Calculation of Liquid-Disordered/Liquid-Ordered Line Tension from Pairwise Lipid Interactions.

The energy penalty for bilayer phase domain interfaces, line tension, is an important quantity for describing the phase domain size transition from the nanometer scale to the micrometer scale and larger. We connected pairwise lipid interaction energies in ternary lipid mixtures with experimentally measured line tensions by using the compositional differences between coexisting liquid-disordered (Ld) and liquid-ordered (Lo) phases known from phase diagrams. Using a mean-field theory model, we developed a computational procedure to map out Ld + Lo phase boundaries and thermodynamic tielines based on a set of pairwise interaction energies. We find that experimentally measured Ld/Lo line tension can be effectively modeled by the sum of pairwise interactions at the interface. This result indicates that pairwise lipid interactions make a major contribution to line tension.

Preoperative chemoradiation therapy for esophageal cancer is a risk factor for the elevation of high mobility group box-1, leading to an increase in postoperative severe pulmonary complications.

We herein clarified the time course of changes in the serum high mobility group box chromosomal protein-1 (HMGB-1) concentrations in esophageal cancer patients after esophagectomy, and investigated whether the perioperative serum HMGB-1 levels correlate with the administration of neoadjuvant chemoradiation therapy (NACRT) and the postoperative clinical course, especially the occurrence of pulmonary complications, in such patients. Sixty patients who underwent right transthoracic esophagectomy for esophageal cancer were enrolled in this study. The relationship between the perioperative serum HMGB-1 levels and NACRT, and the postoperative severe pulmonary complications were evaluated. Patients with severe pulmonary complications (n = 44) tended to have undergone NACRT more often than those without severe pulmonary complications (n = 16). The preoperative and postoperative day 7 serum HMGB-1 concentrations were significantly higher in patients with severe pulmonary complications than those in patients without severe pulmonary complications. In the univariate and multivariate analyses, the use of NACRT and the preoperative elevations in the serum HMGB-1 levels (>4.2 ng/mL) were found to be significantly associated with pulmonary dysfunction. Furthermore, the response to NACRT was found to be significantly associated with the preoperative serum HMGB-1 levels. The use of NACRT contributes to preoperative serum HMGB-1 elevation, and these were risk factors for the occurrence of severe postoperative pulmonary complications in patients with esophageal cancer after thoracic esophagectomy.

Effects of the time interval between clamping and linear stapling for resection of porcine small intestine.

BACKGROUND: Although a wait of several seconds after clamping is recommended when an automatic stapler is used to achieve adequate hemostasis, this wait has not been experimentally clarified. METHODS: To determine whether waiting is necessary between clamping and firing of a linear stapler, this study evaluated the number of staple line bleeding points and histologic changes in stapling sites of porcine small intestine (n = 46). It also assessed the ratio of dry to wet tissue weight (DW ratio) (n = 20) of porcine small intestine clamped between the prongs of a linear stapler. The sites were studied separately as follows: no wait with a four-row device (n = 12), no wait with a six-row device (n = 11), wait with a four-row device (n = 12), and wait with a six-row device (n = 11). The linear stapler was fired immediately after clamping in the no wait group and 1 min after clamping in the wait group. RESULTS: The mean number of staple line bleeding points in 2 to 5 min with the six-row device and in 3 to 5 min with the four-row device after firing were significantly less in the wait group than in the no wait group using the same device (p < 0.05). Cross sections of staple lines showed a higher frequency of mucosal cutting in the no wait group than in the wait group for both the four-row and the six-row devices (both significant at p < 0.01). Although the mean wet tissue weights of anastomotic sites did not change in either group, the mean DW ratio was significantly less in the wait group than in the no wait group (p < 0.01). CONCLUSIONS: A 1-min interval after clamping decreases the amount of clamped tissue. Waiting may thus be necessary to reduce bleeding from stapling sites, which may be related to a decrease in mucosal cutting.

Second primary cancer in survivors following concurrent chemoradiation for locally advanced non-small-cell lung cancer.

Long-term cancer survivors risk development of second primary cancers (SPC). Vigilant follow-up may be required. We report outcomes of 92 patients who underwent chemoradiation for unresectable stage III non-small-cell lung cancer, with a median follow-up of 8.9 years. The incidence of SPC was 2.4 per 100 patient-years (95% confidence interval: 1.0-4.9).

Phase I/II study of docetaxel and cisplatin with concurrent thoracic radiation therapy for locally advanced non-small-cell lung cancer.

Recent studies have suggested the superiority of concomitant over sequential administration of chemotherapy and radiotherapy. Docetaxel and cisplatin have demonstrated efficacy in advanced non-small-cell lung cancer (NSCLC). This study evaluated the safety, toxicity, and antitumour activity of docetaxel/cisplatin with concurrent thoracic radiotherapy for patients with locally advanced NSCLC. Patients with locally advanced NSCLC (stage IIIA or IIIB), good performance status, age or=3 toxicities of 71, 60, 24, and 19%, respectively. Toxicity was significant, but manageable according to the dose and schedule modifications. Dose intensities of docetaxel and cisplatin were 86 and 87%, respectively. Radiotherapy was completed without a delay in 67% of 42 patients. The overall response rate was 79% (95% confidence interval (CI), 66-91%). The median survival time was 23.4+ months with an overall survival rate of 76% at 1 year and 54% at 2 years. In conclusion, chemotherapy with cisplatin plus docetaxel given on days 1, 8, 29, and 36 and concurrent thoracic radiotherapy is efficacious and tolerated in patients with locally advanced NSCLC and should be evaluated in a phase III study.

Spontaneous echo contrast in descending aorta correlates with low blood-flow velocity in carotid arteries and hemostatic abnormalities.

Spontaneous echo contrast in the descending aorta (DA-SEC) was examined as a possible risk factor for cerebral thromboembolism. In 19 patients (10 males, 9 females) in the chronic stage of cerebral infarction, abnormal findings by transesophageal echocardiography, flow dynamics of the common carotid artery (CCA), and hemostatic factors including blood coagulation and fibrinolysis were investigated. In nine patients, DA-SEC was detected, and SEC in left atrium (LA-SEC) was detected in nine patients. The DA-SEC positive group showed decreased blood-flow velocity (BFV) in bilateral CCA, high levels of thrombin-antithrombin III complex (TAT) and prothrombin fragment 1.2 (F1+2), a decrease in platelet count and a slight increase in D-dimer, which means an activated state of thrombin generation and resulting fibrinolysis, compared to the DA-SEC negative group. On the other hand, the LA-SEC positive group showed normal BFV in CCA and only a slight increase in D-dimer. We conclude that the condition producing DA-SEC is a stronger risk factor for cerebral infarction than that producing LA-SEC.

Fractionated administration of irinotecan and cisplatin for treatment of non-small-cell lung cancer: a phase II study of Okayama Lung Cancer Study Group.

A phase II study of fractionated administration of irinotecan (CPT-11) and cisplatin (CDDP) in patients with non-small-cell lung cancer (NSCLC) was conducted. Between January 1996 and January 1998, 44 previously untreated patients with stage IIIB or IV NSCLC were enrolled. CDDP at a dose of 60 mg x m(-2) was given first and followed by CPT-11 at a dose of 50 mg x m(-2). Both drugs were given by 1-hour infusion on days 1 and 8, and repeated every 4 weeks up to 4 cycles. 42 patients were evaluated for response and 44 for survival and toxicity. 20 patients (48%: 95% confidence interval 32-63%) achieved an objective response. The median duration of responses was 8 months, and the median survival time and the 1-year survival rate were 12.5 months and 56.8%, respectively. Major toxicities were neutropenia and diarrhoea. Grade 3 or 4 neutropenia occurred in 70.5% of the patients and one patient died of sepsis. Grade 3 or 4 diarrhoea was experienced in 25.0%, but manageable by conventional therapy. In conclusion, fractionated administration of CPT-11 and CDDP was highly effective for advanced NSCLC with manageable toxicities.

Effects of alpha(2)-adrenergic agonists on lipopolysaccharide-induced aqueous flare elevation in pigmented rabbits.

PURPOSE: To evaluate the effects of the alpha(2)-adrenergic agonists (clonidine, apraclonidine, and guanfacine) on lipopolysaccharide (LPS)-induced aqueous flare elevation in pigmented rabbits. METHODS: Anterior uveitis was induced with an intravenous injection of LPS (0.5 microg/kg) in an ear vein. The reproducibility of experimental uveitis induced by LPS (0.5 microg/kg) was also determined. Clonidine (0.01, 0.05, 0.25, or 1%), apraclonidine (1%), or guanfacine (1%) was topically instilled in the right eye 30 and 5 minutes before and 30 minutes after LPS application (N = 6 animals, respectively). Clonidine (0.25%) was topically administered three times at 30-minute intervals from 240 or 120 minutes before, or 120 or 240 minutes after LPS application (N = 6 animals, respectively). Then 1 mg/kg of yohimbine was injected into an ear vein 30 minutes before each topical three-time instillation of clonidine 1%, apraclonidine 1% or guanfacine 1% (N = 6 animals, respectively). Aqueous flare was measured with a laser flare-cell meter. Aqueous flare elevation was expressed as the area under the curve (AUC) in arbitrary units. Rabbits received the first LPS intravenous injection, and the control values of the AUC were obtained. Three months later, the alpha(2)-agonist and the second LPS administration were given to the same animals. RESULTS: The AUCs (5,184 +/- 1,255 units) after the first application of LPS were similar to those (5,033 +/- 1,290) after the second application 3 months after the first administration. Topical instillation of clonidine inhibited LPS-induced aqueous flare elevation in a dose-dependent manner (0.01-0.25%). Topical instillation of clonidine 1%, apraclonidine 1% or guanfacine 1% inhibited LPS-induced aqueous flare elevation by 98 +/- 2.0% (mean +/- SD), 86 +/- 14% and 94 +/- 5.7%, respectively. Pretreatment with intravenous yohimbine prevented the inhibitory effect on flare elevation induced by each agent. CONCLUSION: The present findings suggested that topical instillation of some alpha(2)-agonists may have an inhibitory effect on ocular inflammation, which is mediated in part by alpha(2)-receptors.

Serum methanol levels in subjects with or without optic nerve head disease.

We evaluated serum methanol levels in subjects with or without optic nerve head disease. Serum methanol levels were determined using gas chromatography in 71 patients with optic nerve head disease and in 127 subjects without optic nerve head disease. Their ages ranged from 17 to 89 years. Serum methanol levels in 127 subjects without optic nerve head disease ranged from 0.12 to 3.86 microg/ml (mean +/- standard deviation, 1.72 +/- 0.86 microg/ml). In the subjects without optic nerve head disease, the differences in the levels between those with cataract versus retinal detachment, men versus women, and between each age-group (50-80 years) were not significant. The methanol levels in patients with optic neuritis (n = 2), Wolfram syndrome (n = 1), Leber hereditary optic neuropathy at the late stage (n = 2), retinitis pigmentosa (n = 23), and primary open-angle glaucoma (n = 16) were less than 3.86 microg/ml. Methanol levels in 1 patient with Leber hereditary optic neuropathy at the acute stage was 5.28 microg/ml. Of 10 patients with primary angle-closure glaucoma, 1 had a slightly elevated level and 9 had levels less than 3.86 microg/ml. Of 17 patients with normal tension glaucoma, 5 had methanol levels higher than 3.86 microg/ml, and 12 patients had levels less than 3.86 microg/ml. The present study shows that serum methanol levels in subjects without optic nerve head disease ranged from 0.12 to 3.86 microg/ml and were much lower than the levels that produce acute ocular symptoms of methanol intoxication. It is possible that high serum methanol levels may play a part in the acute stage of Leber hereditary optic neuropathy and normal tension glaucoma in certain patients. It is unlikely that increased serum methanol levels participate in primary angle-closure glaucoma.

Effects of topical clonidine on prostaglandin-E(2)-induced aqueous flare elevation in pigmented rabbits.

We evaluated the role of topical clonidine on experimental ocular inflammation. Transcorneal diffusion of prostaglandin (PG) E(2), 7. 09 x 10(-2) mmol/l, with the use of a glass cylinder was employed to produce aqueous flare elevation in pigmented rabbits. Clonidine was topically administered and yohimbine was injected intravenously. Aqueous flare was measured with a laser flare cell meter. Topical instillation of 0.25% clonidine inhibited 89% of PGE(2)-induced aqueous flare elevation. Instillation of clonidine at 60 or 30 min before and 10 min after PGE(2) inhibited flare significantly. Pretreatment with intravenous yohimbine decreased the clonidine-induced inhibition of the flare elevation in a dose-dependent manner. It is possible that the anti-inflammatory action of topical clonidine may be mediated partly by alpha(2)-receptors.

Effects of nilvadipine, nicardipine and verapamil on acute rise of aqueous flare induced by iris photocoagulation or intravenous lipopolysaccharides in pigmented rabbits.

The effects of nilvadipine, nicardipine and verapamil on the acute rise of aqueous flare induced by argon laser photocoagulation of the iris or by intravenous injection of lipopolysaccharides (LPS, 0.5 microg/kg) were investigated in pigmented rabbits. Nilvadipine, nicardipine and verapamil were injected intravenously. Aqueous flare was measured with a laser flare cell meter. Following photocoagulation, aqueous flare increased, reached its maximum at 45-75 min and then decreased. After administration of LPS, aqueous flare increased, reached its maximum at 4 h and then returned to baseline levels at about 24 h. Flare reactions were inhibited by nilvadipine in a dose-dependent manner. The elevations were maximally inhibited by nilvadipine 30 min before photocoagulation or intravenous LPS. Two hundred micrograms per kilogram of nilvadipine inhibited 81% of photocoagulation-induced flare elevation, while the same dose of nicardipine and verapamil inhibited 19 and 9% of the elevation, respectively. The same dose of nilvadipine inhibited 51% of LPS-induced flare elevation, while the same dose of nicardipine and verapamil inhibited 6 and 4% of the elevation, respectively. In conclusion, nilvadipine inhibited the experimental elevation of aqueous flare more effectively than did nicardipine and verapamil.

A phase II study of cisplatin and 5-fluorouracil with concurrent hyperfractionated thoracic radiation for locally advanced non-small-cell lung cancer: a preliminary report from the Okayama Lung Cancer Study Group.

A recent meta-analysis and randomized studies have demonstrated that combined chemoradiotherapy is associated with a survival advantage for selected patients with locally advanced unresectable non-small-cell lung cancer (NSCLC). We conducted a phase II study of combined chemoradiotherapy to find a more effective combination of drugs and radiation than those previously reported for such patients. Between January 1994 and November 1996, 50 previously untreated patients with locally advanced unresectable NSCLC (stage IIIA with N2 or IIIB disease) were entered in this study. Patients were required to have Eastern Cooperative Oncology Group performance status < or = 2, age < or = 75 years and adequate organ function. Treatment consisted of three cycles of cisplatin (20 mg m(-2), days 1-5) and 5-fluorouracil (5-FU) (500 mg m(-2), days 1-5) every 4 weeks, and concurrent hyperfractionated thoracic radiation (1.25 Gy twice daily, with a 6-h interfraction interval; total radiation dose, 62.5-70 Gy). Of the 50 patients entered, 37 (74%) responded to this chemoradiotherapy, including two (4%) with complete response. By a median follow-up time of 41.0 months, 35 patients had died and 15 were still alive. The median time to progression for responding patients was 14.1 months (range, 2.6-51.3+ months). The median survival time was 18.7 months, with a survival rate of 66.0% at 1 year, 46.0% at 2 years and 27.6% at 3 years. Survival outcome was strongly affected by the extent of nodal involvement (median survival time, 27.4 months for N0-2 disease (n = 37) vs 10.7 months for N3 disease (n = 13); P = 0.007). The major toxicities of treatment were leukopenia and neutropenia (> or = Grade 3, 58% and 60% respectively). Other toxicities of > or = Grade 3 included thrombocytopenia (26%), anaemia (26%), nausea/vomiting (16%) and radiation oesophagitis (6%). Treatment-related death occurred for one patient. Our findings suggest that cisplatin and 5-FU in combination with concurrent hyperfractionated thoracic radiation is effective and feasible for the treatment of locally advanced unresectable NSCLC. The short-term survival in this study appeared to be more encouraging than those of similar chemoradiation trials. A randomized trial will be needed to compare the combination of cisplatin and 5-FU with other platinum-based regimens together with concurrent hyperfractionated thoracic radiation. In addition, in future studies, inclusion criteria for N3 disease with or without supraclavicular involvement should be reconsidered to correctly evaluate the effect of combined chemoradiotherapy for locally advanced unresectable NSCLC.

Effects of Kakkon-to and Sairei-to on experimental elevation of aqueous flare in pigmented rabbits.

PURPOSE: To evaluate the possible inhibitory effects of Kakkon-to and Sairei-to, traditional Sino-Japanese herbal medicines, on experimental aqueous flare elevation in pigmented rabbits. METHODS: Anterior uveitis was induced either by an application of prostaglandin E2 (PGE2), 10 microg/mL, to the cornea, or an intravenous injection of lipopolysaccharides (LPS), 0.5 microg/kg, in an ear vein. Dose dependency of experimental uveitis induced by LPS (0.1, 0.25, 0.5, or 1.0 microg/kg) was also determined. For pretreatment, about 150 g/day of food containing Kakkon-to (1% w/w) or Sairei-to (0.6% or 2% w/w) was given to two groups of animals for 5 days before experimental uveitis was induced. A third group of animals underwent pretreatment with betamethasone, 130 microg/kg, injection into an ear vein 4 hours before experimental uveitis was induced. A fourth group of rabbits with no herbal medicine or betamethasone pretreatment served as controls. Aqueous flare was measured using a laser flare-cell meter. Aqueous flare intensity was expressed as the area under the curve (AUC) in arbitrary units. RESULTS: The increase in aqueous flare induced by LPS was dose-dependent. The AUC of PGE2 (10 microg/mL) and LPS (0.5 microg/mL) induced aqueous flare elevations were 1,119 and 4,950 arbitrary units, respectively. Kakkon-to (AUC, 1,055) and Sairei-to (AUC, 965) did not inhibit the aqueous flare elevation induced by PGE2. Beta-methasone did inhibit the elevation (AUC, 271). Kakkon-to (AUC, 4,495) did not suppress the aqueous flare elevation induced by LPS. Both 0.6% and 2% Sairei-to (AUC, 2,478, and 978) and beta-methasone (AUC, 443) did suppress the aqueous flare elevation induced by LPS significantly (P < .05). CONCLUSION: Sairei-to could have an inhibitory effect on experimental anterior uveitis induced by LPS.

Seasonal allergic conjunctivitis induced by Japanese pear pollen.

PURPOSE: To evaluate the ocular findings in patients with Japanese pear (Pyrus pyrifolia Nakai) pollinosis. METHODS: Twenty-two farmers working on artificial pollination in Japanese pear orchards were examined for ocular itching, conjunctival conditions, presence of eosinophils in the conjunctival specimen, and nasal symptoms. Serum IgE antibody to Japanese pear pollen was determined in 16 farmers. RESULTS: Of the 22 subjects, 3 (Nos. 3, 4, and 13) exhibited ocular itching, conjunctival hyperemia, eosinophils in the conjunctival specimen, and positive serum IgE antibodies to Japanese pear pollen. In these patients, the conjunctivitis disappeared after treatment with topical cromoglycate. CONCLUSION: The present study demonstrated that seasonal allergic conjunctivitis may be induced by Japanese pear pollen (entomophilous flower pollen).

Inhibitory effect of nilvadipine on disruption of blood-aqueous barrier induced by prostaglandin E2 application in pigmented rabbits: A morphologic study.

The purpose of the present study is to investigate the morphologic sites of breakdown in eyes pretreated with nilvadipine (a calcium channel blocker) that has been shown to inhibit the acute rise of aqueous flare induced by prostaglandin E2 (PGE2). Nilvadipine (100 microg/kg body weight) was injected intravenously in pigmented rabbits. Thirty minutes later, vehicle or PGE2 (10, 50 or 250 microg/ml) was applied on the cornea by use of a glass cylinder. Forty-five minutes later, the animals received horseradish peroxidase (HRP) intravenously and the eyes were enucleated. Distribution of HRP in the anterior segments was observed by electron microscopy. Without nilvadipine pretreatment, HRP was seen in the intercellular space of nonpigmented cells of the eyes treated with 50 microg/ml PGE2 and in the iris stroma of the eyes treated with 250 microg/ml PGE2. With nilvadipine pretreatment, HRP was not observed in these sites. Our results indicate that nilvadipine suppresses disruption of the different sites of the blood-aqueous barrier.

Effect of cautery with irrigation forceps on the remnant liver after hepatectomy in rats.

Monopolar cautery with irrigation forceps (CIF) was devised for use in liver resection that does not require occlusion of inflow to the remnant liver. However, a high power output is required to divide the hepatic parenchyma which boils the irrigation water. This study was performed to investigate the effects of using CIF on the hepatic parenchyma. Histologic and biochemical examination was performed in rats which had undergone hepatectomy using the CIF, irrigating bipolar (IB), Pringle's maneuver with blunt dissection (group P), or a sham operation. A greater cautery distance was obtained with the CIF than the IB. There was no significant difference in the remnant liver function after the 1st postoperative day in any of the groups. CIF is an effective instrument for anatomic or nonanatomic hepatic resection.

Fractionated administration of irinotecan and cisplatin for treatment of lung cancer: a phase I study.

A combination chemotherapy of irinotecan (CPT-11) and cisplatin (CDDP) has been reported to be active for lung cancer. In the previous trial, however, diarrhoea and leucopenia became the major obstacle for sufficient dose escalation of CPT-11 to improve the treatment outcome. We conducted a phase I study to investigate whether the fractionated administration of CDDP and CPT-11 at escalated dose was feasible and could improve the treatment outcome. Twenty-four previously untreated patients with unresectable non-small-cell lung cancer (NSCLC) or extensive disease of small-cell lung cancer (SCLC) were eligible. Both CDDP and CPT-11 were given on days 1 and 8, and repeated every 4 weeks. The dose of CDDP was fixed at 60 mg m(-2) and given by 1-h infusion before CPT-11 administration. The starting dose of CPT-11 was 40 mg m(-2), and the dose was escalated by an increase of 10 mg m(-2). The maximally tolerated dose of CPT-11 was determined as 60 mg m(-2) because grade 4 haematological or grade 3 or 4 non-haematological toxicities developed in six patients out of 11 patients evaluated. Diarrhoea became a dose-limiting toxicity. The objective response rates were 76% for NSCLC and 100% for SCLC. The recommended dose of CPT-11 and CDDP in a phase II study will be 50 mg m(-2) and 60 mg m(-2) respectively.

[Recent issue in the treatment of small-cell lung cancer].

Chemotherapy is currently a primary treatment modality for small-cell lung cancer (SCLC). However, in the limited stage, a combination of chemotherapy and thoracic irradiation (TI) was found to be superior to chemotherapy alone by meta-analysis. Recently, concurrent administration of cisplatin and etoposide with TI may be an optimal treatment. The usefulness of prophylactic cranial irradiation in complete responders was also confirmed by meta-analysis. Dose-intensive weekly chemotherapy failed to improve the treatment outcome in the extensive stage. Randomized trials to verify the effectiveness of high-dose chemotherapy with peripheral blood stem cell transplantation are in progress.