The role of leukocytes during acute phase inflammation in crystalline silica-induced lung injury

Silicosis is characterized by progressive granulomatous and fibrogenic response in the lung. Inhaled crystalline silica (Qt) induces activation of pulmonary macrophages and leukocyte infiltration in the lung of Qt-treated animals. We investigated the role of leukocyte infiltration and L-selectin during the acute phase of inflammation in developing chronic lung injury in Qt-treated rats. Seventy Wistar male rats were treated with a single transtracheal instillation of Qt (25 mg/kg). Rats were treated intraperitoneally with anti L-selectin monoclonal antibody (mAb), F(ab')2 HRL-3 (HRL-3, a blocking mAb), or RF(ab')2 HRL-2 (HRL-2, a non-blocking mAb)for 4 days before and after Qt injection. Administration of HRL-3 reduced approximately 50% of leukocyte infiltration in the BAL, whereas HRL-2 treatment prior to Qt stimulation showed time-dependent increase of BAL leukocytes. CINC and GRO levels as well as peripheral blood cell counts were similar in HRL-2- or HRL-3-treated animals in the first 4 days of the study. Three months after Qt treatment, extensive granuloma-containing macrophages and leukocytes developed in the lung of the HRL-3-treated rats as compared with the HRL-2-treated rats. Ratio of CD4+ to CD8+ T cells in granulomas did not differ between the HRL-3 and HRL-2 groups. Results suggest that an early phase of leukocyte activation was diminished by blocking L-selectin with the antibody, but treatment with anti-L-selectin increased the formation of granulomas in the Qt-treated rats.     

Acute myocardial infarction with patent infarct-related artery: selection of treatment based on qualitative analysis of coronary angiograms during the acute phase

To evaluate the benefit of emergency coronary angioplasty (PTCA) among patients with acute myocardial infarction having patent infarct-related arteries, we investigated 104 patients who received thrombolysis and/or PTCA within 24 hrs after onset of symptoms. The morphology of coronary artery lesions was qualitatively assessed by angiography and categorized as symmetrical or asymmetrical narrowing with smooth margins (S-group, 72 cases) and asymmetrical narrowing in the form of convex intraluminal obstruction representing a thrombus (T-group, 32 cases). Soon after intervention, angiographic success (residual stenosis less than 75%) was achieved in 85% with PTCA (92% in the T-group vs 82% in the S-group) and in 29% without PTCA (53% vs 16%). At hospital discharge, the figures were 82% with PTCA (75% vs 87%) and 43% without PTCA (73% vs 30%). The incidence of re-infarction and/or total occlusion of the infarct-related artery was 9% with PTCA in both the T- and S-groups but 26% in those without PTCA (6% in the T-group vs 31% in the S-group). These data suggest that in patients with patient infarct-related arteries and severe original stenosis, PTCA has an advantage over thrombolysis alone. Qualitative analysis of coronary morphology by angiography provides a framework for selecting adequate therapy.     

Fatty acid induced insulin resistance in rat-1 fibroblasts overexpressing human insulin receptors: impaired insulin-stimulated mitogen-activated protein kinase activity

Summary Saturated fatty acids cause insulin resistance but the underlying molecular mechanism is still unknown. We examined the effect of saturated non-esterified fatty acids on insulin binding and action in transfected Rat-1 fibroblasts, which over-expressed human insulin receptors. Incubation with 1.0 mmol/l palmitate for 1–4 h did not affect insulin binding, insulin receptor autophosphorylation, insulin-stimulated tyrosine kinase activity toward poly(Glu⁴:Tyr¹), pp185 and Shc phosphorylation and PI3-kinase activity in these cells. However, the dose response curve of insulin-stimulated glucose transport was right-shifted. Palmitate inhibited the maximally insulin-stimulated mitogen activated protein (MAP) kinase activity toward synthetic peptide to 7 % that of control. The palmitate treatment influenced neither cytosolic protein kinase A activity nor cAMP levels. These results suggested that 1) palmitate did not inhibit the early steps of insulin action from insulin binding to pp185 or Shc phosphorylation but inhibited insulin-stimulated MAP kinase, and that 2) palmitate decreased insulin sensitivity as manifested by inhibited insulin-stimulated glucose uptake. In conclusion, the mechanism of saturated non-esterified fatty acid induced insulin resistance in glucose uptake may reside at post PI3-kinase or Shc steps, including the level of MAP kinase activation. [Diabetologia (1997) 40: 894–901] Received: 15 January 1997 and in revised form: 9 April 1997     

Tongue-coating as risk indicator for aspiration pneumonia in edentate elderly

Silent aspiration of oral microorganisms is a major cause of aspiration pneumonia. To establish oral hygiene criteria for the prevention of aspiration pneumonia in edentulous elderly persons, we investigated the relationship between presence of tongue-coating and number of oral bacteria in saliva and episodes of pneumonia. A total of 71 edentulous Japanese people aged 65 years or older living in nursing homes were enrolled in the study. A tongue plaque index (TPI) was used to evaluate quantity of tongue-coating, with TPI0 signifying no tongue-coating and TPI1 signifying presence of tongue-coating. Edentate elderly with TPI1 demonstrated significantly higher salivary bacterial counts than those with TPI0 (p < 0.05). The number of elderly patients developing aspiration pneumonia was larger (p < 0.005) in patients with TPI-based poor scores (average TPI > 0.5) than in those with TPI-based good scores. The relative risk of developing pneumonia in the good tongue hygiene group compared with in the poor tongue hygiene group was 0.12, 95% confidence interval (CI): 0.02–0.9. The results demonstrate that tongue-coating is associated with number of viable salivary bacterial cells and development of aspiration pneumonia, suggesting that tongue-coating is a risk indicator of aspiration pneumonia in edentate subjects.     

Effect of cimetidine on gastric mucus glycoprotein biosynthesis

The effects of cimetidine on gastric mucus glycoprotein biosynthesis in rat gastric mucosa were investigated using organ culture technique. 2 h following oral administration of cimetidine (40 mg/kg body weight), corpus tissue was placed in the organ culture. Mucus glycoprotein synthesis was accelerated to 137% of control (p less than 0.01). In order to investigate the direct effect of cimetidine on mucus glycoprotein biosynthesis, corpus tissue was cultured in the medium containing cimetidine. 100 microM cimetidine enhanced mucus glycoprotein biosynthesis to 174% (p less than 0.01). Cimetidine was found to stimulate gastric mucus glycoprotein biosynthesis both in vivo and in vitro.     

Risk factors for recurrent bile duct stones after endoscopic papillotomy

BACKGROUND: The long term outcome of endoscopic papillotomy (EPT) is not well known. The aims of this study were to clarify the clinical course of post-EPT patients and to detect predictors for bile duct stone recurrence. METHODS: A total of 1042 consecutive patients who underwent EPT for bile duct stones from December 1975 to September 1998 were prospectively followed up. Patients were divided into four groups according to gall bladder (GB) status: "acalculous GB" group, "calculous GB" group, "cholecystectomy" group, and "prior cholecystectomy" group. Reliable follow up information was obtained for 983 (94.3%) of the 1042 patients. The following factors were considered in the evaluation of predisposing risk factors for recurrence of bile duct stones: age, sex, gall bladder status, periampullary diverticulum, number of bile duct stones, diameter of bile duct stones, diameter of bile duct, lithotripsy, precutting, pneumobilia, and early complications. RESULTS: Recurrence occurred in 111 patients. The "acalculous GB" group was less prone to recurrence than the "prior cholecystectomy" group and the "calculous GB" group. The relative risks (RR) for the latter two compared with the former group were 2.26 (95% confidence interval (CI) 1.24-4.14; p=0.0078) and 2.16 (95% CI 1.21-3.87; p=0.0093), respectively. Other prognostic factors were lithotripsy (RR 2.37; 95% CI 1.47-3.81; p=0.0004) and pneumobilia (RR 1.57; 95% CI 1.01-2.43; p=0.044). CONCLUSIONS: Gall bladder status, lithotripsy, and pneumobilia were significantly related to bile duct stone recurrence after EPT.     

High glucose stimulates hepatic stellate cells to proliferate and to produce collagen through free radical production and activation of mitogen-activated protein kinase.

BACKGROUND: Nonalcoholic steatohepatitis is a clinicopathologic condition that may progress to liver fibrosis. Hyperglycemia is supposed to be one of the factors inducing hepatic fibrogenesis, but the mechanism has not been fully clarified. Oxidative stress is increasingly found in patients with diabetes/hyperglycemia in which conditions reactive oxygen species (ROS) are produced. METHODS: We performed experiments using hepatic stellate cells (HSCs) in culture in order to confirm the effect of high glucose concentrations on cell proliferation, type I collagen production, ROS production and activation of mitogen-activated protein (MAP) kinase pathway. RESULTS: High glucose stimulated cell growth of HSCs and up-regulated the levels of activated/phosphorylated extracellular signal-regulated kinase 1/2 and free radical production in HSCs. The MAP kinase phosphorylation and cell proliferation were suppressed by diphenylene iodonium chloride, an NADPH oxidase inhibitor, and by calphostin C, a protein kinase C (PKC)-specific inhibitor. Increased type I collagen mRNA and protein levels were also observed in HSCs at high glucose concentrations. CONCLUSIONS: Our findings indicate that high glucose concentrations may stimulate ROS production through PKC-dependent activation of NADPH oxidase, and induce MAP kinase phosphorylation subsequent to proliferation and type I collagen production by HSCs.     

Impact of aging on the development of hepatocellular carcinoma in patients with hepatitis C virus infection in Japan

BACKGROUND: It is difficult to study the long-term outcome of hepatitis C virus (HCV) infection because chronic infection is often asymptomatic and duration of the disease is prolonged. The clinical outcome of HCV infection remains unclear in patients of advanced age. METHODS: Among 575 patients consecutively diagnosed with hepatocellular carcinoma (HCC) from 1988 to 1999 at Hiroshima University, we examined 430 with HCV. We studied the differences between males and females in the following characteristics: age at first diagnosis of HCC, Child grade, various tumour factors, history of blood transfusion, duration to development of HCC, and history of alcohol intake. RESULTS: The incidence of HCC patients with HCV increased in elderly persons, including female patients. Background liver function was significantly better for female patients (P < 0.001). In both genders, the duration between blood transfusion and diagnosis of HCC was significantly shorter when the patients received blood transfusion at an older age (P < 0.001). In habitual drinkers, the average age at first diagnosis of HCC was significantly younger (P < 0.001), and duration to development of HCC significantly shorter (P < 0.05). The percentage of atomic bomb survivors among HCV-positive HCC patients was significantly higher than that among HCV-negative HCC patients (P < 0.05). CONCLUSIONS: Patients with HCV might exhibit slow disease progression and develop HCC finally with aging regardless of gender. Patients of advanced age with HCV, even female patients, should therefore be closely followed.