Epidemiological study of cholesteatoma in Fukuoka City.

OBJECTIVE AND DESIGN: To investigate the pathogenesis of cholesteatoma, we planned to conduct a cohort study. As a first step, we conducted an epidemiological study in Fukuoka City, Japan to determine the incidence of cholesteatoma treated both with and without surgery. We also conducted a case-control study to investigate the pathogenesis of cholesteatoma. RESULTS: The annual incidence of cholesteatoma, including cases treated without surgery, was 6.8-10.0 in a population of 100 000. The results of the case-control study suggested that a past history of otitis media and habitual sniffing caused by a patulous eustachian tube play a role in the pathogenesis of cholesteatoma. CONCLUSIONS: The annual incidence of cholesteatoma, including cases treated without surgery, was considered to not be high enough to perform a cohort study. The results of the case-control study suggest that otitis media and habitual sniffing due to a patulous eustachian tube, contribute to the onset of cholesteatoma.

Ab initio calculation of strain effect on the magnetic properties of the thiogermanate [(CH3)4N]2FeGe4S10.

The magnetic properties of the thiogermanate TMA(2)FeGe(4)S(10) (TMA=[(CH(3))(4)N](+)), and the influence of large strain are investigated by ab initio density functional theory calculations. An analysis of the electronic structure is provided considering antiferromagnetic (AFM), ferromagnetic (FM) and nonmagnetic configurations for the thiogermanate at the equilibrium states. A small difference in total energy between the FM and AFM states suggests that the thiogermanate TMA(2)FeGe(4)S(10) may possess a low Curie temperature. Changes in electronic structure and magnetic moment of the thiogermanate under strain are closely related to the distortion of FeS(4) tetrahedral units. With the help of a simplified molecule model, we show that, while the origin of the drastic change in magnetism under high isotropic compressions mainly originates from the decrease in the Fe-S interatomic bond length, the changes in the electronic structure between - 10% and + 15% isotropic strains are mainly due to the variations of the interatomic bond angles. Little effect of shear strain on the magnetic properties is found since the FeS(4) tetrahedral units rotate under shear, hence keeping their shape.

Ideal shear strength under compression and tension in C, Si, Ge, and cubic SiC: an ab initio density functional theory study.

Ideal shear strength under superimposed normal stress of cubic covalent crystals (C, Si, Ge, and SiC) is evaluated by ab initio density functional theory calculation. Shear directions in [112] and [110] on the (111) plane are examined. The critical shear stress along the former direction is lower than that along the latter in all the crystals unless the hydrostatic tension is extremely high. In both the [112]-shear and [110]-shear, critical shear stress is increased by compression in C but is decreased in the other crystals. The different response of the critical shear stress to normal stress is due to the strength of the bond-order term, i.e., dependence of the short-range interatomic attraction on the bond-angle.

Visceral fat accumulation is a significant risk factor for white matter lesions in Japanese type 2 diabetic patients.

BACKGROUND: The presence of white matter lesions (WML) is an important prognostic factor for the development of stroke. The elevated visceral fat accumulation (VFA) has been reported to be closely related to the development of atherosclerosis. This preliminary study was therefore designed to test the hypothesis that the presence of WML correlates with VFA and insulin resistance in type 2 diabetic patients not receiving insulin treatment. MATERIAL AND METHODS: Based on brain magnetic resonance imaging (MRI), 95 type 2 diabetic patients were divided into two groups: WML-positive group (aged 59 +/- 7 years, mean +/- SD n = 37) and WML-negative group (aged 58 +/- 5, years, n = 58). The level of blood glucose was assessed by fasting plasma glucose (FPG), fasting immunoreactive insulin, homeostasis model assessment (HOMA) index, and haemoglobin A1c. The fat distribution was evaluated by measuring the visceral fat accumulation by abdominal computerized tomography at the umbilical level. RESULTS: The body mass index was higher in the WML-positive group than in the WML-negative group (P < 0.005). Plasma levels of triglycerides were higher while high-density lipoprotein cholesterol was lower in the WML-positive group than in the WML-negative group (P < 0.05 and P < 0.01, respectively). FPG (P < 0.01), insulin concentrations (P < 0.0001), HOMA index (P < 0.0001) and VFA (<0.0001) levels were higher in the WML-positive group than in the WML-negative group. Multivariate logistic analysis revealed that WML was independently predicted by the high VFA and insulin resistance (P < 0.001, P < 0.0001, respectively). CONCLUSIONS: The results of this preliminary study indicate that the presence of WML was associated with the high VFA and insulin resistance in Japanese patients with type 2 diabetes mellitus. Further larger cohort studies are warranted to confirm these findings.

Hyperhomocysteinaemia is a significant risk factor for white matter lesions in Japanese type 2 diabetic patients.

The presence of white matter lesions (WML) is an important prognostic factor for the development of stroke. Plasma total homocysteine (tHcy), which increases with diabetes, has been flagged as a novel predictor for cerebrovascular events. We tested the hypothesis that the presence of WML correlates with tHcy and insulin resistance in type 2 diabetic patients not receiving insulin treatment. Based on brain magnetic resonance imaging findings, 81 type 2 diabetic patients were divided into two groups, with-WML group (57 +/- 8 years, mean +/- standard deviation, n = 31) and without-WML group (57 +/- 6 years, n = 50). The blood glucose level was assessed by fasting plasma glucose (FPG), fasting immunoreactive insulin, Homeostasis Model Assessment (HOMA) Index and hemoglobin A1c. The body mass index was higher in the with-WML group than in the without-WML group (P < 0.05). Plasma levels of triglyceride were higher whilst high-density lipoprotein cholesterol was lower in the with-WML group than in the without-WML group (P < 0.05 and P < 0.0001 respectively). FPG (P < 0.005), insulin concentrations (P < 0.0001), HOMA Index (P < 0.0001) and tHcy (<0.0001) levels were higher in the with-WML group than in the without-WML group. Multivariate logistic analysis revealed that WML was independently predicted by the high tHcy and insulin resistance. Our findings indicate that the presence of WML was associated with the high tHcy and insulin resistance in these Japanese patients with type 2 diabetes mellitus.

Pioglitazone shift circadian rhythm of blood pressure from non-dipper to dipper type in type 2 diabetes mellitus.

BACKGROUND: Insulin resistance significantly correlated with a non-dipper type of essential hypertension. Thiazolidinediones (TZD), oral hypoglycaemic agents that act as insulin sensitizers, have been demonstrated in multiple in vivo and in vitro studies to possess antihypertensive properties. This study examined the efficacy of TZD therapy with pioglitazone at transforming the circadian rhythms of blood pressure from a non-dipper to a dipper type. MATERIALS: We examined 31 patients with type 2 diabetes mellitus during both a baseline period and a period of treatment with pioglitazone. Patients received 15 mg day(-1) pioglitazone for four weeks and 30 mg day(-1) for 12 weeks. Twenty-four hour ambulatory blood pressure monitoring (ABPM) and laboratory data (blood tests for cardiovascular risk factors) were obtained at the beginning and end of the study. RESULTS: In non-dippers (n = 16), but not dippers (n = 15), we observed a significant interaction between pioglitazone therapy and nocturnal falls in systolic and diastolic blood pressure. This examination indicated that the magnitude of the nocturnal blood pressure fall was affected by pioglitazone therapy. In non-dippers, but not dippers, a significant correlation was observed between the percent decrease in nocturnal BP and the homeostasis model assessment (HOMA) index (r = 0.774, P = 0.0007). CONCLUSIONS: The present study demonstrated that pioglitazone can restore the nocturnal BP declines in parallel to reductions in the HOMA index, suggesting that insulin resistance may play an important role in the genesis of circadian BP rhythms. TZD-based treatment may thus have the additional therapeutic advantage of reducing the risk of cardiovascular complications by transforming the circadian rhythm of BP.

Development of colonic necrosis following severe acute pancreatitis.

We herein describe a 70-year-old male patient who developed colonic necrosis following severe acute pancreatitis. He was referred to our hospital with a diagnosis of acute pancreatitis. In the course of the disease, he developed sudden and massive hematochezia and died. The autopsy findings revealed large bowel ischemia with transmural infarction. The possible pathogenic mechanisms of colonic ischemia are also discussed.

A case of multiple myeloma which developed into multiple extramedullary involvement in the terminal stage.

A 69-year-old man with a diagnosis of multiple IgG class myeloma received combination chemotherapy. He achieved a partial response with an undetected M spike. However, he demonstrated new lytic bone lesions and multiple extramedullary involvement 10 months after the initial presentation. Polymerase chain reaction (PCR) analysis using a framework 3 (Fr3) V-region primer clarified a discrete band in the extramedullary tumor, while it yielded 4 bands including the same size as the extramedullary tumor produced in the bone marrow sample obtained before the chemotherapy. These findings suggest that a resistant and non-secretory clone was selected by the combination chemotherapy.

Association of polymorphism in the NeuroD/BETA2 gene with type 1 diabetes in the Japanese.

NeuroD/BETA2, a transcription factor of the insulin gene, also plays an important role in the development of pancreatic beta-cells. Recently, the NeuroD/BETA2 gene has been mapped to the long arm of human chromosome 2 (2q32) where the IDDM7 gene has previously been mapped, implying its involvement in diabetes. To identify mutations in the NeuroD/BETA2 gene that may predispose patients to develop diabetes, we studied the gene in 50 Japanese subjects with diabetes (4 with type 1 and 46 with type 2) by the polymerase chain reaction (PCR) followed by single-strand conformation polymorphism and sequencing analyses. Further analysis was performed in 392 Japanese subjects (60 with type 1 and 158 with type 2 diabetes and 174 healthy control subjects) by mismatch PCR restriction fragment length polymorphism. We found a DNA polymorphism of the NeuroD/BETA2 gene. A nucleotide G-to-A transition results in the substitution of alanine to threonine at codon 45 (Ala45Thr). The frequencies of heterozygotes for the Ala45Thr variant were 9.8% in the control subjects, 9.5% in the patients with type 2 diabetes, and 25.0% in the patients with type 1 diabetes, a significant difference (P = 0.006). Because the variant of the NeuroD/BETA2 gene (Ala45Thr) is associated with type 1 but not type 2 diabetes, it may be implicated in the loss of pancreatic beta-cells in type 1 diabetes.

The value of colour Doppler ultrasonography for small bowel involvement of adult Henoch-Schönlein purpura.

Three patients presented with a non-thrombocytopenic purpuric rash on their upper and lower limbs, abdominal pain, diarrhoea, and arthralgia. Grey scale ultrasound showed abnormally thickened walls of the small bowel. Colour Doppler showed blood flow signals in the diseased bowel wall in all patients. Subsequent barium and endoscopic studies showed oedematous bowel loops with petechial lesions. Biopsy from the purpuric rash of the skin demonstrated vasculitis of subdermal small vessels. The clinical diagnosis of Henoch-Schönlein purpura was made in each case. This paper describes the efficacy of grey scale and colour Doppler ultrasonography in the assessment of the small bowel involvement of Henoch-Schönlein purpura.

Interaction of some drugs on the pharmacokinetics or pharmacodynamics of MPC-1304, a dihydropyridine Ca2+ antagonist.

The aim of this study was to assess the pharmacokinetics and subsequent pharmacodynamic interaction of MPC-1304, a dihydropyridine Ca2+ antagonist, with other drugs in animal experiments. We measured the systolic blood pressure and heart rate of conscious spontaneously hypertensive rats implanted with battery-operated biotelemetry devices after combined administration of various drugs. Cimetidine (10 mg/kg) did not affect the reduction in systolic blood pressure and the increase in heart rate induced by MPC-1304, whereas it significantly increased the plasma concentration of a metabolite of MPC-1304 (M-1) compared to that detected when MPC-1304 was administered alone. When MPC-1304 was consecutively administered in combination with rifampicin (400 mg/kg) for 9 days, the plasma concentrations of MPC-1304 and of M-1 significantly decreased compared to those found when MPC-1304 alone was given. In spite of these reductions in plasma concentrations, rifampicin did not attenuate the hypotensive action induced by MPC-1304. When prazosin, reserpine, or methyldopa was administered in combination with MPC-1304, the hypotensive action was enhanced as compared to that by MPC-1304 alone or to that by the co-administered drug used alone (prazosin, reserpine, or methyldopa). Quinidine (10 mg/kg) affected neither the hypotensive action induced by MPC-1304 nor the plasma concentrations of MPC-1304 and M-1. These results indicate that cimetidine and rifampicin interact with MPC-1304 pharmacokinetically, without apparently changing the hypotensive action of MPC-1304, whereas quinidine does not affect the metabolism of MPC-1304, and that other hypotensive drugs, such as prazosin, reserpine, and methyldopa, potentiate the hypotensive action of MPC-1304.

An autopsy case of B-cell lymphoma associated with macroglobulinemia (IgM-k).

While he was treated for macroglobulinemia showing symptoms, a 65-year-old man developed an enlargement of the left lateral cervical lymph node. Biopsy specimens of the cervical lymph node revealed large-cell non-Hodgkin's lymphoma. The lymphoma cells had rearrangement in the immunoglobulin heavy chain and kappa light chain genes. There was osteolysis involving right metatarsal bones. And, a tumor appeared on the upper hard palate in the terminal stage. Autopsy specimens showed infiltration of lymphoma cells into multiple organs. Production of monoclonal immunoglobulin M was detected only slightly and focally in the tumors. Plasmacytic differentiation as in Waldenström's macroglobulinemia was not seen in any organs except the tumor on the upper hard palate. From these findings, it is speculated that B-cell lymphoma might have developed in the course of macroglobulinemia.

Clinical features of 25 patients with aplastic anemia.

We experienced 27 patients with aplastic anemia (AA) during the period of 1984 to 1988. Of these, clinical characteristics of 25 patients who were followed up until death or at least for 2 years were evaluated. In terms of the degree of the initial hematological impairment, the patients were separated into 3 groups: 9 (36%) in severe, 11 (44%) in moderate, and 5 (20%) in mild impairment. The survival rates in 24 months after diagnosis were 44% in severe, 64% in moderate, and 100% in mild, indicating close relation between the degree of the initial hematological impairment and survival rates. 9 patients in a severe group received blood transfusion, anabolic steroids and/or high-dose corticosteroids, but these treatments resulted in an unsatisfactory outcome. It is suggested that they need other therapeutic modalities, including bone marrow transplantation. When the initial hematological data were compared between a group of patients who were alive for more than two years and a group of patients who died within two years, the mean granulocyte counts and reticulocyte counts of these two groups showed significant differences. However, the mean platelet counts were not significantly different. This indicates that the initial granulocyte count and reticulocyte count are indicators of prognosis in AA, and that the initial platelet count does not influence the prognosis.

[Streptomycin-induced severe aplastic anemia successfully treated with high-dose methylprednisolone pulse therapy and rhG-CSF].

An 83-year-old male was admitted with pulmonary tuberculosis. He was started on rifampicin, isoniazid, and streptomycin (SM). The hematological data at 12 weeks after the treatment showed pancytopenia (RBC: 2.14 x 10(6)/microliters, Hb: 7.2g/dl, Plt: 1.8 x 10(4)/microliters, WBC: 700/microliters). All the above medicines were discontinued and he received bolus methylprednisolone (bmPSL) and recombinant human granulocyte-colony stimulating factor (rhG-CSF). After 3 cycles of bmPSL, red blood cells and platelets gradually increased. White blood cells also increased in response to rhG-CSF. Bone marrow aspirate and biopsy specimens showed normocellularity, indicating recovery from aplastic anemia. Drug lymphocyte stimulation test was positive for SM.

[Significance of measuring 5-fluorouracil incorporated into RNA of tumor tissue as a parameter for the antitumor activity of 5-fluorouracil and its analogs].

A sensitive method for determination of incorporation of non-radiolabeled 5-fluorouracil (FUra) into RNA (F-RNA) of tumor tissue samples was established and was shown to be applicable to clinical materials. RNA fractions containing incorporated FUra were extracted from perchloric acid precipitates of tissue sonicates by KOH hydrolysis. FUra in RNA fractions was released by HCl hydrolysis at 100 degrees C and its levels were determined by GC-MS. The sensitivity of this method was 100 fold higher than that of HPLC method. F-RNA levels were dose dependent and correlated well with antitumor efficacy of the drugs. F-RNA levels in FUra resistant murine tumors were significantly lower than that in parent tumors despite of the lack of difference in FUra concentrations in tumor tissue. Based on these results, it is suggested that measurement of F-RNA levels together with the determination of FUra concentration and the inhibition rate of thymidylate synthase should be considered as a good parameters of the evaluation of antitumor efficacy of FUra and its analogs both in experimental and clinical settings.

Metabolism of tegafur in rat liver observed by in vivo 19F magnetic resonance spectroscopy and chromatography.

Metabolism of tegafur in the rat liver was observed by in-vivo 19F magnetic resonance spectroscopy (MRS). After MRS observation, tegafur and q-fluorouracil (5-FU) in the liver were determined by a chromatographic method for comparison with the results of 19F-MRS. Rats were divided into 3 groups: 1) CCl4-induced liver injury group, 2) uracil combined group, 3) control group. Catabolism to fluoro-beta-alanine was suppressed in both the liver injury group and the uracil combined group. Low peaks of 5-FU and fluoronucleotides could be found only in the uracil combined group. The result of 19F MRS observation of each group was in agreement with the result of determination of tegafur and 5-FU by chromatography. This showed that substances which could be observed by 19F-MRS were in proportion to all intracellular fluoro-containing substances. 19F-MRS can provide direct information on the metabolism of fluoropyimidines non-invasively and it might be a useful aid in choosing suitable chemotherapy for patients.

Induction of DNA synthesis by fibroblast growth factor in temperature-sensitive cell-cycle mutants of rat 3Y1 fibroblasts arrested at restrictive temperature.

Four temperature-sensitive cell-cycle mutants of rat 3Y1 clonal fibroblasts representing separate complementation groups (3Y1tsD123, 3Y1tsF121, 3Y1tsG125 and 3Y1tsH203) are arrested at restrictive temperature, primarily with a G1-phase DNA content (temperature arrest). We examined various factors affecting signal transduction for activity which induces DNA synthesis at the restrictive temperature when added to the temperature-arrested cultures of these mutants. The factors examined were theophylline, dibutyryl cyclic AMP, cholera toxin (CT), dibutyryl cyclic GMP, sodium nitroprusside, phorbol 12-myristate 13-acetate, 1-oleoyl 2-acetylglycerol, bombesin, vasopressin, basic fibroblast growth factor (FGF), platelet-derived growth factor, A23187, monensin, epidermal growth factor (EGF), insulin and fetal calf serum (FCS). None of these factors induced DNA synthesis in 3Y1tsH203. In one mutant (3Y1ts121), FGF, EGF and FCS individually induced DNA synthesis. In the other 2 mutants (3Y1tsD123 and 3Y1tsG125), FGF and CT individually induced DNA synthesis. The FGF-induced DNA synthesis was suppressed by islet-activating protein (IAP) in 3Y1tsD123 and 3Y1tsG125, but not in 3Y1tsF121. The CT-induced DNA synthesis was also suppressed by IAP, as previously shown. When temperature-arrested cultures were shifted to a permissive temperature, all 4 mutants initiated DNA synthesis in the presence of IAP. These results suggest that (1) a cell can prepare for the initiation of DNA synthesis by using several independent signal transduction pathways, and (2) in a given situation, the cell uses a particular pathway because of its availability, which depends on the culture conditions.

Combinative improving effect of increased solubility and the use of absorption enhancers on the rectal absorption of uracil in beagle dogs.

An improvement of the rectal absorption of uracil was examined by the application of absorption enhancers in addition to the increased solubility of uracil. Uracil was ground with additives such as MgO, sodium 2,6-dihydroxybenzoate, human serum albumin or hydroxypropylmethylcellulose acetate succinate. Aqueous, oily and powdery formulations, which consisted of the ground mixtures, nicotinamide, urea and absorption enhancers such as polyoxyethylene (23) cetylether (BC-23) or sodium caprate, were prepared. Uracil solubility in the aqueous formulations was increased about 4-13 times that in the corresponding control formulations. When rectally administered to beagle dogs, marked increases in the plasma uracil level were observed in some of the cases of aqueous and oily formulations. In the powdery formulations and formulations containing macromolecular additives, however, absorption improvements was not observed. The results indicated that an improvement in the absorption of uracil was caused by the combinative improving effect of the increased uracil solubility and the promoting effect of absorption enhancers.

Proliferative behaviour of fibroblasts in plasma-rich culture medium.

We examined the proliferative behaviour in tertiary culture cells of human skin fibroblasts (HSF) as well as cells of the rat 3Y1 diploid fibroblast line placed on a plastic substratum in a nutrient-rich medium containing high concentrations of platelet-poor plasma (PPP). Autochthonous human PPP was used for the HSF cells and heat-treated (at 56 degrees C for 30 min) bovine PPP was used for the 3Y1 cells. In both types of cells, the saturation cell density rose with increasing PPP concentration and reached a plateau at 30-90% PPP. When the cells were cultivated in serum, the saturation densities were the same as those with the same concentrations of corresponding PPP in both the HSF and 3Y1 cells. When the cells were arrested at a saturation cell density in a medium containing 10% PPP and then were refed with a fresh medium containing 90% PPP, DNA synthesis and cell division occurred in both types of fibroblasts. This effect was either reduced in the HSF cells or enhanced in the 3Y1 cells by the addition of platelet lysate. TGF-beta 1 added to the fresh medium containing 90% PPP also inhibited the induction of DNA synthesis in the HSF cells but not in the 3Y1 cells. The inhibitory effect of the platelet lysate was neutralized by anti-TGF-beta 1 IgG. On the other hand, PDGF added to the fresh medium had no effect on either type of cells. These results suggest that cultured fibroblasts are capable of proliferating on a plastic substratum under fluid conditions that essentially reflect the fluid environment of the body, as long as sufficient nutrients are supplied. Platelet lysate represses the proliferation of HSF cells, possibly through the inhibitory effect of TGF-beta 1, and promotes the proliferation of 3Y1 cells by growth factor(s) other than PDGF and TGF-beta 1.