version (GHQ-12) was used. A second-stage investigation was then conducted, which used many instruments containing the Composite International Diagnostic Interview (CIDI) and Groningen Social Disability Scale (GSDS). As a result, 1555 patients participated in the first-stage, 483 were selected and 336 (69.5%) participated in the second-stage investigation. No significant differences were seen in age or sex between the GHQ score groups among the 1555 subjects of the core sample. The background factors of the two hospital samples differed significantly in the distribution of age, sex and physical diseases. There were some differences in the participation between men and women in age and GHQ score. It was then suggested that variances should be considered in such an epidemiological study.

Further evidence of westernization of dementia prevalence in Nagasaki, Japan, and family recognition.

The present study examined the prevalence of dementia in the Nagasaki Prefecture. The purposes of our investigation were (a) to study the relationship between aging and the prevalence of dementia and the ratio of Alzheimer's disease (AD) to vascular dementia (VD), (b) to understand the features of early-onset dementia as seen in patients from 60 to 65 years, and (c) to examine the recognition of dementia by family members. The subjects of the study, a total of 4,368, were all 60 years old and over and were residing in the three areas of Nagasaki Prefecture at the time of the investigation, August 1995. We adopted a two-stage design. The first-stage questionnaire that we developed was delivered to subjects, and we selected for the second stage those subjects who met the criteria outlined in the Methods section. The second-stage investigation was an interview by community nurses and psychiatrists. The prevalence of dementia in subjects 60 years and over was 6.2% (men: 5.9%; women: 6.8%). The prevalence increased with age. The AD/VD ratio was 1.4, and was similar to the recent trend in Japan in that the ratio has reversed to resemble the western pattern. In regard to the family members' recognition of illness, the higher the severity of dementia, the higher the recognition ratio of family members became. Only half of these subjects were recognized as having dementia by their family members. In conclusion, the westernization of the AD/VD ratio in Japan was proved. There was little study about family recognition of dementia. In this study, it was remarkable that only half of the subjects were recognized as having dementia by their family members.

Factors affecting disability in patients attending the internal medicine departments of general hospitals.

The aim of this study was to investigate the effect of sociodemographic factors, physical factors and mental factors on the physical and social disability of patients attending outpatient clinics of general hospitals. Physical and psychiatric morbidity in 1580 consecutive patients attending the internal medicine department of general hospitals was assessed using a stratified two-stage sampling design method. Of the total, 336 patients completed the second stage interview composed of Primary Care Version of Composite International Diagnostic Interview and Groningen Social Disability Schedule to assess sociodemographic, physical and mental factors. In this study, restricted activity days, disability days and Brief Disability Questionnaire were used for the assessment of physical disability, and Groningen Social Disability Schedule was used for social disability. Sociodemographic, physical and mental factors were all related to disability. Among sociodemographic factors, unemployment was associated with physical disability and social disability mildly. Among physical factors, the severity of physical disease was not associated with disability and medically explained somatic symptoms were associated with disability. Furthermore, the mental factor was more strongly associated with physical and social disability. It could be said that the mental factor is more strongly associated with physical and social disability than sociodemographic or physical factors. In addition, even mild mental symptoms not leading to ICD-10 mental disorders affected disability. From the viewpoint of the patients' burden, it is important to assess the mental symptoms as well as physical status in outpatient clinics of internal medicine or primary care.

A monoarthritis model in rabbits induced by repeated intra-articular injections of lipopolysaccharide.

We attempted to develop a monoarthritis model using repeated intra-articular injections of high-dose Lipopolysaccharide (LPS). Furthermore, the effect of dexamethasone on this arthritis model by intra-articular administration was studied to examine whether the model can be used to screen anti-rheumatic drugs in a short time. Arthritis was induced by one, two or three intra-articular injections of LPS (5-50 micrograms/joint) at 4-day intervals into the knee joint. The rabbits were sacrificed at 7 days following the last injection of LPS. Three intra-articular injections of LPS at 50 micrograms/joint resulted in persistent joint swelling. Hyperplasia of synovium with some discolouration was macroscopically observed. Infiltration of mononuclear cells and lymphoid follicles were histologically observed as the synovial lesions. Concerning the articular bone/cartilage, trabecular destruction of gastrocnemius sesamoid bone and severe loss of safranin-O staining of articular cartilage were observed. Immunohistochemical analysis revealed that inflammatory cells and lymphoid follicles in the synovial lesions consisted predominantly of CD4+ T cells, with few CD8+ T cells. Treatment with dexamethasone markedly reduced the joint swelling and the articular destruction. The results suggest that this arthritis model in rabbits can be utilized to screen anti-rheumatic drugs as a model of rheumatoid arthritis.

Variation of the total amount of fluoride in blood of young women during the menstrual cycle.

We have previously reported the distribution and the forms of fluorides in the blood of men. This study is concerned with the distribution of fluorides in the blood of young women and sex-related differences in the fluoride metabolism related to the calcium metabolism keeping the postmenopausal osteoporosis in mind. The present study shows that women, aged 18 to 20 years, retain more fluorides in blood compared with men and that the nonionic fluoride level in blood varies during a menstrual cycle, whereas the ionic fluoride level is constant. Since fluoride has strong affinity for calcium, behavior of fluoride may reflect that of calcium balance during the menstrual cycle. However, fluoride which binds to calcium is believed to be ionic. Therefore, there must be a transformation between ionic fluoride and nonionic fluoride in order to keep the homeostasis.

[CPE chemotherapy for tongue carcinoma--clinical effects and side effects].

UNLABELLED: Recent advances in chemotherapy have markedly improved the treatment results for oral cancer. Among many chemotherapeutic regimens, the usefulness of multiple combination chemotherapy with cisplatin as the primary drug has been frequently reported. During the past 6-year period, we have performed combination chemotherapy with cisplatin as the primary drug, peplomycin, and etoposide (CPE chemotherapy) as one of the chemotherapeutic regimens for oral cancer. The subjects were 11 patients (7 males and 4 females) with tongue cancer treated by CPE chemotherapy as neoadjuvant chemotherapy at our department between March, 1990 and April, 1995. RESULTS: PR in 8 (73%), and NC in 3 (27%). No patient showed CR and PD. The side effects observed were reversible findings such as transient myelosuppression, nausea-vomiting, and alopecia. No patient showed severe or persistent suppression of hematopoietic function.

Dexamethasone suppresses mucus production and MUC-2 and MUC-5AC gene expression by NCI-H292 cells.

Excessive production of airway mucus is a characteristic feature of many chronic inflammatory lung diseases. Although current pharmacological approaches to excessive mucus production are limited, glucocorticoids appear to be the most effective among a few useful drugs. The exact evidence for the effectiveness of glucocorticoids on mucus production has not been fully elucidated to date. The purpose of this study is to clarify the effect of dexamethasone on mucus production and mucin gene expression in a human pulmonary mucoepidermoid carcinoma cell line (NCI-H292). NCI-H292 cells produced hyaluronidase-resistant high-molecular-weight glycoconjugates (HMWG), which elute in the void volume on Sepharose CL-4B column chromatography. Dexamethasone significantly suppressed the basal production of [3H]glucosamine-or [3H]serine-labeled HMWG in NCI-H292 cells. In Northern blot analysis, dexamethasone attenuated steady-state mRNA levels of MUC-2 and MUC-5AC mucin genes. These data indicate that dexamethasone suppresses the basal production of HMWG and decreases steady-state mRNA levels of mucin genes in airway mucus-producing cancer cells.

Pyridine derivatives stimulate phosphatidylcholine secretion in primary cultures of rat type II pneumocytes.

We have examined the effects of pyridine derivatives on phosphatidylcholine secretion in primary cultures of rat type II pneumocytes. Of 12 pyridine derivatives, 4-aminopyridine, 4-dimethylaminopyridine and 4-pyrolidinopyridine had a stimulatory effect on phosphatidylcholine secretion, whereas other derivatives had little effect. The stimulatory effect of 4-aminopyridine was concentration- and time-dependent, and was inhibited by the acetoxymethyl ester of 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (3 microM), an intracellular Ca2+ chelator. In addition, the stimulatory effect of 4-aminopyridine was suppressed by W-7(N-(6-aminohexyl)-5-chloro-1-napthalene-sulphonamide)(10 microM), a calmodulin inhibitor, and sphingosine (10 microM) and staurosporine (0-1 microM), protein kinase C inhibitors. These results indicate that several pyridine derivatives stimulate phosphatidylcholine secretion in type II pneumocytes.

Substance P stimulates the loss of cell-associated high molecular weight glycoconjugates from cultured hamster tracheal epithelial cells through polymorphonuclear leucocytes activation.

Abnormal and excessive mucus secretion is a characteristic feature of many chronic inflammatory lung diseases accompanied by the influx of polymorphonuclear leucocytes (PMNs) into the airway and the release of substance P from the peripheral endings of primary sensory neurons. We examined whether PMNs activated by substance P (10 microM) can affect the secretion of high-molecular-weight glycoconjugates (HMWG), which is used as a marker of mucus, from cultured hamster tracheal epithelial cells. We measured both the released and the cell-associated HMWG. Substance P-activated PMNs (10(6) cells/ml) reduced the amount of cell-associated HMWG to 76% of the control level, but did not affect the amount of the released HMWG. The reduction of the amount of cell-associated HMWG was inhibited by ONO-5046, a specific elastase inhibitor. In addition, the HMWG was digested by the activated PMNs. These findings suggested that substance P stimulates the loss of the cell-associated HMWG and degrades the released HMWG from cultured hamster tracheal epithelial cells through PMNs activation.

[Combined acute ascending aneurysm and chronic descending thoracic aneurysms].

A 66-year-old woman with a known chronic descending thoracic dissecting aneurysm was admitted following a chest X-ray which revealed a widening in the mediastinum and an increased cardiothoracic ratio. Echocardiography and chest CT showed a combined ascending thoracic dissecting aneurysm with a tripple lumen, pericardial effision, moderate aortic regurgitation, and the chronic descending thoracic dissection with incompletely thrombosed aneurysm. The chest CT also showed a normal aortic arch. The diagnosis was then made as combined acute ascending aortic dissection (DeBakey II) and chronic descending aortic dissection (DeBakey III). A 2-stage operation was planned, involving first a graft replacement of the ascending aorta, and then one month later a graft replacement of the descending aorta.

[A case of successful operation for chronic aortic dissection (DeBakey 1 type) complicated with cerebral infarction].

We report a successful operation for a patient of chronic aortic dissection complicated with cerebral infarction. A 60-year-old woman has been treated suffering from cerebral infarction for 7 years. She was referred to our hospital for abnormal chest X-ray and complaint of dry cough. The enhanced CT scan and aortogram demonstrated chronic aortic dissection (DeBakey I) extending from ascending aorta to the abdominal aortic bifurcation with occlusion of right common carotid artery and dilated ascending aorta and aortic arch. The onset of aortic dissection seemed to be, from a clinical point of view, coincident with the onset of cerebral infarction seven years ago. The replacement of the ascending aorta and aortic arch with woven Dacron velour graft were performed under hypothermic and selective cerebral perfusion. The postoperative course was uneventful although complicated with transient recurrence nerve palsy and she has been doing well.

Involvement of protein kinase C in mucus secretion by hamster tracheal epithelial cells in culture.

Abnormal regulation of airway mucus secretion may underlie many pulmonary diseases. The exact evidence for the involvement of intracellular signaling mechanisms in mucus secretion has not been fully elucidated to date. The purpose of this study is to clarify the involvement of protein kinase C in the secretion of high-molecular-weight glycoconjugates (HMWG) by hamster tracheal epithelial cells in culture, which elute in the void volume on Sepharose CL-4B column chromatography. HMWG were secreted by the cells cultured on the thick collagen gel, but not on the plastic plate. Two known activators of protein kinase C, 4 beta-phorbol 12 alpha-myristate 13-acetate (PMA) and 1-oleoyl-2-acetyl-sn-glycerol (OAG), stimulated HMWG secretion. In contrast, 4 alpha-phorbol 12,13-didecanoate, a biologically inactive phorbol, did not influence HMWG secretion. D-Sphingosine, an inhibitor of protein kinase C, suppressed the maximal PMA- (10(-8) M) and OAG- (200 microM) stimulated HMWG secretion. PMA induced protein kinase C translocation from cytosol to membrane. These data indicate that protein kinase C is involved in HMWG secretion in hamster tracheal epithelial cells in culture.

Increased beta 2-microglobulin in both parotid and submandibular/sublingual saliva from patients with Sjögren's syndrome.

Samples of unstimulated saliva from patients with sialoadenopathy were collected by microcapillary tube (1 microliter), and their beta 2-microglobulin (B2-MG) content determined by a sandwich enzyme immunoassay. A higher than normal (control) concentration of the globulin was present in both parotid and submandibular/sublingual saliva from the patients with Sjögren's syndrome but not in the samples from the patients with sialoadenitis or diabetes mellitus. The increase in B2-MG in saliva from patients with Sjögren's syndrome may reflect that immunolopathological events are important in the degeneration of both glands in this disease. Therefore, the determination of B2-MG in saliva may be a simple, non-invasive technique for confirming the diagnosis of Sjögren's syndrome as an autoimmune disease.

[Intra-arterial combination chemotherapy using both regimen selected by chemosensitivity test and caffeine to increase effect for osteosarcoma in extremity].

We treated three patients with osteosarcoma in extremity with intra-arterial combination chemotherapy using a regimen selected by succinate dehydrogenase inhibition chemosensitivity test, and used caffeine to enhance its effect. In two patients with osteosarcoma in distal diametaphysis of the radius and extraskeletal osteosarcoma in sole of the foot, the effect of intra-arterial combination chemotherapy was increased and followed by the functional limb salvage procedure. But in one patient with osteosarcoma in the proximal tibia, the effect of pre-operative intra-arterial combination chemotherapy could not be increased, so amputation was required. He was changed to a post-operative intra-venous combination chemotherapy regimen selected by chemosensitivity test of the surgical material. All patients have been continuously disease-free at five to twelve months after surgery.

[A case of left ventricular hemangioma].

Left ventricle hemangioma in a 54-year-old man is reported. He was admitted to our hospital for chest discomfort. Coronary angiograms showed normal coronary arteries and a contrast blush in the left interventricle septum. Transesophageal echocardiogram also demonstrated the small floating tumor in the ventricular septum below the right coronary cusp. With the aid of cardiopulmonary bypass, the tumor was resected completely through transaortic approach. Histological examination revealed capillary hemangioma. The patient had uneventful recovery. To our knowledge, this is the seventh case of a left ventricular hemangioma treated surgically reported in the world literature.