Biomedical subjects

Y Matsuzawa

Publications and source records attributed to Y Matsuzawa.

At least 19 recordsLinked to original sources

PubMed1999

Transformation and morphological changes of murine L cells by transfection with a mutated form of beta-catenin.

To shed light on the oncogenic nature of mutant beta-catenin, we introduced a form of the cDNA that lacked an entire exon 3 into L cells derived from murine s.c. tissue. Aberrant beta-catenin protein accumulated in the cytoplasm and nuclei of these cells (designated L-MT), whereas in L cells transfected with wild-type beta-catenin (designated L-N), normal beta-catenin protein was expressed at a level similar to that of parental cells. L-MT cells also changed morphologically from a fibroblast-like appearance to a more cuboidal shape. Their rate of proliferation was the same as that of L cells and L-N cells, but the saturation density of L-MT cells appeared to increase in association with a multilayer growth pattern. Furthermore, L-MT cells required a lower concentration of serum in the growth medium than did parental cells. These alterations in cell growth and morphology suggested that mutated beta-catenin was stabilized in the transfected cells and induced the oncogenic phenotype.

Animals↗

PubMed1999

Expression of human scavenger receptor class B type I in cultured human monocyte-derived macrophages and atherosclerotic lesions.

The scavenger receptor class B type I (SR-BI) and its human homologue CLA-1 (CD36 and LIMPII Analogous-1) have recently been identified to bind HDL and mediate the selective uptake of HDL lipids. Tissue distribution of both murine and human receptors is quite similar, in that they are expressed abundantly in liver and steroidogenic tissues. However, expression and function of the human SR-BI (hSR-BI), in the periphery of reverse cholesterol transport such as macrophages, are still unclear. In the present study, we have raised two different kinds of anti-hSR-BI polypeptide antibodies (Abs): one against the extracellular domain and the other against the intracellular domain. We have investigated the expression of hSR-BI mRNA and immunoreactive mass in freshly isolated cultured human monocyte-derived macrophages (hMphi) and in atherosclerotic lesions. Contrary to the earlier report, hSR-BI mRNA was expressed in cultured hMphi and markedly upregulated with differentiation, determined by Northern blot and reverse transcriptase-based polymerase chain reaction analyses. The mRNA expression pattern during differentiation of hMphi was very similar to those of SR class A and another member of SR class B, CD36. Protein expression was confirmed by Western blot analyses with the above Abs to show a major 83-kDa band. Modified lipoproteins such as oxidized LDL and acetylated LDL induced a 5-fold increase in mRNA and protein expression of hSR-BI. Confocal immunofluorescence microscopy demonstrated that hSR-BI immunoreactive mass was detectable as a heterogeneous, punctate staining pattern. Furthermore, immunohistochemical analysis showed that immunoreactive mass of hSR-BI was detected in foam cells in human aortic atherosclerotic lesions and that there was no significant difference of staining patterns between the two Abs. This study clearly demonstrates that hSR-BI is expressed in the lipid-laden macrophages in human atherosclerotic lesions, suggesting that it is very important to know its function and regulation in hMphi to understand the biological utility of this molecule.

Animals↗

PubMed1999

Effects of exogenous human heparin-binding epidermal growth factor-like growth factor on DNA synthesis of hepatocytes in normal mouse liver.

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) has been reported to stimulate DNA synthesis of the hepatocytes in culture and highly express in regenerating rat liver after partial hepatectomy. We examined mitogenic effects and activation of transcription factors caused by exogenous human HB-EGF (hHB-EGF) in mouse liver. The mean labeling index in hepatocytes of hHB-EGF-injected mice was 2.6%, a significant increase over that in saline-injected controls (under 0.01%). By exogenous hHB-EGF injection, activation of transcription factors such as nuclear factor (NF)-kappaB and activator factor (AP)-1 was observed in the liver. By Northern blot analysis, hepatocyte growth factor (HGF) gene expression in the liver was found to be induced in the hHB-EGF-injected mice. In conclusion, intravenously injected hHB-EGF showed a limited but definite effect on the DNA synthesis of hepatocytes in the mice liver. HB-EGF may serve as a hepatotrophic factor in vivo.

Animals↗

PubMed1999

The requirement of both intracellular reactive oxygen species and intracellular calcium elevation for the induction of heparin-binding EGF-like growth factor in vascular endothelial cells and smooth muscle cells.

Heparin-binding EGF-like growth factor (HB-EGF), which is a potent mitogen for vascular smooth muscle cells (SMC) and fibroblasts, has been reported to be strongly implicated in atherosclerosis and wound healing. HB-EGF mRNA is known to be induced by thrombin, angiotensin-II, basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), and HB-EGF itself in SMC. In vascular endothelial cells (EC), its mRNA is induced by tumor necrosis factor-alpha and interleukin-1beta. Only phorbol 12-myristate 13-acetate is a common inducer for HB-EGF mRNA. The present study shows that calcium ionophore A23187 also induced HB-EGF mRNA in both SMC and in EC and that both intracellular reactive oxygen species (ROS) and an increase in calcium levels were essential for the induction of this growth factor mRNA. While HB-EGF caused an increase in both intracellular ROS and calcium in SMC, it increased only calcium, but not the intracellular ROS in EC. When the intracellular ROS was elevated by treatment with hydrogen peroxide (H2O2) or by depletion of glutathione by buthionine sulfoxamine, both HB-EGF and thrombin were observed to upregulate HB-EGF mRNA in EC. These data suggest that H2O2, produced by activated leukocytes in inflammatory lesions, upregulates HB-EGF mRNA by cooperating with thrombin, angiotensin-II, and the above growth factors. Since activated macrophages under the EC are thought to elevate the ROS in neighboring EC, this mechanism might play a major role in the progression of atherosclerosis and for wound healing.

Buthionine Sulfoximine↗

PubMed1999

A mutation in the extracellular cysteine-rich repeat region of the beta3 subunit activates integrins alphaIIbbeta3 and alphaVbeta3.

Inside-out signaling regulates the ligand-binding function of integrins through changes in receptor affinity and/or avidity. For example, alphaIIbbeta3 is in a low-affinity/avidity state in resting platelets, and activation of the receptor by platelet agonists enables fibrinogen to bind. In addition, certain mutations and truncations of the integrin cytoplasmic tails are associated with a high-affinity/avidity receptor. To further evaluate the structural basis of integrin activation, stable Chinese hamster ovary (CHO) cell transfectants were screened for high-affinity/avidity variants of alphaIIbbeta3. One clone (AM-1) expressed constitutively active alphaIIbbeta3, as evidenced by (1) binding of soluble fibrinogen and PAC1, a ligand-mimetic antialphaIIbbeta3 antibody; and (2) fibrinogen-dependent cell aggregation. Sequence analysis and mutant expression in 293 cells proved that a single amino acid substitution in the cysteine-rich, extracellular portion of beta3(T562N) was responsible for receptor activation. In fact, T562N also activated alphaVbeta3, leading to spontaneous binding of soluble fibrinogen to 293 cells. In contrast, neither T562A nor T562Q activated alphaIIbbeta3, suggesting that acquisition of asparagine at residue 562 was the relevant variable. T562N also led to aberrant glycosylation of beta3, but this was not responsible for the receptor activation. The binding of soluble fibrinogen to alphaIIbbeta3(T562N) was not sufficient to trigger tyrosine phosphorylation of pp125(FAK), indicating that additional post-ligand binding events are required to activate this protein tyrosine kinase during integrin signaling. These studies have uncovered a novel gain-of-function mutation in a region of beta3 intermediate between the ligand-binding region and the cytoplasmic tail, and they suggest that this region is involved in integrin structural changes during inside-out signaling.

Amino Acid Substitution↗

PubMed1999

Stromal cell CD9 regulates differentiation of hematopoietic stem/progenitor cells.

CD9 belongs to the transmembrane 4 superfamily, and has been shown to influence cell proliferation, motility, and adhesion. We show here that ligation of CD9 modifies proliferation and/or differentiation of hematopoietic stem/progenitors. Pluripotent EML-C1 hematopoietic cells were cocultured with MS-5 stromal cells in the presence of KMC8.8, an anti-CD9 antibody. Numbers of recovered EML-C1 cells were slightly reduced and the antibody caused the hematopoietic cells to migrate beneath the adherent stromal cell layer. Of particular interest, EML-C1 cells recovered from CD9-ligated cultures had undifferentiated properties. Separate pretreatment of the two cell types with antibody showed that stromal-cell CD9 mediated these responses. Spontaneous expression of erythroid marker was completely blocked and there was a shift towards undifferentiated clonogenic progenitors. Immunoprecipitation studies showed that stromal-cell CD9 associates with the beta1 subunit of integrin, as well as a novel 100 kD protein. Antibody cross-linking of cell surface CD9 increased the amount of 100 kD protein that was subsequently coprecipitated with CD9. These observations show that stromal-cell CD9 influences physical interactions with hematopoietic cells and may be one factor that determines the degree of stem cell differentiation.

Animals↗

PubMed1999

Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity.

We isolated the human adipose-specific and most abundant gene transcript, apM1 (Maeda, K., et al., Biochem. Biophys. Res. Commun. 221, 286-289, 1996). The apM1 gene product was a kind of soluble matrix protein, which we named adiponectin. To quantitate the plasma adiponectin concentration, we have produced monoclonal and polyclonal antibodies for human adiponectin and developed an enzyme-linked immunosorbent assay (ELISA) system. Adiponectin was abundantly present in the plasma of healthy volunteers in the range from 1.9 to 17.0 mg/ml. Plasma concentrations of adiponectin in obese subjects were significantly lower than those in non-obese subjects, although adiponectin is secreted only from adipose tissue. The ELISA system developed in this study will be useful for elucidating the physiological and pathophysiological role of adiponectin in humans.

Adiponectin↗

PubMed1999

Both Stat3-activation and Stat3-independent BCL2 downregulation are important for interleukin-6-induced apoptosis of 1A9-M cells.

A unique subclone of a bone marrow-derived stromal cell line, BMS2.4, produces soluble factors that inhibit proliferation of several types of hematopoietic cell lines. An understanding of these molecules may be informative about negative regulatory circuits that can potentially limit blood cell formation. We used expression cloning to identify interleukin-6 (IL-6) as one factor that suppressed growth of a pre-B-cell variant line, 1A9-M. Moreover, IL-6 induced macrophage-differentiation and apoptosis of 1A9-M cells. During this process, IL-6 downregulated expression of BCL2 in 1A9-M cells and stimulated BCL-XL expression, but had no effect on p53, Bax, or Bak gene expression. Mechanisms for transduction of IL-6-induced signals were then evaluated in IL-6-stimulated 1A9-M cells. Whereas the signal transducer and activator of transcription 3 (Stat3) was phosphorylated and activated, there was no effect on either Stat1 or Stat5. The importance of BCL2 and Stat3 on IL-6-induced macrophage-differentiation and apoptosis was studied with 1A9-M cells expressing human BCL2 or a dominant-negative form of Stat3, respectively. IL-6-induced apoptosis, but not macrophage-differentiation, was blocked by continuously expressed BCL2. A dominant-negative form of Stat3 inhibited both macrophage-differentiation and apoptosis induced by IL-6. However, diminished Stat3 activity did not prevent IL-6-induced downregulation of the BCL2 gene. Therefore, activation of Stat3 is essential for IL-6-induced macrophage-differentiation and programmed cell death in this model. Whereas overexpression of BCL2 abrogates the apoptotic response, Stat3-independent signals appear to downregulate expression of the BCL2 gene.

Apoptosis↗

PubMed1999

Effect of farnesyltransferase overexpression on cell growth and transformation.

A series of studies using farnesyltransferase (FTase) inhibitors that the inhibition of FTase function suppresses the growth of ras-transformed cells in vitro and in vivo. However, whether FTase is directly involved in the regulation of cell proliferation remains to be demonstrated. To investigate whether overexpression of FTase results in altered cell growth and transformation, we thus used NIH3T3 cells transfected with cDNA constructs of both alpha and beta subunits of human FTase. FTase-overexpressing cells resulted in a 3- to 13-fold increase in the expression of the alpha and beta subunit protein of FTase and a 1.5- to 3-fold increase in the level of the enzyme activity compared with untransfected NIH3T3 cells or vector-transfected cells. Further investigations using metabolic labeling indicated that farnesylation of Ras was enhanced in FTase-overexpressing cells. Insulin-like growth factor-I, platelet-derived growth factor (PDGF), and basic fibroblast growth factor (bFGF) more potently enhanced DNA synthesis and anchorage-dependent growth in FTase-overexpressing cells than in control cells, in a dose-dependent manner. In particular, PDGF and bFGF also induced dose-dependently enhanced colony formation in soft agar in FTase-overexpressing cells. Furthermore, in FTase-transfectants, bFGF stimulated high activation of mitogen-activated protein kinase. Interestingly, FTase-transfectants developed progressive tumors in nude mice. Light and electron microscopy showed that the tumors were characteristic of fibrosarcoma, which were distinct from v-ras-induced tumors. Overexpression of FTase in NIH3T3 cells thus amplifies growth-factor-mediated cell growth and transformation, and FTase-overexpressing cells form tumors in nude mice.

3T3 Cells↗

PubMed1999

Immunological abnormalities in islets at diagnosis paralleled further deterioration of glycaemic control in patients with recent-onset Type I (insulin-dependent) diabetes mellitus.

AIMS/HYPOTHESIS: To determine whether the clinical heterogeneity observed in the development of Type I (insulin-dependent) diabetes mellitus correlates with immunohistochemical differences observed at diagnosis. METHODS: Patients (n = 17) with recent-onset diabetes clinically considered to be insulin dependent (Type I), underwent pancreatic biopsy for immunohistological analysis. These patients were divided into two groups based on the presence or absence of islet immunological abnormalities (insulitis or hyperexpression of MHC class I antigens or both). The patients were also HLA typed and tested for islet cell antibodies and antibodies to glutamic acid decarboxylase (GAD-Ab). All patients were followed monthly for 2 years and their fasting plasma glucose, haemoglobin A1c and daily insulin doses were recorded. The clinical course of patients with islet immunological abnormalities was compared with that of patients without those abnormalities. RESULTS: Patients with and without islet immunological abnormalities did not differ with regard to HLA type or islet cell antibodies. Antibodies to glutamic acid decarboxylase correlated with the presence of insulitis and MHC class I hyperexpression. These local immunological abnormalities were also associated with higher haemoglobin A1c values (p < 0.05) and a trend towards greater insulin requirements. Further, patients with the islet abnormalities had higher fasting plasma glucose concentrations 2 years after the biopsy than at the time of the biopsy (p < 0.05). CONCLUSION/INTERPRETATION: The heterogeneous clinical course observed following diagnosis in patients with Type I diabetes correlates with islet immunological abnormalities. Insulitis and hyperexpression of MHC class I correlate with deteriorating glycaemic control.

Adolescent↗

PubMed1999

Three new mutations in the hepatocyte nuclear factor-1alpha gene in Japanese subjects with diabetes mellitus: clinical features and functional characterization.

AIMS/HYPOTHESIS: Mutations in the hepatocyte nuclear factor-1alpha gene are a common cause of the type 3 form of maturity-onset diabetes of the young. We examined the clinical features and molecular basis of hepatocyte nuclear factor-1alpha (HNF-1alpha) diabetes. METHODS: Thirty-seven Japanese subjects with early onset Type II (non-insulin-dependent) diabetes mellitus and 45 with Type I (insulin-dependent) diabetes mellitus were screened for mutations in this gene. Functional properties of mutant HNF-1alpha were also investigated. RESULTS: Three new mutations [G415R, R272C and A site of the promoter (+ 102G-to-C)] were found. Insulin secretion was impaired in the three subjects. Insulin and glucagon secretory responses to arginine in the subject with the R272C mutation were also diminished. Molecular biological studies indicated that the G415R mutation generated a protein with about 50% of the activity of wild-type HNF-1alpha. The R272C mutation had no transactivating or DNA binding activity and acted in a dominant negative manner. The + 102 G-to-C mutation in the A site of the promoter activity was associated with an increase in promoter activity and it had 42-75% more activity than the wild-type sequence. CONCLUSION/INTERPRETATION: Mutations in the HNF-1alpha gene may affect the normal islet function by different molecular mechanisms.

Adult↗

PubMed1999

Augmented growth response to IGF-1 via increased IRS-1 in Chinese hamster ovary cells expressing kinase-negative insulin receptors.

AIMS/HYPOTHESIS: Although both increased cell growth and impaired insulin signalling have been associated with diabetes, this association has not been investigated. Insulin-like growth factor-1 (IGF-1), a structural and functional analog of insulin, may play a part in the aberrant insulin receptor-mediated signalling observed in diabetes. METHODS: To investigate the consequence of this impaired signalling on cell proliferation and transformation, we transfected Chinese hamster ovary cells with cDNA encoding a kinase-defective insulin receptor. RESULTS: In these mutant cells, the mitogenic and metabolic effects of insulin were reduced compared with control cells (p < 0.05) and this was due to a dominant negative effect. In contrast, these mutant cells showed a higher mitogenic response to IGF-1 than control cells, although IGF-1 receptor expression was similar in both cell lines. There was no statistically significant difference in mitogenic response, however, to platelet-derived growth factor, basic fibroblast growth factor and heparin-binding epidermal growth factor-like growth factor. Variables of the IGF-1 signalling pathway, including tyrosine phosphorylation of insulin receptor substrate-1 and activation of mitogen-activated protein kinase and phosphatidyl inositol 3 kinase, were also augmented in mutant cells. Insulin receptor substrate-1 message and protein abundance were higher in mutant than in control cells. Moreover, mutant cells had a higher mitogenic potential in low-serum-containing medium, suggesting that these cells have a transformed phenotype. CONCLUSION/INTERPRETATION: These findings suggest that an impaired insulin signalling may upregulate insulin receptor substrate-1 and that this, in turn, leads to increased IGF-1 signalling, a phenomenon that is possibly associated with increased cell growth in diabetes.

Adaptor Proteins, Signal Transducing↗

PubMed1999

Different expression patterns of nitric oxide synthase isozymes in various gynecological cancers.

The expression of nitric oxide synthase (NOS) in human gynecological cancers, including ovarian cancers, uterocervical cancers, and endometrial cancers for example, was examined by the reverse transcriptase/polymerase chain reaction, coupled with Southern hybridization and by immunohistochemistry. Nitric oxide synthase II (NOS II), an inducible form, was expressed in more than 90% of the cancers. Nitric oxide synthase I (NOS I), a neuronal form, was expressed in 58% of all the ovarian cancers, in which the serous type is found more frequently (5 out of 7) than the mucinous type (2 out of 6), and in all clear-cell cancers. The frequency of NOS I expression in uterocervical cancers and endometrial cancers was relatively low. Nitric oxide synthase III (NOS III), an endothelial form, was detected in 25% of ovarian and 33% of endometrial cancers, while no expression was detected in uterocervical cancers. In terms of cancer types, all clear-cell adenocarcinomas and most of the serous-type adenocarcinomas expressed both NOS I and NOS II, while most uterine squamous carcinomas and endometrial adenocarcinomas expressed only NOS II. However, there was no correlation between the frequency of NOS expression and patients' age or the clinical stage of the disease. Since NO increases vascular permeability and blood flow, the high frequency of NOS expression in gynecological cancers may serve to stimulate and promote tumor growth.

Blotting, Southern↗

PubMed1999

Gastrin induces heparin-binding epidermal growth factor-like growth factor in rat gastric epithelial cells transfected with gastrin receptor.

BACKGROUND & AIMS: Parietal cells express heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF). However, it is unknown whether HB-EGF mediates the trophic action of gastrin. The purpose of this study was to determine whether gastrin modulates the expression of HB-EGF, which mediates the proliferative effects of gastrin on gastric epithelial cells. METHODS: RGM1 cells, a rat gastric epithelial cell line, were transfected with a human gastrin receptor complementary DNA. Gastrin induction of messenger RNAs (mRNAs) for EGF-related polypeptides was assayed by Northern blotting. Processing of cell surface-associated proHB-EGF and secretion of HB-EGF were determined by flow cytometry and Western blotting, respectively. Tyrosine phosphorylation of the EGF receptor was assayed by immunoprecipitation and Western blotting with an antiphosphotyrosine antibody. Cell growth was evaluated by [3H]thymidine incorporation. RESULTS: Gastrin induced expression of HB-EGF mRNA, processing of proHB-EGF, release of HB-EGF into the medium, and tyrosine phosphorylation of the EGF receptor. The growth-stimulatory effects of gastrin were partly inhibited by anti-rat HB-EGF serum and completely blocked by AG1478, an EGF receptor-specific tyrphostin. CONCLUSIONS: The findings suggest that HB-EGF at least partially mediates the proliferative effects of gastrin on gastric epithelial cells.

Animals↗

PubMed1999

Activation of monocytes in vivo causes intracellular accumulation of lipoprotein-derived lipids and marked hypocholesterolemia--a possible pathogenesis of necrobiotic xanthogranuloma.

Necrobiotic xanthogranuloma (NXG) is a rare histiocytic disease with generalized xanthomatosis. However, most cases with NXG are normolipidemic or hypolipidemic. The mechanism for the formation of xanthoma in NXG has not yet been clarified. We observed a case of NXG with severe hypocholesterolemia (total cholesterol: 1.69 mmol/l) and analyzed the function of monocytes in this case. Histological examinations by light microscopy revealed a large amount of lipid deposition in the patient's freshly isolated monocytes. The patient's monocytes showed a 3-fold increase in cholesteryl ester content and a 3-fold enhancement of acetyl low density lipoprotein (LDL) uptake compared with the control monocytes. However, no significant difference was noted in the expression of CD36 protein and the mRNA levels of scavenger receptor-class A (SR-A) between the monocytes of the patient and the control. The phagocytotic ability of the patient's monocytes was enhanced 1.5-fold compared with that of the control monocytes. These findings suggest that the activated monocytes may have degraded the modified LDL via a pathway other than CD36 or SR-A, and accumulated a great amount of lipids in vivo. In conclusion, the present study has demonstrated a possible pathogenesis of NXG that the activation of monocytes in vivo may contribute to the intracellular accumulation of lipoprotein-derived lipids leading to non-inherited xanthomatosis and the marked hypocholesterolemia.

Aged↗

PubMed1999

Analysis of serum lipid levels in Japanese men and women according to body mass index. Increase in risk of atherosclerosis in postmenopausal women. Research Group on Serum Lipid Survey 1990 in Japan.

Relatively low serum lipid levels are thought to be an important factor contributing to the low incidence of ischemic heart diseases (IHD) in Japanese. It has been proven that obesity or overweight constitutes a basal condition for several risk factors in atherosclerosis. The purpose of this study is to obtain data on serum lipids and lipoprotein profiles in relation to body mass index (BMI), which will enable us to compare the nature and weight of metabolic risk factors in atherosclerosis between Japanese and people in Western countries. Data of total serum cholesterol, triglyceride, and HDL-cholesterol levels of Japanese men and women obtained from a large-scale survey in 1990 were analysed according to BMI for different age groups. Apolipoprotein A-I and B and Lp(a) were also measured in randomly selected samples and their contribution as a risk factor was estimated especially in postmenopausal women. The subjects in two age groups of men (20-39 and 40 59 years) and women (20 39 and 50-69 years) were graded into quintiles according to the BMI. The middle grades of BMI were 21.9-23.3 and 22.4-23.6 for younger and older men, and 20.0-21.1 and 22.2-23.6 for younger and older women, respectively. These values are much lower than those in Western populations, the border between the IVth and the top quintile almost corresponding to the average for Americans. Total cholesterol showed a tendency to shift into higher ranges in all age groups in both men and women as BMI increased, with the highest distribution remaining in the range of 160-199 mg/dl (4.2-5.2 mmol/l). The average cholesterol levels for the top quintile of BMI were still lower than most of the average values in Western populations. The distribution of cholesterol in higher ranges was much greater and the difference according to BMI was smaller in older women than in men. In both men and women, whether younger or older, about 90% of the subjects in the lower quintiles of BMI had triglyceride levels lower than 150 mg/dl. The distribution in the higher range of triglyceride was small in women, not only at younger ages but also in postmenopausal women at the top quintile of BMI. About 85% of the younger women with a middle grade of BMI had an HDL-cholesterol level higher than 50 mg/dl. The values in postmenopausal women were still higher than in men aged 40-59 years. Shift of the distribution curves of HDL-cholesterol according to BMI was similar in all groups and more remarkable than the change in triglyceride. The average HDL-cholesterol levels at the top quintile were almost comparable to the average values in Western countries; the difference in HDL-cholesterol levels between the two populations can mostly be explained by the difference in BMI. Smokers showed a slightly lower total cholesterol and significantly (3-4 mg/dl) lower HDL-cholesterol levels, although there was no difference in distribution of BMI between smokers and non-smokers. Relatively low total cholesterol levels even in smokers has probably contributed to the low incidence of IHD in spite of the high frequency of smoking in Japanese population. Mean Lp(a) levels showed a tendency to increase after age 40 in women. BMI itself did not have a correlation with serum Lp(a) levels. The distribution curve of Lp(a) shifted to higher levels as total cholesterol increased and the tendency was most remarkable in women around or after the menopause. It was remarkable in older women that as the total cholesterol or apo B level increased there was also an increased prevalence of abnormal ECG with a pattern of myocardial ischemia. Postmenopausal women seem to have a great risk of atherosclerosis regarding the lipid and lipoprotein profile even in the Japanese population.

Adult↗

PubMed1999

Reduced plasma transforming growth factor-beta1 levels in patients with chronic hepatitis C after interferon-alpha therapy: association with regression of hepatic fibrosis.

BACKGROUND/AIM: Transforming growth factor-beta1 is involved in liver fibrosis. Our aim was to examine the association of plasma transforming growth factor-beta1 levels with the degree of liver fibrosis. METHODS: We analyzed plasma transforming growth factor-beta1 levels in 43 patients with chronic hepatitis C treated with interferon-alpha using a transforming growth factor-beta1 ELISA. The content of transforming growth factor-beta1 in liver tissue obtained by needle biopsy (n=13) was also analyzed. The degree of liver fibrosis was assessed histologically and morphometrically. RESULTS: Plasma transforming growth factor-beta1 levels were significantly correlated with transforming growth factor-beta1 content in liver tissue (r=0.83, p<0.001), indicating that plasma levels correspond with tissue cytokine. Plasma transforming growth factor-beta1 levels in patients (8.1+/-1.1 ng/ml) before interferon-a therapy were significantly higher than in controls (1.9+/-0.3 ng/ml) (p<0.01). Plasma levels were significantly correlated with the degree of fibrosis (p<0.01). Plasma transforming growth factor-beta1 levels were significantly decreased in sustained responders (from 5.2+/-1.0 ng/ml to 2.9+/-0.7 ng/ml), relapsed patients (from 9.8+/-2.0 ng/ml to 3.4+/-0.6 ng/ml), and nonresponders (from 9.3+/-2.1 ng/ml to 3.9+/-0.9 ng/ml) at the end of therapy (p<0.05 for all comparisons). Significant regression of liver fibrosis after therapy was observed in both sustained responders and nonresponders (p<0.05 for both). CONCLUSIONS: These observations suggest that plasma transforming growth factor-beta1 levels appear to be associated with the degree of liver fibrosis.

Aged↗

PubMed1999

Expiratory and inspiratory chest computed tomography and pulmonary function tests in cigarette smokers.

This study evaluated small airway dysfunction and emphysematous destruction of lung parenchyma in cigarette smokers, using chest expiratory high-resolution computed tomography (HRCT) and pulmonary function tests (PFT). The degree of emphysematous destruction was classified by visual scoring (VS) and the average HRCT number at full expiration/full inspiration (E/I ratio) calculated in 63 male smokers and 10 male nonsmokers (group A). The Brinkman smoking index (BI), defined as cigarettes x day(-1) x yrs, was estimated. Sixty-three smokers were divided into three groups by PFT: group B1 (n=7), with normal PFT; group B2 (n=21), with diffusing capacity of the lung for carbon monoxide (DL,CO) > or = 80% predicted, forced expiratory volume in one second (FEV1) < 80% pred and/or residual volume (RV) > 120% pred; and group B3 (n=35), with DL,CO < 80% pred, FEV1 < 80% pred and/or RV > 120% pred. Heavy smokers (BI > or = 600) (n=48) showed a significant increase in emphysema by both VS and E/I. E/I was significantly elevated in both group B2 (mean+/-SD 0.95+/-0.05) and B3 (0.96+/-0.06) compared with group B1 (0.89+/-0.03). VS could not differentiate group B2 (3.9+/-5.0) from B1 (1.1+/-1.6). These findings suggest that the expiration/inspiration ratio reflects hyperinflation and airway obstruction, regardless of the functional characteristics of emphysema, in cigarette smokers.

Forced Expiratory Volume↗