Tongue surface model can predict radiation tongue mucositis due to intensity-modulated radiation therapy for head and neck cancer.

Acute radiation tongue mucositis has a profound effect on talking and eating. We examined whether the dose-volume histogram obtained from the tongue surface model correlates with mucositis severity, and whether it is useful for predicting acute radiation tongue mucositis in patients with head and neck cancer treated with intensity-modulated radiation therapy. Thirty-six patients who received intensity-modulated radiation therapy for head and neck cancer were analysed for acute radiation tongue mucositis according to the Common Terminology Criteria for Adverse Events, version 4.0, as well as the Radiation Therapy Oncology Group scoring systems. The corresponding high-dose locations in anatomical sub-regions in the tongue surface model and the development of high-grade acute radiation tongue mucositis were compared. The mucositis sites coincided with the high-dose anatomical sub-regions in the tongue surface model. There was a clear dose-response relationship between the mean dose to the tongue and the acute radiation tongue mucositis Radiation Therapy Oncology Group grade. According to the dose-volume histogram, patients receiving 16.0-73.0 Gy to the tongue were susceptible to grade 2-3 toxicity. The tongue surface model can predict the site and severity of acute radiation tongue mucositis. In future, radiation treatment plans ccould be optimized using this model.

Genistein, a tyrosine kinase inhibitor, enhanced radiosensitivity in human esophageal cancer cell lines in vitro: possible involvement of inhibition of survival signal transduction pathways.

PURPOSE: The effect of genistein, a tyrosine kinase inhibitor, on radiosensitivity was examined, especially focusing on "survival signal transduction pathways." METHODS AND MATERIALS: Two human esophageal squamous cell cancer cell lines, TE-1 (p53, mutant) and TE-2 (p53, wild), were used. Radiosensitivity was determined by clonogenic assay, and activation of survival signals was examined by Western blot. RESULTS: Genistein (30 microM) greatly enhanced radiosensitivity in these cell lines by suppressing radiation-induced activation of survival signals, p42/p44 extracellular signal-regulated kinase and AKT/PKB. Significant increase in the percentage of apoptotic cells and increased poly[ADP-ribose] polymerase cleavage were observed in TE-2, but not in TE-1 even after combination of genistein with irradiation. In terms of changes in expression of p53-related proteins, increase in expression of Bax and decrease in that of Bcl-2 were observed in TE-2 but not in TE-1, suggesting that the main mode of cell death induced by genistein in a cell line with wild type p53 differed from that with mutant p53. CONCLUSIONS: This study suggested that survival signals, including p42/p44 ERK and AKT/PKB, may be involved in determining radiosensitivity, and genistein would be a potent therapeutic agent that has an enhancing effect on radiation.

Caffeine enhanced radiosensitivity of rat tumor cells with a mutant-type p53 by inducing apoptosis in a p53-independent manner.

The radiosensitizing effects of caffeine on two rat yolk sac tumor cell lines with a different p53 status were investigated. A reduction of radiation-induced G(2) arrest was caused by caffeine at a concentration of 2 mM in both cell lines. The reduction of survival was observed in a combination of radiation and 2 mM caffeine only in a lower radiation dose range, but not in a higher dose range in NMT-1 with a wild type p53. Radiosensitization of caffeine was recognized even in a higher dose range for cells with a mutant-type p53. Apoptosis, which was not prominent after irradiation alone or caffeine treatment alone, was induced by irradiation in combination with caffeine in cells with a mutant-type p53 through a p53-independent pathway.

An isoenzyme-selective inhibitor of phosphodiesterase 4 and 1, KF19514, may be useful in the treatment of systemic anaphylaxis: an in vivo study in rabbits.

The present study was conducted to determine whether an inhibitor of phosphodiesterases 4 and 1, KF19514, is useful in the treatment of systemic anaphylaxis in fentanyl-anesthetized rabbits. Eighty-two rabbits were randomly allocated to 7 groups. Groups I-1 (0.01 mg x kg(-1)), I-2 (0.1 mg x kg(-1)), and I-3 (1 mg x kg(-1)) received KF19514 10 minutes before antigen challenge, with Group II serving as control. Group IV and Group V received KF19514 and aminophylline 1 minutes after antigen challenge, respectively, with Group III serving as control. The survival rate was higher in Groups I than in Group II, rates were similar in Groups I-1, I-2, and I-3. The survival rate was also higher in Group IV than in Group III. Pulmonary resistance (R(L)) was significantly lower in Groups I-2 and I-3 than in Group II. Dynamic pulmonary compliance (C(dyn)) was significantly higher in Group I-3 than in Group II. Heart rate and central venous pressure were similar in Groups I and II. In Groups III, IV, and V, heart rate and mean arterial pressure were comparable, but central venous pressure in Group IV was significantly lower than in Group V. In conclusion, the administration of KF19514, an inhibitor of PDEs 4 and 1, to rabbits either before or after antigen challenge improved bronchoconstriction provoked by systemic anaphylaxis with minimal concomitant cardiovascular side effects compared with aminophylline, suggesting that this agent may be useful in the treatment of systemic anaphylaxis.

In vivo production of nitric oxide in the canine heart in IgE-mediated anaphylaxis.

We investigated the production of nitric oxide (NO) in the canine anaphylactic heart in vivo using an NO-selective electrode. Seven dogs with positive sensitivity to Ascaris Suum were studied. Ascaris Suum was administered into the systemic circulation to induce anaphylaxis, and NO, blood pressure, heart rate, end-diastolic left ventricular pressure, cardiac output, and the maximum rate of rise of left ventricular pressure were monitored for 60 min. The electrode was placed on the surface of the left ventricle adjacent to the interventricular branches of the left coronary artery. NO concentration increased significantly during the period from 2 to 3 min, and tended to increase during the period from 4 to 15 min after antigen challenge, and almost returned to baseline after 20 min. In conclusion, increases in NO in the heart are only observed during the early phase of anaphylaxis.

An inhibitor of poly(adenosine 5'-diphosphoribose) synthetase, 3-aminobenzamide, does not improve cardiovascular depression, bronchospasm, or survival associated with systemic anaphylaxis in rabbits in vivo.

We investigated whether an inhibitor of poly(adenosine 5'-diphosphoribose) synthetase (PARS) is beneficial in anaphylaxis. Twenty-eight rabbits were randomly allocated to three groups: Group I (control) received .9% NaCl solution 10 min before antigen challenge followed by the infusion of the same solution. Group II (3-aminobenzamide 20 mg.kg-1) received 20 mg.kg-1 of 3-aminobenzamide (a PARS inhibitor) 10 min before antigen challenge followed by the continuous infusion of 20 mg.kg-1 of 3-aminobenzamide. Group III received 40 mg.kg-1 10 min before antigen challenge followed by the continuous infusion of 20 mg.kg-1 of 3-aminobenzamide. Survival were similar between three groups. Heart rate, mean arterial pressure (MAP), central various pressure, and pulmonary resistance did not differ between three groups. Dynamic pulmonary compliance did not differ in the early phase after the antigen challenge; however, it was significantly lower in Group III than in Groups I and II 15 min after the initiation of anaphylaxis. 3-aminobenzamide per se did not affect heart rate, MAP, central venous pressure, pulmonary resistance, or dynamic pulmonary compliance in animals without systemic anaphylaxis. In conclusion, this PARS inhibitor did not improve cardiovascular depression or bronchospasm in the early phase of systemic aggregated anaphylaxis in rabbits in vivo, implying that the pathophysiological changes associated with systemic anaphylaxis may not be related to activation of an energy-consuming DNA repair cycle triggered by PARS.

Production of nitric oxide in anaphylaxis in rabbits.

To verify production of nitric oxide (NO) in anaphylaxis, we measured NO in peripheral tissue in anaphylactic rabbits using an NO-sensitive electrode. Rabbits were sensitized to horse serum, which was later administered over 10 s into the systemic circulation to induce anaphylaxis. Blood pressure (BP), central venous pressure (CVP), heart rate, and NO were recorded continuously for 80 min after antigen challenge. The NO-sensitive electrode was placed between the superficial abdominal fascia and the rectus abdominis fascia. The NO concentration increased to 3000-4800 pA (about 3-4.8 microM NO) within 4 min after initiation of anaphylaxis, at which time BP was decreased and CVP increased; however, NO production was continuously observed 30-60 min after antigen challenge, during which time changes in BP and CVP were not correlated with changes in NO concentration. In conclusion, NO production can be detected using an NO-selective electrode in anaphylactic rabbits.

An inhibitor of nitric oxide synthase, N omega-nitro-L-arginine-methyl ester, attenuates hypotension but does not improve cardiac depression in anaphylaxis in dogs.

We investigated whether a nitric oxide synthase (NOS) inhibitor improves cardiovascular depression associated with anaphylaxis. After induction of anaphylactic circulatory depression, one group received an NOS inhibitor (Group I, n = 6) and the other received saline solution (Group II, n = 5). Mean arterial pressure and right atrial pressure were significantly higher in Group I than in Group II. Hematocrit was significantly lower in Group I than in Group II. Cardiac output, stroke volume, mean pulmonary arterial pressure, the maximum rate of increase in left ventricular pressure, and the time constant of the fall in isovolumic left ventricular pressure did not differ between the groups. In conclusion, L-NAME attenuates hypotension, but does not improve cardiac depression in anaphylaxis in dogs. Our finding that NOS inhibitor did not improve cardiac function implies that the production of NO in anaphylaxis may have a protective effect with regard to cardiac performance.

Nitric oxide synthase inhibition is detrimental to cardiac function and promotes bronchospasm in anaphylaxis in rabbits.

We studied the effects of a nitric oxide synthase (NOS) inhibitor, N omega-nitro-L-arginine-methyl ester (L-NAME), on cardiac depression and bronchospasm provoked by systemic anaphylaxis in vivo in rabbits. Animals pretreated with L-NAME showed lower survival rates than control animals pretreated with normal saline. The survival rate in L-NAME-pretreated animals was increased by the administration of L-arginine after initiation of anaphylaxis. Cardiac output fell significantly in animals pretreated with L-NAME compared with controls, although venous return was increased. In animals pretreated with L-NAME, pulmonary resistance was significantly increased, and administration of arginine attenuated the bronchospasm. In conclusion, these results, along with the low survival rates in the L-NAME-treated animals, suggest that NO production may be beneficial to cardiac depression and bronchospasm in anaphylaxis in vivo.

Pilot study of UFT combined with 5 consecutive days cisplatin in non-small cell lung cancer.

Combined use of 5-fluorouracil (5-FU) and cisplatin has proven to have synergistic effects in many experimental systems and clinical studies. UFT, an oral preparation of uracil and tegafur in a 4:1 molar ratio, was reported to have enhanced activity as compared with 5-FU or tegafur alone against various human tumors. Based on those results, we conducted a pilot study to confirm the feasibility and antitumor effect of UFT in combination with cisplatin in patients with advanced non-small cell lung cancer (NSCLC). UFT was orally administered at a dose of 400 mg/m2 according to a protocol for step-wise prolongation of the administration period, such as days 1-14 in step I, days 1-21 in step II, days 1-28 in step III. During to course, cisplatin was administered at a fixed dose of 20 mg/m2/day on days 8 through 12. The course was repeated every 4 weeks. Numbers of patients enrolled in steps I, II, III were six, ten and six (a total of 22), respectively. There were three females and 19 males, PS scored 0/1/2 = 7/14/1, stage IIIA/IIIB/IV = 3/8/11. Adenocarcinoma/squamous cell carcinoma/large cell carcinoma = 11/7/4, and median age 68 (range 52-79). All 22 patients were evaluable for toxicity, and 21 for efficacy. Compliance of UFT declined as the administration period of UFT was prolonged. In step I, one patient had grade 3 toxicity of each neutropenia, thrombocytopenia, nausea/vomiting and diarrhea. In step II, grade 3, 4 neutropenia was seen in four patients, grade 3 thrombocytopenia and anorexia in one patient, and grade 3 nausea/vomiting in four patients. In step III, there was grade 3 neutropenia in two patients and grade 3 anorexia in one patient. All other toxicities were mild. The overall response rate was 38% (one CR and 7 PR, 95% C.I.: 21-59%). Combination therapy with oral UFT and 5-day infusion of cisplatin is feasible with substantial antitumor effect against advanced NSCLC. Since UFT compliance decreased in step III (no patient in step III received > 2 courses of treatment), we considered the step II schedule to be worth for further evaluation in a combination phase II study.

Analysis of conformational changes at the unique loop adjacent to the ATP binding site of smooth muscle myosin using a fluorescent probe.

Recent crystallographic studies have shown that smooth muscle myosin has three highly conserved unique loops, loop B (320-327), loop M (687-699), and loop N (125-134), similar to other myosins, skeletal muscle and dictyostelium myosins. We previously demonstrated that the effect of actin is mediated by a conformational change in one of the loops, loop M comprising amino acids 677 to 689 of skeletal muscle myosin [Maruta and Homma (1998) J. Biochem. 124, 528-533]. In the present study, in order to clarify the role of these smooth muscle myosin loops in energy transduction, we specifically labeled the loops with a fluorescent photoreactive ADP analogue, 3'-O-(N-methylanthraniloyl)-8-azido-ADP (Mant-8-N(3)-ADP), and then measured the fluorescent polarization. When Mant-8-N(3)-ADP was trapped by aluminium fluoride or vanadate into the ATPase site, Mant-8-N(3)-ADP was covalently incorporated into loop N (125-134). In contrast, Mant-8-N(3)-ADP trapped by beryllium fluoride was covalently incorporated into both loop M (687-699) and loop N (125-134) at an almost equimolar ratio. Actin binding to smooth muscle myosin S1 (SMO-S1) labeled at only loop N (125-134) increased the polarization due to the viscosity of actin. In contrast, S1 labeled at both loops N and M showed a much smaller increase in polarization. Our results indicate that the probe at loop M (687-699) of smooth muscle myosin moved to a less hindered region, suggesting that actin binding induces conformational changes at loop M (687-699) similar to those of the corresponding loop (677-689) in skeletal muscle myosin, as previously demonstrated in our laboratory.

Clinical application of low dose-rate brachytherapy combined with simultaneous mild temperature hyperthermia.

BACKGROUND: Recent biological research has shown that mild temperature hyperthermia (MTH) around 41 degrees C simultaneously combined with low dose-rate irradiation (LDRI) is an effective treatment modality for cancer. The aim of the study was to assess the clinical usefulness of a combination of MTH and simultaneous low dose-rate brachytherapy. MATERIALS AND METHODS: Seven superficial and 8 deep-seated tumors were included in this protocol. Two tumors had no previous treatment and the remainder were recurrent tumors which had arisen from previously treated sites. The average major diameters of superficial and deep tumors were 8.6 and 7.0 cm, respectively. The average values for Tmin in superficial and deep tumors were 41.5 and 40.7 degrees C, respectively. Brachytherapy was delivered by 137Cs and/or 192Ir LDRI sources. RESULTS: For superficial tumors, six of the seven tumors responded to the treatment (4 achieved CR, 2 PR, 1 NC) and four tumors did not recur within the follow-up period of 5-15 months. All of the deep tumors responded and 5 achieved CR, 3 PR. Four tumors recurred 4-17 months after the treatment and the remainder showed no local recurrence within the follow-up period of 4-31 months. CONCLUSION: MTH simultaneously combined with LDRI was an effective method for treating progressive and bulky tumors with a previous treatment history.

[Cell density and hexagonality of lens epithelium in human cataracts].

One hundred and ninety flat preparations of human lens epithelium attached to the anterior capsule, obtained during surgical extracapsular cataract extraction (ECCE), were studied. The median cell density of all preparations was 4,701 cells/sqmm. The lens epithelium of the patients exceeding 50 years of age showed lower density than that of younger patients (p less than 0.05). The epithelium of females showed a higher density than that of male patients. With increasing maturity of cataracts, the cell density decreased (p less than 0.05). Moreover the cell density of DM patients was significantly lower than that of non-DM patients (p less than 0.05). This result may be explained by the sorbitol pathway theory. There were no significant differences among any cases in term of hexagonality.

[Intercalation monitoring PCR(IM-PCR), its principle and application: quantitative monitoring of HCV RNA in the course of IFN therapy].

We developed intercalation-monitoring PCR(IM-PCR), a homogeneous quantitative assay of DNA/RNA by PCR in the presence of a fluorescent DNA intercalative dye, while monitoring the fluorescence intensity of the PCR reaction mixture in the course of PCR cycles. We demonstrated the application of this assay to quantify HCV RNA in serum samples from patients with chronic hepatitis C. This assay gave efficient and reproducible results in a clinically useful dynamic range below 10(6) copies of HCV RNA for interferon therapy.

[Alpha 2-plasmin inhibitor plasmin complex in patients undergone surgery in femoral neck fracture].

The alpha 2-plasmin inhibitor-plasmin complex (alpha 2-PI-PM), alpha 2-plasmin inhibitor (alpha 2-PI) and some functions of coagulation and hemostasis were assayed on aged patients who were operated for femoral neck fracture. After the surgery, APTT, PT, fibrinogen, AT-III and platelet counts were in normal range or slightly deviated, which did not match with the DIC diagnostic standard. FDP levels in the operation group (337 +/- 303 ng/ml) were significantly increased compared to the level of the normal aged persons (64 +/- 9.9 ng/ml). The alpha 2-PI-PM in the operation group was 2.92 +/- 3.56 micrograms/ml, which was significantly higher than the alpha 2-PI-PM level (0.76 +/- 0.45 micrograms/ml) in the normal aged persons. Moreover, 3 in 7 operation cases, showed the increase of alpha 2-PI-PM levels over 5 micrograms/ml. The alpha 2-PI-PM in DIC group was 5.29 +/- 5.17 micrograms/ml. These data suggest that the patients are in the pre DIC state after surgery. In titers of FDP and alpha 2-PI, there were no differences between patients treated with and without heparin. alpha 2-PI-PM levels were improved in 5 out of 7 cases with the heparin treatment. On the other hand only one in 6 cases who did not receive heparin therapy showed the improvement of alpha 2-PI-PM level. In some cases without heparin treatment, the alpha 2-PI-PM level increased in the course of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

[The spread of subarachnoid hyperbaric dibucaine in the term parturient].

To study the effect of patient's age, height, body mass index (BMI), site of injection, and volume injected on determining the spread of hyperbaric spinal anesthesia in the term parturient, we performed a retrospective analysis on 86 parturients who had received 0.3% hyperbaric dibucaine for cesarean section. All patients received subarachnoid injection of the drug in the left lateral decubitus position on a horizontal operating table. After the drug was injected, the final cephalad level of analgesia to pinprick was measured. Multiple regression analysis revealed that BMI and volume injected had relatively stronger relation with the spread of sensory analgesia, when compared to the others. However, neither of them was a significant determinant of the level of analgesia. In conclusion, patient's age, height, BMI, site of injection and volume injected were not significant determinants of hyperbaric dibucaine spinal anesthesia in the term parturient.

[Continuous epidural buprenorphine for postoperative pain relief in patients after lower abdominal surgery].

Postoperative analgesia with epidurally injected buprenorphine and its side effects were investigated in 100 patients who had received lower abdominal surgery. All patients received initially 8 ml of bupivacaine and 0.1 mg of buprenorphine. Following bolus epidural injection, five different groups of 20 patients each received either bupivacaine alone (group A), 5 micrograms.ml-1 buprenorphine.bupivacaine mixture (group B), 8 micrograms.ml-1 buprenorphine.bupivacaine mixture (group C), 12 micrograms.ml-1 buprenorphine.bupivacaine mixture (group D), or 15 micrograms.ml-1 buprenorphine.bupivacaine mixture (group E) by a portable disposable device at a rate of 1 ml.h-1 for 48 h. The analgesic efficacy in group E was superior to those in groups A, B, C or D. No significant difference in the incidence of side-effect was found among groups C, D, E. We conclude that a dose of a approximately 15 micrograms.h-1 might be optimal for postoperative pain relief after lower abdominal surgery.

[Usefulness of measurement of mast cell tryptase for differential diagnosis of anaphylaxis and anaphylactoid reaction].

We described a case of anaphylaxis diagnosed by the evaluation of plasma mast cell tryptase and a case of anaphylactoid reaction. In a patient undergoing pulmonary lobectomy, anaphylaxis, showing the elevation of plasma tryptase, was provoked by physiological glue for hemostasis during the operation. During the operation, cardiovascular collapse occurred suddenly, at which time the cause was not diagnosed. After completion of the operation and removal of drapes, diffuse urticaria with wide erythema on the torso and the upper extremity was noticed. Suspecting allergic adverse reaction, plasma tryptase was measured 2h and 5h after the start of the episode, showing 34.6 ng.ml-1 at 2h and 15.3 at 5h. Because these elevations of plasma tryptase indicated degranulation of mast cells, evaluation of the causative drugs was performed 7 weeks after the episode. Physiological glue was confirmed to be causative drug. In another patient for total hysterectomy and bilateral oophorectomy, adverse reaction occurred after completion of the operation and extubation. Increase in plasma histamine concentration to 4.94 ng.ml-1 that could induce systemic reaction was noticed; however, concentrations of plasma tryptase 25 min, 3h and 7h after the episode were not elevated. This finding indicated that the adverse reaction was not based on degranulation of mast cell, and was anaphylactoid reaction provoked by nonspecific histamine-release. In conclusion, measurement of plasma tryptase is a useful method for differential diagnosis of anaphylaxis and anaphylactoid reaction.

[Efficacy of the artificial ventilation for the treatment of IgE-mediated anaphylactic shock in dog].

To evaluate efficacy of artificial ventilation with 100 % oxygen for treatment of IgE-mediated anaphylaxis, we compared survival of control ventilated dogs with one of dogs with spontaneous ventilation. Fourteen dogs sensitized to Toxica canis were randomly assigned to two groups: spontaneous respiration group (Group S, n = 8) and artificial ventilation group (Group A, n = 6). All dogs were anesthetized with pentobarbital. In Group S, all dogs breathed spontaneously with constant flow of 4 l.min-1 of oxygen. Spontaneous respiration maintained an end-tidal CO2 level between 40 and 50 mmHg. In Group A, the dogs, paralyzed with pancuronium, were ventilated mechanically with 100 % oxygen, and the tidal volume was adjusted to maintain an end-tidal CO2 level between 35 and 40 mmHg. After measurements of pulmonary resistance (RL), dynamic compliance (Cdyn), and circulatory parameters at baseline, Ascaris suum antigen was administered intravenously into the systemic circulation to induce IgE-mediated anaphylaxis. RL, Cdyn and circulatory parameters were recorded continuously for 120 min after antigen challenge. Analysis of arterial blood gases was done throughout the study. Survival rates were 100 % and 50 % in Group A and Group S, respectively. In 7 of 8 dogs in Group S, apnea was observed during the period of 1 min to 5 min after antigen challenge, and the apnea continued during the period of 30s to 22 min. Four dogs died during the period of 20 min to 30 min after antigen challenge. In both groups, RL increased significantly and Cdyn decreased significantly after antigen challenge.(ABSTRACT TRUNCATED AT 250 WORDS)

[Anesthesia in a patient with history of multiple drug allergies].

A 38-year-old woman was admitted for intranasal ethmoidectomy. She had a history of serious anaphylactic reactions, including respiratory distress, hypotension and unconsciousness, to nonsteroidal anti-inflammatory drugs (Loxonin, Niflan) and antibiotics (Kefral, Minomycin). Preoperative intradermal skin tests against anesthesia-related drugs showed positive reactions to succinylcholine and vecuronium. After bilateral maxillary nerve block with 0.5 % bupivacaine (negative intradermal test) 3 ml, anesthesia was induced with diazepam, nitrous oxide, oxygen and sevoflurane. Trachea was intubated smoothly without muscle relaxants. Anesthesia was maintained with nitrous oxide, oxygen and sevoflurane 0.5-1 %. The anesthesia and postoperative course of this patient were uneventful. To confirm the initiation of allergic reaction to anesthetics used in the patient, serum histamine, tryptase, and complement 1, 3 and 4 factors were measured at 3 points: preoperatively, immediately after the induction, and after extubation. They showed normal levels. These results showed that no allergic reaction occurred perioperatively. In conclusion, the valuable information was provided for the choice of anesthetics by thorough evaluation of the past history and intradermal testing.