Impact of sex and its interaction with age on the management of and outcome for patients with acute myocardial infarction in 4 Japanese hospitals

Background Several studies from the United States and from European countries have detected sex and age differences in clinical characteristics, management, and outcomes of acute myocardial infarction. The aim of this study was to determine how sex and age influence the management of and outcome for patients with acute myocardial infarction in Japan. Methods A retrospective cohort study was performed by means of patient chart review at 4 teaching hospitals in Japan. There was a total of 482 patients (136 females [28%], 346 males [72%]) admitted consecutively with a diagnosis of acute myocardial infarction between July, 1995 and June, 1996. Results Female patients were older and had more comorbid diseases than male patients. Female patients also tended to have more cardiac complications during hospitalization and a greater 30-day mortality (10% vs 4%, P < .05). After adjustment for baseline characteristics and age/sex interaction, it was found that female patients were less likely to undergo thrombolytic therapy, cardiac catheterization, or revascularization, and they had a greater 30-day mortality. These sex differences in cardiac catheterization and revascularization were more pronounced for older patients. On the other hand, the sex differences in 30-day mortality were greater for younger patients. Conclusions Our data suggest that cardiac catheterization, revascularization and 30-day mortality may have been related to patient sex and age, but further study is needed. (Am Heart J 2002;144:101-7.)     

Effect of montelukast in a guinea pig model of cough variant asthma

Cough variant asthma is known as a major cause of chronic cough. Fundamental features of cough variant asthma are prolonged non-productive cough responding to bronchodilator therapy, no history of wheezing or dyspnea attack, normal cough sensitivity and slightly increased bronchial responsiveness. Recently, we reported the animal model of cough variant asthma. The aim of this study was to clarify the involvement of cysteinyl leukotrienes (cysLTs) in this model by using a specific leukotriene receptor antagonist, montelukast. Cough number and specific airway resistance (sRaw) were measured during the antigen inhalation (1.5 min) and following 18.5 min, which was carried out 72 h after the first antigen inhalation in actively sensitized guinea pigs, and then total cell number and cell differentials in bronchoalveolar lavage fluid (BALF) were measured. Montelukast significantly reduced the antigen re-inhalation-induced cough, increase in sRaw, and increase in total cell number in BALF. In conclusion, cysLTs may play an important part in antigen-induced cough associated with bronchoconstriction and airway inflammation in cough variant asthma.     

Relationships between working status and health or health-care utilization among Japanese elderly

Background:   As we have previously proposed redefining elderly from "65 years and over" to "75 and over" in Japan, many elderly Japanese now keep working beyond the traditional retirement age, around 60–65 years of age, in this rapidly aging society. It is important to assess the influence of working status on health and health-care utilization among elderly Japanese.
Methods:   We evaluated a random sample of community-dwelling Japanese elderly, aged 55–74 years. Data were collected using a health diary strategy. For health-related quality of life (HRQOL), we used SF-8 with a physical component summary (PCS8) and a mental component summary (MCS8). Health-care utilization included visiting physicians as well as using dietary and physical complementary and alternative medicine (CAM).
Results:   Among 679 participants aged 65–74 years (40.6% men), there were 254 (37.4%) working and 425 (62.6%) non-working. PCS8 and MCS8 were not significantly different between the working status groups. There were no differences in the rate for visiting physicians and using dietary and physical CAM between the working and non-working, except for those aged 70–74 years, who exhibited a higher rate for visiting a physician among the non-working. A higher annual personal income showed a significant association with better PCS8 ( P  = 0.031) and a trend towards better MCS8 ( P  = 0.055). The older participants were more likely to report better MCS8 than the young regardless of working status ( P  = 0.007).
Conclusion:   Working status itself does not appear to associate with health and health-care utilization among elderly Japanese. Working with a higher income may potentially improve HRQOL.     

Growth differentiation factor-9 induces Smad2 activation and inhibin B production in cultured human granulosa-luteal cells

The TGF beta family member growth differentiation factor-9 (GDF-9) is an oocyte-derived factor that is essential for mammalian ovarian folliculogenesis. GDF-9 mRNAs have been shown to be expressed in the human ovarian follicle from the primary follicle stage onward, and recombinant GDF-9 has been shown to promote human ovarian follicle growth in vitro. In this study with primary cultures of human granulosa-luteal (hGL) cells, we investigated whether recombinant GDF-9 activates components of the Smad signaling pathways known to be differentially activated by TGF beta and the bone morphogenetic proteins (BMPs). As with TGF beta, GDF-9 treatment caused the phosphorylation of endogenous 53-kDa proteins detected in Western blots with antiphospho-Smad2 antibodies (alpha PS2). However, unlike BMP-2, GDF-9 did not activate the phosphorylation of antiphospho-Smad1 antibody (alphaPS1)-immunoreactive proteins in hGL cells. Infection of hGL cells with an adenovirus expressing Smad2 (Ad-Smad2) confirmed that GDF-9 activates specifically phosphorylation of the Smad2 protein. Infection of hGL cells with Ad-Smad7, which expresses the inhibitory Smad7 protein, suppressed the levels of both GDF-9-induced endogenous and adenoviral alpha PS2-reactive proteins. Furthermore, GDF-9 increased the steady state levels of inhibin beta(B)-subunit mRNAs in hGL cells and strongly stimulated the secretion of dimeric inhibin B. Again, Ad-Smad7 blocked GDF-9-stimulated inhibin B production in a concentration-dependent manner. We identify here for the first time distinct molecular components of the GDF-9 signaling pathway in the human ovary. Our data suggest that GDF-9 mediates its effect through the pathway commonly activated by TGF beta and activin, but not that activated by many BMPs. The results are also consistent with the suggestion that in addition to endocrine control of inhibin production by gonadotropins, a local paracrine control of inhibin production is likely to occur via oocyte-derived factors in the human ovary.     

Volume reduction surgery for advanced hepatocellular carcinoma

Purpose The aim of this study was to evaluate the prognostic impact of reductive surgery on the survival of patients with advanced hepatocellular carcinoma (HCC).Methods Eligible patients had a main tumor greater than 10 cm in diameter with multiple intrahepatic metastases (>5 nodules), and good liver function (Child-Pugh class A), but no tumor thrombus in the main portal vein. The main tumor was surgically removed but the metastases were not removed and were treated with repeated transcatheter hepatic arterial chemo-embolization (TAE).Results From Jun 1997 to May 2003, 13 patients (median age 61 years, range: 48–74) were prospectively enrolled. The median diameter of the main tumor was 14 cm (range 11.5–18.0). No major surgical complications were observed and the median hospital stay was 12 days (range 7–20). The first TAE was performed 1 month after hepatectomy in all patients and was repeated for median of 5 (range: 1 to 16) times. Complete remission was observed in two patients. One patient had recurrence afterwards but another patient survived 41 months without recurrence. Three patients survived more than 3 years. The overall 1-, 3-, and 4-year survival rates of the 13 patients were 67.7%, 40.6%, and 40.6%, respectively.Conclusions Volume reduction surgery followed by TAE might prolong the survival of patients with a large HCC and intrahepatic metastases, especially those with a main tumor on the right side.Source of support: this study was supported by grants-in-aid for cancer research from the Ministry of Health, Labour and Welfare of Japan.     

src homology 2 domain-containing tyrosine phosphatase SHP-1 controls the development of allergic airway inflammation

Th2 cells are generated from naive CD4 T cells upon T cell receptor (TCR) recognition of antigen and IL-4 stimulation and play crucial roles in humoral immunity against infectious microorganisms and the pathogenesis of allergic and autoimmune diseases. A tyrosine phosphatase, SHP-1, that contains src homology 2 (SH2) domains is recognized as a negative regulator for various intracellular signaling molecules, including those downstream of the TCR and the IL-4 receptor. Here we assessed the role of SHP-1 in Th1/Th2 cell differentiation and in the development of Th2-dependent allergic airway inflammation by using a natural SHP-1 mutant, the motheaten mouse. CD4 T cells appear to develop normally in the heterozygous motheaten (me/+) thymus even though they express decreased amounts of SHP-1 (about one-third the level of wild-type thymus). The me/+ naive splenic CD4 T cells showed enhanced activation by IL-4 receptor-mediated signaling but only marginal enhancement of TCR-mediated signaling. Interestingly, the generation of Th2 cells was increased and specific cytokine production of mast cells was enhanced in me/+ mice. In an OVA-induced allergic airway inflammation model, eosinophilic inflammation, mucus hyperproduction, and airway hyperresponsiveness were enhanced in me/+ mice. Thus, SHP-1 may have a role as a negative regulator in the development of allergic responses, such as allergic asthma.     

Enhanced carbon tetrachloride-induced liver fibrosis in mice lacking adiponectin

BACKGROUND & AIMS: Obesity is one of the risk factors for liver fibrosis, in which plasma adiponectin, an adipocytokine, levels are decreased. Hepatic stellate cells play central roles in liver fibrosis. When they are activated, they undergo transformation to myofibroblast-like cells. Adiponectin suppresses the proliferation and migration of vascular smooth muscle cells, whose characteristics are similar to those of hepatic stellate cells. Adiponectin could have biological significances in liver fibrosis. METHODS: The role of adiponectin on liver fibrosis induced by the administration of carbon tetrachloride twice a week for 12 weeks was tested by using adiponectin-knockout mice and an adenovirus-mediated adiponectin-expression system. We also investigated the effect of adiponectin in activated hepatic stellate cells. RESULTS: When mice were administered carbon tetrachloride (300 microL/kg body weight) twice a week for 12 weeks, knockout mice showed extensive liver fibrosis with an enhanced expression of transforming growth factor-beta 1 and connective tissue growth factor compared with wild-type mice (P < 0.05). Injection of adenovirus producing adiponectin (AdADN) before carbon tetrachloride (1000 microL/kg body weight) treatment prevented liver fibrosis in wild-type mice (P < 0.001). Injection of AdADN at 6 weeks attenuated liver fibrosis even though carbon tetrachloride was given for an additional 6 weeks (total of 12 weeks). In cultured hepatic stellate cells, adiponectin suppressed platelet-derived growth factor-induced proliferation and migration and attenuated the effect of transforming growth factor-beta 1 on the gene expression of transforming growth factor-beta 1 and connective tissue growth factor and on nuclear translocation of Smad2. CONCLUSIONS: The findings indicate that adiponectin attenuates liver fibrosis and could be a novel approach in its prevention.     

The effects of dynein inhibition on the autophagic pathway in glioma cells

Autophagy has multiple physiological functions, including protein degradation, organelle turnover and the response of cancer cells to chemotherapy. Because autophagy is implicated in a number of diseases, a better understanding of the molecular mechanisms of autophagy is needed for therapeutic purposes, including rational design of drugs. Autophagy is a process that occurs in several steps as follows: formation of phagophores, formation of mature autophagosomes, targeting and trafficking of autophagosomes to lysosomes, formation of autolysosomes by fusion between autophagosomes and lysosomes, and finally, degradation of the autophagic bodies within the lysosomes. It has been suggested that autophagosome formation is driven by molecular motor machineries, and, once formed, autophagosomes need to reach lysosomes, enriched perinuclearly around the microtubule‐organizing centre. While it is recognized that all these steps require the cytoskeletal network, little is known about the mechanisms involved. Here we assessed the role of cytoplasmic dynein in the autophagic process of human glioma cells to determine the part played by dynein in autophagy. We observed that chemical interference with dynein function led to an accumulation of autophagosomes, suggesting impaired autophagosome‐lysosome fusion. In contrast, we found that overexpression of dynamitin, which disrupts the dynein complex, reduced the number of autophagosomes, suggesting the requirement of the dynein‐dynactin interaction in the early membrane trafficking step in autophagosome formation. These results suggest that dynein plays a variety of crucial roles during the autophagic process in glioma cells.