Clinicopathological and prognostic significance of interleukin-8 expression and its relationship to KRAS mutation in lung adenocarcinoma.

BACKGROUND: On the basis of our recent findings of oncogenic KRAS-induced interleukin-8 (IL-8) overexpression in non-small cell lung cancer, we assessed the clinicopathological and prognostic significances of IL-8 expression and its relationship to KRAS mutations in lung adenocarcinomas. METHODS: IL-8 expression was examined by quantitative RT-PCR using 136 of surgical specimens from lung adenocarcinoma patients. The association between IL-8 expression, clinicopathological features, KRAS or EGFR mutation status and survival was analysed. RESULTS: IL-8 was highly expressed in tumours from elderly patients or smokers and in tumours with pleural involvement or vascular invasion. In a non-smokers' subgroup, IL-8 level positively correlated with age. IL-8 was highly expressed in tumours with KRAS mutations compared with those with EGFR mutations or wild-type EGFR/KRAS. Lung adenocarcinoma patients with high IL-8 showed significantly shorter disease-free survival (DFS) and overall survival (OS) than those with low IL8. DFS and OS were significantly shorter in the patients with mutant KRAS/high IL-8 than in those with wild-type KRAS/low IL-8. Cox regression analyses demonstrated that elevated IL-8 expression correlated with unfavourable prognosis. CONCLUSIONS: Our findings suggest that IL-8 expression is associated with certain clinicopathological features including age and is a potent prognostic marker in lung adenocarcinoma, especially in oncogenic KRAS-driven adenocarcinoma.

Alterations in the thermic response to chlorpromazine in rats exposed prenatally to central nervous system depressants.

The thermic response to acute administration of chlorpromazine (5 mg/kg, i.p.) was assessed in rats exposed prenatally to haloperidol (0.1 mg/kg), phenobarbital (10 mg/kg), nitrazepam (2 mg/kg), propylene glycol (1 ml/kg) or saline, once daily from days 1-21 or 15-21 of gestation. The response in all animals was tested only once. The administration of chlorpromazine to 8- or 13-week-old male and female rats treated with saline (1-21 d) induced marked hypothermia for a 6-hr period of observation. Male and female rats treated with haloperidol (1-21 d) showed a delayed hyperthermic response to chlorpromazine at 8 weeks of age; the males showed an increase in rectal temperature at 3 hr and the females from 3 to 6 hr. Thirteen-week-old males but not females treated with haloperidol (1-21 d) showed a hyperthermic response to chlorpromazine during the first 2 hr. Eight-week-old male and female rats treated with phenobarbital (1-21 d) showed hypothermia, whereas 13-week-old male rats of another group treated with phenobarbital (1-21 d) showed significant hyperthermia after the administration of the chlorpromazine. The hypothermic response of the rats treated with nitrazepam (1-21 d) to chlorpromazine was similar to that in the vehicle (propylene glycol)-treated controls. The male rats treated with phenobarbital (15-21 d) responded to chlorpromazine with significant hyperthermia from 30 min to 1 hr. There was no alteration in thermic response to chlorpromazine in rats born to mothers treated with one tenth of the dose of phenobarbital, haloperidol or nitrazepam.(ABSTRACT TRUNCATED AT 250 WORDS)

Gomisin A, a lignan component of Schizandora fruits, inhibits development of preneoplastic lesions in rat liver by 3'-methyl-4-dimethylamino-azobenzene.

The effects of gomisin A, a lignan component of Schizandra fruits, on development of preneoplastic lesions in the liver after a short-term (3 weeks) feeding of 3'-methyl-4-dimethyl-aminoazobenzene (3'-MeDAB) to male Donryu rats were investigated, and compared with the effects of phenobarbital. Gomisin A inhibited both increases of the level of glutathione-S-transferase placental form (GST-P) and the number and size of GST-P positive foci in the liver increased after treatment with 3'-MeDAB. Moreover, although the population of diploid nuclei was increased and that of tetraploid nuclei was decreased by pretreatment with 3'-MeDAB, gomisin A returned this to near the normal ploidy pattern. But phenobarbital increased the level of GST-P and the number and size of GST-P positive foci with little affect on the ploidy population changed by 3'-MeDAB. Thus, the effect of gomisin A on hepatocarcinogenesis was inhibitory in contrast with that of phenobarbital. This study suggests that gomisin A is a candidate for a chemopreventive drug inhibiting the promotion process in hepatocarcinogenesis.

Sequential grouping of nonhistone chromosomal protein from pig thymus.

1. To establish a practical method to prepare nonhistone chromosomal proteins (NHP's) in substantial quantity, a sequential group fractionation procedure for NHP's from pig thymus chromatin has been developed by a combination of methods based on the intrinsic properties, such as binding force in chromatin, molecular weight, and acidity and/or basicity of the protein components. 2. The loosely bound NHP's in chromatin have been grouped into 11 subfractions, and tightly bound ones into 6 subfractions, 2 of which were histones. The loosely bound NHP's were chiefly acidic to neutral in contrast with the tightly bound components, which were basic. In addition, the NHP's of high molecular weight were in general acidic to neutral, while the lower molecular weight components were mainly basic. 3. The present method is applicable to the preparation of representative fractions of NHP on the scale of 50--400 mg from 1 kg of pig thymus.

Isolation and some properties of two fragments with inhibitory activity obtained from adzuki bean proteinase inhibitor by peptic digestion.

Proteinase inhibitor II' from adzuki beans was subjected to peptic digestion. One of the resulting fragments, which inhibited chymotrypsin but not trypsin, was composed of 27 amino acid residues. The fragment was confirmed to be derived from the chymotrypsin-inhibitory domain of the original inhibitor. Another fragment, which inhibited trypsin only, contained 38 amino acid residues and consisted of two peptide chains. One of them, consisting of 25 amino acid residues, corresponded to the original reactive site region for trypsin. These fragments were also obtained from inhibitor II by peptic digestion. These findings, confirm that these inhibitors, which do not inhibit chymotrypsin and trypsin simultaneously, have separate and independent domains for the inhibition of each enzyme. The active fragments are homologous in chemical structures with the two fragments from soybean Bowman-Birk proteinase inhibitor. However, unlike the fragments from Bowman-Birk inhibitor, our chymotrypsin-inhibitory fragment was a potent inhibitor of the enzyme and was as resistant as the intact inhibitor to the attack of excess chymotrypsin. The trypsin-inhibitory fragment had a lower anti-tryptic action than the original inhibitor and was gradually inactivated by trypsin. These differences between our fragments and those of the Bowman-Birk inhibitor are probably a result of the replacement of a few amino acid residues in the reactive site regions.

Anti-aldosteronergic effect of torasemide.

The diuretic actions of torasemide and furosemide were studied in normotensive rats and in deoxycorticosterone acetate (DOCA)-saline-loaded hypertensive rats. Torasemide (0.3-3 mg/kg) and furosemide (3-30 mg/kg) had a dose-dependent and significant diuretic action in normotensive rats. Potassium retention was only observed in the case of torasemide. Torasemide also had a dose-dependent and significant diuretic action in DOCA-saline-loaded hypertensive rats, whereas furosemide did not. Higher doses of torasemide (10 mg/kg) and furosemide (100 mg/kg) increased both plasma renin activity and aldosterone concentration in normotensive rats in a similar manner. In vivo aldosterone receptor binding was determined to test the possible anti-aldosteronergic effect of torasemide. Torasemide inhibited the binding of aldosterone to its receptor in the cytoplasmic fraction of rat kidney in a dose-dependent manner, while furosemide produced no effect. These results suggest strongly that an anti-aldosteronergic action of torasemide contributes to producing less kaliuresis.

In vivo platelet response to lipopolysaccharide in mice: proposed method for evaluating new antiplatelet drugs.

We previously found evidence (based on the use of 5HT as a marker) that i.v. injection of a lipopolysaccharide (LPS) into mice induces a rapid accumulation of platelets in liver and lung. Our previous studies lacked measurement of the platelet count itself, but we have now compared the LPS-induced changes in 5HT levels with the change in platelet count. We also examined the effects on the platelet response of some drugs that act on platelets. In mice, sublethal doses of LPS induced parallel decreases in platelets and 5HT in the blood. The 5HT lost from the blood accounted well for the 5HT accumulated in liver and lung. Soon after this accumulation, the levels of platelets and 5HT in the blood recovered in parallel, and these recoveries corresponded well with the decreases in 5HT occurring in liver and lung. Aspirin and dexamethasone were effective at both reducing pulmonary platelet-accumulation and promoting their return to the circulation. By contrast, oestrogen tended to reduce the return of platelets from lung to circulation. Heparin did not inhibit pulmonary platelet-accumulation but it did decrease their return to the circulation. These results suggest that (i) in response to sublethal doses of LPS, platelets translocate into the liver and lung, then return to the circulation; (ii) this platelet response involves mechanisms that can be modified by drugs; and (iii) the use of this platelet response as a tool for drug evaluation might help identify new drugs with therapeutic potential.

Inhibition of early 3-methyl-4-dimethylaminoazobenzene-induced hepatocarcinogenesis by gomisin A in rats.

The effects of gomisin A, a lignan component of Schizandra fruits, on hepatocarcinogenesis caused by 3'-methyl-4- dimethylaminoazobenzene (3'-MeDAB) in male Donryu rats were investigated. Gomisin A significantly inhibited the appearance of foci stained for glutathione S-transferase placental form (GST-P) in the liver of rats given feed with 0.06% 3'-MeDAB. Gomisin A (30 mg/kg/daily, po) decreased the concentration of 3'-MeDAB-related azo dyes in the liver, and increased their excretion in the bile. The ratio of diploid to tetraploid nuclei increased during ingestion of 3'-MeDAB, but gomisin A delayed the increase. After the withdrawal of 3'-MeDAB, carcinogen-related azo dyes were not detected in the liver or bile, but the proportion of diploid nuclei remained high, although it decreased with a 0.03% gomisin A diet. The results suggested that the effects of gomisin A are related to improved liver function and reversal of abnormal ploidization.

Deoxycholic acid as an endogenous risk factor for hepatocarcinogenesis and effects of gomisin A, a lignan component of Schizandra fruits.

Although hepatocarcinogensis has been reported to be promoted by exogenous administration of bile acids, the relation of endogenous bile acids to hepatocarcinogenesis is not completely understood. This study investigates the relationship between serum concentration of bile acids, the appearance of preneoplastic change, glutathione S-transferase placental form (GST-P)-positive foci in the liver of male Donryu rats which had been fed 0.06% 3'-methyl-4-dimethylamino-azobenzene (3'-MeDAB), and the effects of gomisin A, previously reported to inhibit the tumor promotion process. During the feeding of 3'-MeDAB for 5 weeks, the concentrations of serum bile acids were found to have increased significantly to several times the levels found at the start of the experiment. The increase of serum bile acids, especially deoxycholic acid (DCA), and the appearance of preneoplastic lesions, the number and area of GST-P-positive foci in the liver, were significantly inhibited by simultaneous oral administration of gomisin A (30 mg/kg). When DCA (100 mg/kg) was orally administered after an initiation by 3'-MeDAB, serum bile acids and preneoplastic changes were significantly increased, these increases were inhibited by combined feeding of 0.03% gomisin A in the diet. There were good correlations between the serum concentration of DCA and the number of GST-P-positive foci in the liver in both experimental protocols. These results confirm that DCA is an endogenous risk factor for hepatocarcinogenesis and suggest that anti-promoter effect of gomisin A is based on improving metabolism of bile acids, including DCA.

Compressing data volume of left ventricular cineangiograms.

In this paper a method of compressing data volume for left ventricular cineangiograms is proposed. This method enables digital-optical discs to store the cineangiograms with an equivalent recording density to that of HDTV VTR's while preserving the quality of the original image. The data volume of the cineangiograms is compressed by approximating function and storing its coefficients. With this method, each cineangiogram frame is first decomposed into three regions: the inner part, the inner wall, and the background (using a statistical method previously reported by the authors). Each region is then compressed by means of a difference operation and an adaptive approximation with smooth functions. Performance is tested on 20 cases using actual cineangiograms. The specifications were verified for a spatial resolution of 1000 TV lines, a dynamic range of 60 dB, an SNR of 40 dB [pp/rms], volume compression to 7% of the original volume, and 0.19 [second/frame] for decoding on a 1.7 MFLOPS computer.

Diuretic profile of a novel loop diuretic torasemide in rats and dogs.

In the present study, the authors have examined the diuretic action of a novel loop diuretic torasemide and compared it to those of other diuretics, employing normal rats and dogs. Oral administration of torasemide elicited a dose-dependent increase in urine volume and electrolyte excretion, and elevated the urinary Na/K ratio in rats. These effects were more potent than those of the other diuretics furosemide, trichlormethiazide, indapamide and spironolactone. Moreover, torasemide exhibited a similar or higher urinary Na/K ratio than the combination of these diuretics and spironolactone. In a study employing anaesthetized dogs, i.v. injection of torasemide resulted in a higher urinary Na/K ratio in comparison to furosemide, in addition to potent and long-lasting diuretic activity.

[Survey of sensitivities of clinical isolates to antibacterial agents (annual report)].

Research groups were formed in 20 institutions nationwide to investigate carbapenem resistance of clinical isolates. Activities of various antibacterial agents, principally carbapenems, were tested against clinical isolates collected from these institutions. The broth microdilution method was used to determine the minimum inhibitory concentrations (MICs) of 17 antibacterial agents for 1,326 strains of 11 bacterial species isolated at the institutions between October and December 1994. The results are as follows: 1. Carbapenems exhibited strong antibacterial activities against MSSA and Streptococcus pneumoniae. Their activities against Enterococcus faecalis were comparable to that of ABPC. Carbapenems showed low activities against MRSA. 2. OFLX exhibited the greatest antibacterial activity against Haemophilus influenzae, followed by MEPM. Antibacterial activities of the other carbapenems were comparable to those of FMOX, CTM, and ABPC. 3. The carbapenems showed high activities against Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, and Bacteroides fragilis group. Their activities were greater than those exhibited by other beta-lactam antibacterial agents. The carbapenems also exhibited stronger antibacterial activities against Serratia marcescens than the other beta-lactam antibacterial agents, but some resistant strains were detected. 4. The antibacterial activities of carbapenems against Pseudomonas aeruginosa were comparable to those of CAZ, AZT, AMK.

[Survey of the sensitivities of clinical isolates to antibacterial agents (annual report)].

Research groups were formed in 21 institutions nationwide to investigate carbapenem resistance. The activities of various antibacterial agents, principally carbapenems, were tested against clinical isolates collected from these institutions. The broth microdilution method was used to determine the minimum inhibitory concentrations (MIC) of 17 antibacterial agents for 1,241 strains of 11 bacterial species isolated at all institutions between October and December 1996. The results were as follows: Carbapenems exhibited strong antibacterial activities against MSSA and Streptococcus pneumoniae and showed low activities against MRSA. Their activities against Enterococcus faecalis were comparable to that of ampicillin and piperacillin. The carbapenems showed high activities against Haemophilis influenzae, Escherichia coli, Klebsiella pneumoniae. Enterobacter cloacae. Serratia marcescens and Bacteroides fragilis group. Their activities were greater than that exhibited by other beta-lactam antibacterial agents, but some resistant strains of Serratia marcescens were detected. The antibacterial activity of carbapenems against Pseudomonas aeruginosa was comparable to that of CAZ, and there were some resistant strains.

[Survey of the sensitivities of clinical isolates to antibacterial agents (annual report)].

Research groups were formed in 21 institutions nationwide to investigate carbapenem resistance. The activities of various antibacterial agents, principally carbapenems were tested against clinical isolates collected from these institutions. The broth microdilution method was used to determine the minimum inhibitory concentrations (MIC) of 17 antibacterial agents for 1,282 strains of 11 bacterial species isolated at all institutions between October and December 1995. The results were as follows: 1. Carbapenems exhibited strong antibacterial activities against MSSA and Streptococcus pneumoniae. Their activities against Enterococcus faecalis were comparable to that of ABPC. Carbapenems showed low activities against MRSA. 2. OFLX exhibited the greatest antibacterial activity against Haemophilus influenzae, followed by MEPM. The antibacterial activities of the other carbapenems were comparable to those of FMOX and CTM. 3. The carbapenems showed high activities against Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, and Bacteroides fragilis group. Their activities were greater than that exhibited by other beta-lactam antibacterial agents. The carbapenems also exhibited greater antibacterial activities against Serratia marcescens than the other beta-lactam antibacterial agents, but some resistant strains were detected. 4. The antibacterial activities of carbapenems against Pseudomonas aeruginosa were comparable to those of CAZ, AZT, AMK.

[Changes in the antibacterial activity of chemotherapeutic agents (especially carbapenems) for 10 species of clinical isolates between 1994 and 1996. Surveillance group of the sensitivities of clinical isolates to antibacterial agents].

During October and December of each year of from 1994 to 1996, 3,849 strains of 10 species of bacteria were isolated from clinical materials in 21 institutions nationwide. The minimum inhibitory concentrations (MICs) for these bacteria of four carbapenems (imipenem [IPM], panipenem [PAPM], meropenem [MEPM], and biapenem [BIPM]) and other representative antibacterial agents were measured to investigate annual changes in antibacterial activity. Carbapenems showed potent activity against methicillin-sensitive S. aureus (MSSA), S. pneumoniae, E. faecalis, H. influenzae, E. coli, K. pneumoniae, E. cloacae, S. marcescens, and the B. fragilis group, with the activity being stable. However, these drugs showed weak activity against methicillin-resistant S. aureus (MRSA) and P. aeruginosa. The antibacterial activity (MIC90) against the tested organisms generally remained stable. Particularly, there was annual improvement of the MIC90 values of IPM and BIPM for S. pneumoniae, as well as the values of IPM and PAPM for H. influenzae, and those of IPM, PAPM, and BIPM for S. marcescens. On the other hand, the activity of carbapenems (including IPM) against MRSA was not necessarily strong, but there was annual improvement of MIC90 values.

[Midterm results of bilateral enlargement of the aortic valve ring for valve replacement].

From 1989, 4 patients underwent bilateral enlargement of the aortic valve ring for valve replacement. Age at the operation ranged from 2 to 8 (mean 6) years; body weight ranged from 14.9 to 25.4 (mean 19.0) kg. This procedure enabled us to implant a prosthesis 3 to 4 sizes larger (19 to 23 mm) than that measured with the native aortic annulus (13 to 17 mm). There was no late death and no cardiac event over a mean follow-up period of 6.2 years. Pressure gradient across the prosthesis measured by echocardiography was 40 mmHg in 1 patient who underwent aortic valve replacement with the use of 19 mm St. Jude Medical valve at 2 years of age. There was no significant pressure gradient in other 3 patients. All patients showed normal left ventricular function. We conclude that bilateral enlargement of the aortic valve ring for valve replacement has provided good midterm results with no mortality and no cardiac event.

[Concomitant mitral valvuloplasty and fenestrated total cavopulmonary connection: a case report].

A seven-year-old boy with tricuspid atresia successfully underwent a fenestrated total cavopulmonary connection and mitral valvuloplasty. Preoperative cardiac catheterization showed a mean pulmonary artery pressure of 16 mmHg. Pulmonary arteriography showed poor development of the branches (PA index: 180). Echocardiography revealed mild to moderate mitral valve incompetence due to prolapse of anterior leaflet. Mitral valve was exposed through the trans-septal approach. The excess chorda length was tucked into a longitudinal split in the top of the posterior papillary muscle. Then wedge resection of the redundant segment of the anterior leaflet and bilateral annuloplasty were performed. Finally, a total extracardiac cavopulmonary anastomosis with a 6 mm fenestration was completed. Postoperative clinical course was uneventful, and he is doing well with no recurrence of mitral incompetence 1 year after the operation.

Unanticipated troubles in video-assisted thoracic surgery: a proposal for the classification of troubleshooting.

INTRODUCTION: Most thoracic surgeons encounter atypical cases or unexpected situations that usually lead them to convert minimally invasive surgery to open thoracotomy. But are there other options besides open surgery? The purpose of this study was to suggest a video-assisted thoracic surgery (VATS) classification system and present tips for the application of VATS to atypical cases or unexpected situations. We have categorized VATS procedures for atypical cases or unexpected situations into two groups: the modification of techniques/instruments and the creation of additional access incisions. METHODS: We retrospectively reviewed VATS with optional additional techniques. We used direct visualization or monitoring as the situation demanded, switching back and forth between the monitor and direct vision. RESULTS: Of the 33 cases we reviewed, 27 patients had malignant lung disease and 6 had benign lung disease. All patients underwent lobectomies including one or more of the following: bronchoplasty (n = 12), control of the main pulmonary artery (n = 9), total adhesiotomy (n = 7), combined resection with the diaphragm (n = 3), and separation of totally fused fissures (n = 2). The mean length of the skin incision was 8 cm, the mean total operating time was 208 min, and the mean blood loss was 173 mL No operative or hospital deaths occurred. CONCLUSIONS: Veteran surgeons can instinctively deal with intraoperative variance, but we frequently see inexperienced surgeons panic and change the course of their procedures. A VATS classification system may have educational benefits for newer surgeons. We believe that the creation of a categorized coping plan will help inexperienced surgeons deal with unanticipated problems.

Sex-related hyperthermic response to chlorpromazine in the offspring of rats treated with imipramine.

The body temperature in male rats born to mothers treated with saline or imipramine (5 mg/kg, IMI-F1) from day 1 to day 21 of gestation showed a significant decline between 8 and 13 weeks of age. The magnitude of the decline was greater in the IMI-F1 rats than in saline-F1 rats. In contrast, the body temperature in the IMI-F1 female rats showed a significant rise between 8 and 13 weeks of age. Adult IMI-F1 male rats showed a significant hyperthermia for 1-2 h after an injection of chlorpromazine while the littermate female rats and the control male and female rats showed a marked hypothermia. The results suggest that prenatal exposure to imipramine induces sex-related alterations in the thermoregulatory centers.

[Torasemide (LUPRAC): a review of its pharmacological and clinical profile].

Loop diuretics potently excrete water and electrolytes and therefore have been widely prescribed for the treatment of various kinds of edema for a long time. The potent diuretic action of loop diuretics, however, often causes hypokalemia, and therefore potassium sparing diuretics have also been supplied as a concomitant drug. Torasemide (LUPRAC), a novel diuretics, shows not only an effective loop diuretic action but also a potassium sparing action due to its anti-aldosteronergic effect. Torasemide also has a high bioavailability and is only slightly influenced by meals in humans. In addition, its pharmacodynamic features contribute to its stable diuretic action without any individual differences. In animal experiments, torasemide showed about a tenfold more potent diuretic action in comparison with furosemide, an authentic loop diuretic. On the one hand, the increase in the urinary potassium excretion by torasemide was relatively slight compared to the increase in urinary sodium excretion and, as a result, the urinary sodium to potassium (Na+/K+) ratio increased. The diuretic profile of torasemide was equal to that of the concomitant use of furosemide and an anti-aldosteronergic drug, spironolactone. Torasemide showed a significant efficacy and safety in comparison with furosemide in the patients with edema in both domestic and foreign clinical studies. Moreover, torasemide also showed a decreased rate of cardiac death in comparison to furosemide in patients with chronic heart failure in a large-scale clinical study (TORIC Study). The difference in cardiac death between these two diuretics has been suggested to depend on the anti-aldosteronergic effect of torasemide. In Japan, no new loop diuretics have been developed in over 10 years. Torasemide is therefore expected to be useful as an effective diuretic for diseases with edema.