Contribution of HLA genes to genetic predisposition in diffuse panbronchiolitis

Diffuse panbronchiolitis (DPB) in East Asia is a distinctive chronic obstructive pulmonary disease of unknown etiology. We hypothesize that the disease susceptibility is due to genetic predisposition unique to Asians. Association between human leukocyte antigen (HLA)-Bw54 and the disease was previously reported. In the present study, using newly developed polymerase chain reaction (PCR)- based methods, we directly analyzed HLA class I and II alleles in 76 Japanese patients. HLA-A, -B, and -C antigens were screened by the conventional typing method, and then B22-group alleles including HLA-B54 were genotyped by single-strand conformation polymorphism analysis. Alleles of HLA-DRB1 gene were fully determined by the microtiter plate hybridization method. Thirty-seven percent of the patients possessed HLA-B*5401 allele conserved predominantly in East Asians, as compared with 15% of 110 healthy volunteers (chi2 = 12.4, p = 0.0004). In addition, 4% of the patients possessed B*5504 also unique to Asians but a rare allele which was not found in normal control subjects in this study. Typing of HLA-DRB1 class II gene did not demonstrate strong positive association with the disease. A33, B44, and DRB1*1302 showed negative association with the disease. We conclude that distinctive molecular structure of HLA-B alleles or a closely linked gene in the HLA region contributes to genetic predisposition in diffuse panbronchiolitis. This may partly explain why this disorder is found primarily in Asians.     

Inhibitory effects of ginsenoside Rh2 on tumor growth in nude mice bearing human ovarian cancer cells

Ginsenoside Rh2 (Rh2), isolated from an ethanol extract of the processed root of Panax ginseng CA Meyer, inhibits the growth of B16 melanoma cells. This study was designed to evaluate the ability of Rh2 to inhibit growth of human ovarian cancer cells (HRA) in vitro and in nude mouse. Rh2 inhibited proliferations of various established human ovarian cancer cell lines in a dose-dependent manner between 10 and 60 microM in vitro and induced apoptosis at around the IC50 dose. When HRA cells were inoculated s.c. into the right flank of nude mice, all mice formed a palpable tumor within 14 days. Although i.p. administration of Rh2 alone hardly inhibited the tumor growth, when Rh2 was combined with cis-diamminedichloroplatinum(II) (CDDP) the tumor growth was significantly inhibited, compared to treatment with CDDP alone. When mice were treated p.o. with Rh2 daily (but not weekly), the tumor growth was significantly (P<0.01) inhibited, compared to CDDP treatment alone. When Rh2 was combined with CDDP, the degree of tumor growth retardation was not potentiated. The survival time was significantly (P<0.05) longer than that of medium alone-treated controls or the group treated with CDDP alone. Then, we examined whether p.o. administration of Rh2 has a dose-dependent inhibitory effect on the tumor growth. I.p. and weekly administration of CDDP had more potent antitumor activity in the order of 1 mg/kg, 2 mg/kg and 4 mg/kg, whereas p.o. and daily administration of Rh, (0.4 to 1.6 mg/kg) not only had antitumor activity comparable to that of 4 mg/kg CDDP, but also resulted in a significant increase of the survival. Doses of Rh2 used in this study did not result in any adverse side-effects as confirmed by monitoring hematocrit values and body weight, unlike 4 mg/kg CDDP, which had severe side-effects. It is noteworthy that p.o. but not i.p. treatment with Rh2 resulted in induction of apoptotic cells in the tumor in addition to augmentation of the natural killer activity in spleen cells from tumor-hearing nude mice. Thus, particularly in view of the toxicity of CDDP, Rh2 alone would seem to warrant further evaluation for treatment of recurrent or refractory ovarian tumor.     

Drug-induced pneumonitis caused by sulfamethoxazole, trimethoprim during treatment of Pneumocystis carinii pneumonia in a patient with refractory ulcerative colitis

We recently treated a patient with intractable ulcerative colitis complicated with Pneumocystis carinii pneumonia in whom sulfamethoxazole/trimethoprim caused pneumonitis. The pneumonitis was difficult to differentiate from worsening of the infection or the appearance of another opportunistic infection. The patient's history of sulfasalazine (sulfonamide)-induced pneumonitis made diagnosis possible. The CD4/CD8 ratio of lymphocyte subsets in bronchoalveolar lavage fluid was decreased at the diagnosis of Pneumocystis carinii pneumonia and this ratio had increased when drug-induced pneumonitis was diagnosed. Topical administration of beclomethasone dipropionate by enema was a safe and effective for the treatment of such a compromised patient with active colitis.     

Mechanical stretch induces hypertrophic responses in cardiac myocytes of angiotensin II type 1a receptor knockout mice

Many lines of evidence have suggested that angiotensin II (AngII) plays an important role in the development of cardiac hypertrophy through AngII type 1 receptor (AT1). To determine whether AngII is indispensable for the development of mechanical stress-induced cardiac hypertrophy, we examined the activity of mitogen-activated protein kinase (MAPK) family and the expression of the c-fos gene as hypertrophic responses after stretching cultured cardiac myocytes of AT1a knockout (KO) mice. When cardiac myocytes were stretched by 20% for 10 min, extracellular signal-regulated protein kinases (ERKs) were strongly activated in KO cardiomyocytes as well as wild type (WT) myocytes. Both basal and stimulated levels of ERKs were higher in cardiomyocytes of KO mice than in those of WT mice. Activation of another member of the MAPK family, p38(MAPK), and expression of the c-fos gene were also induced by stretching cardiac myocytes of both types of mice. An AT1 antagonist attenuated stretch-induced activation of ERKs in WT cardiomyocytes but not in KO cardiomyocytes. Down-regulation of protein kinase C inhibited stretch-induced ERK activation in WT cardiomyocytes, whereas a broad spectrum tyrosine kinase inhibitor (genistein) and selective inhibitors of epidermal growth factor receptor (tyrphostin, AG1478, and B42) suppressed stretch-induced activation of ERKs in KO cardiac myocytes. Epidermal growth factor receptor was phosphorylated at tyrosine residues by stretching cardiac myocytes of KO mice. These results suggest that mechanical stretch could evoke hypertrophic responses in cardiac myocytes that lack the AT1 signaling pathway possibly through tyrosine kinase activation.     

Analysis of pulmonary manifestations in patients with rheumatoid arthritis

We studied chest X rays of 911 patients with rheumatoid arthritis (RA). The findings showed interstitial shadow in 28 patients (3.1%), pleuritis in 13 patients (1.4%) and nodular shadow in 3 patients (0.3%). RA patients with interstitial pneumonia were commonly male and older. And they had significantly high levels of rheumatoid factor (RF), RAPA and IgG-RF in serum, but they were not associated with high score of Lansbary index. All patients with more than 1500 IU/ml in RF value had a complication of interstitial pneumonia. These results suggest the importance of chest X-ray in the management of RA patients with high titer in RF.     

Preventive effect of erythromycin on experimental bleomycin-induced acute lung injury in rats

BACKGROUND: The increase in the incidence of iatrogenic injury to the extrahepatic biliary tree that has been documented since the introduction of laparoscopic cholecystectomy (LC) has been explained as a 'learning curve' problem. The early New Zealand experience has been published and the present study was undertaken to determine whether there had been any change in the incidence, nature and management of laparoscopic biliary injuries (LBI) after further experience with LC. METHODS: A nationwide audit was undertaken in 1995 by two confidential postal questionnaires: to all active general surgeons (n=184, response rate 60%), and to all endoscopists performing endoscopic retrograde cholangiopancreatography (ERCP) (n=18, response rate 100%). RESULTS: The total number of LBI was 21, compared with 41 for 1991-92. The site and nature of the injuries were similar for the two survey periods. More of the injuries appeared to be diagnosed after the operation and prior to discharge (25% vs 47%). Calculating the national incidence of LBI was not possible without complete reporting, but in the subset of surgeons responsible for the LBI there was no apparent decrease in the incidence of all LBI (2.8% vs 2.9%), those requiring active re-intervention (2.4% vs 2.7%) and major duct injury (1.1% vs 0.7%), despite a significant increase in the surgeons' prior experience with LC (20% vs 61% of surgeons had performed more than 100 LC). There were some concerning trends in management: a less frequent use of ERCP in patients with LBI diagnosed after surgery (76% vs 65%) and a higher proportion of patients with minor injuries managed by re-operation (26% vs 50%). CONCLUSIONS: The present study indicates that iatrogenic biliary injury is a persistent problem in New Zealand, despite increasing experience with LC, and suggests the need for more intensive scrutiny of operative technique and training. There is scope to manage more patients with minor duct injuries conservatively.     

Joining of NiAl to iron-based alloys by reactive casting

Nickel monoaluminide, NiAl, is exothermically synthesized from elemental liquids of aluminum and nickel and is simultaneously joined to iron-based alloys, such as carbon steels and stainless steels, by the reactive casting method, which is based on the pouring of the elemental liquids onto the base material. The exothermic reaction between the aluminum and nickel liquids produces extremely superheated NiAl liquid. Heat of the NiAl liquid is transferred to the base material, and the contact surface is melted to a depth depending on both the preheating temperature of the base material and the thickness of the NiAl produced. After solification on the base material, NiAl is strongly joined to the base material, showing a joint strength exceeding the inherent strength of NiAl. The high joint strength is attributed to a very fine, rodlike eutectic structure at the joint interface that consists of a mixture of β-NiAl and γ-iron with an interrod spacing of approximately 100 nm.     

Cytotoxic effect of ammonia produced by Helicobacter pylori urease on the cultural cells

We investigated the action of the ammonia produced by Helicobacter pylori urease on the cultured cells. The urease was purified from supernatant fluid of sonicated cell of H. pylori cultured on blood agar for 2 days at 37 degrees C under microaerophilic condition. Purification was carried out by DEAE-Sepharose chromatography, Phenyl-Sepharose chromatography, Sephacryl S-200 SF chromatography and fast protein liquid chromatography on Mono-Q. Vero, HeLa and Intestin 407 cells with or without the addition of 30 mM urea were exposed to the purified urease. Those cells showed cytotoxic effects within 80 minutes after addition of purified urease in the presence of urea. The ammonia production was observed on tissue culture medium within 10 minutes, and the ammonia concentration ranged from 5.56 mg/ml to 7.3 mg/ml and pH in the medium was over pH 9.0. No such effect was observed on the cells exposed to urease without urea. Ammonia water added to Vero cells showed the same cytotoxic effect within 70 minutes on the production of ammonia and raised the pH. However, when the cells were exposed to the ammonia water pre-neutralized to a given pH 7-8 using 1 N HCl cytotoxic effect was not observed. It was concluded that the cytotoxic effect of H. pylori urease was dependent on ammonia generated by hydrolysis of urea.     

Clinical studies on ceftriaxone in respiratory tract infections. CTRX Study Group

We report that the results of clinical studies on ceftriaxone (CTRX) in respiratory tract infections (RTIs). Clinical efficacies and side effects of CTRX were as follows; 1. Clinical efficacies of CTRX in a total of 61 cases with RTIs were excellent in 11 cases, good in 23, fair in 11, poor in 12 and unknown in 4. Thus the overall clinical efficacy rate was 59.6%. In cases of patients with lung cancers, the efficacy rate was 42.9%. 2. Clinical efficacy rates with once daily dosage were 50.0% with a dose level of 1 g CTRX and 54.8% with that of 2 g CTRX. 3. Side effects were observed in 2 cases (3.1%) and laboratory abnormalities were observed in 1 case (1.6%). They were not serious, however. These data suggest that CTRX is one of the useful cephalosporins in treatment of RTIs.     

Phase I and pharmacologic study of irinotecan in combination with cisplatin for advanced lung cancer

Macroscopic T-type Ca2+ currents, which are often observed in fetal and neonatal cardiac muscle cells, were not found in normal (0 of 17) adult feline ventricular myocytes. However, they were present in most (15 of 21) myocytes isolated from adult feline left ventricles with long-standing pressure-overload-induced hypertrophy. This is the first study to provide evidence in a large mammal, such as the cat, that T-type Ca2+ channels may be reexpressed in adults in association with hypertrophy resulting from slow progressive pressure overload. Importantly, this expression was stable for the duration of the hypertrophy process and was not associated with abrupt pressure overload. T-type Ca2+ currents were separated from L-type Ca2+ currents by exploiting the differences in their voltage dependence of steady-state inactivation. Depolarizations from -80 mV revealed a rapidly activating inward current that peaked in magnitude at -30 mV (-1.8 +/- 0.9 [mean +/- SD] pA/pF) and fully inactivated within 100 milliseconds in 15 of 21 hypertrophied myocytes studied. Further depolarizations activated progressively less T-type Ca2+ current, so that at +10 mV the L-type Ca2+ current predominated. In the hypertrophied myocytes that demonstrated both T-type and L-type Ca2+ currents, two distinct peaks occurred in their current-voltage relations. T-type Ca2+ currents were not evident in any of the 17 normal adult feline left ventricular myocytes studied. The purpose of T-type Ca2+ currents in hypertrophy is unclear. However, their presence may make hypertrophied myocardium more prone to spontaneous action potentials and increase the likelihood for arrhythmias in partially depolarized hypertrophied myocardium.