Role for enhanced faecal excretion of bile acid in hydroxysteroid sulfotransferase-mediated protection against lithocholic acid-induced liver toxicity.

The efficient clearance of toxic bile acids such as lithocholic acid (LCA) requires drug-metabolizing enzymes. We therefore assessed the influence of pregnenolone 16alpha-carbonitrile (PCN) treatment on LCA-induced hepatotoxicity and disposition of LCA metabolites using female farnesoid X receptor (FXR)-null and wild-type mice. Marked decreases in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, and hepatic tauroLCA (TLCA) concentrations were found in LCA-fed wild-type mice co-treated with PCN. Whereas induction of Cyp3a and hydroxysteroid sulfotransferase (Sult2a) proteins was observed in FXR-null and wild-type mice, clear increases in biliary 3alpha-sulfated TLCA but not total 6alpha-hydroxy LCA (taurohyodeoxycholic acid and hyodeoxycholic acid) were only observed in PCN-treated wild-type mice. Biliary 3alpha-sulfated TLCA output rate was increased 7.2-fold, but accounts for only 4.2% of total bile acid output rate in LCA and PCN-co-treated wild-type mice. Total 3alpha-sulfated LCA (LCA and TLCA) was, however, the most abundant bile acid component in faeces suggesting that efficient faecal excretion of biliary 3alpha-sulfated TLCA through escape from enterohepatic circulation. FXR-null mice, which have constitutively high levels of the Sult2a protein, were fed a diet supplemented with 1% LCA and 0.4% dehydroepiandrosterone (DHEA), a typical Sult2a substrate/inhibitor. The faecal total 3alpha-sulfated bile acid excretion was reduced to 62% of FXR-null mice fed only the LCA diet. Hepatic TLCA concentration and serum AST activity were significantly higher in FXR-null mice fed DHEA and LCA diet than in FXR-null mice fed the LCA diet or DHEA diet. These results suggest that hepatic formation of 3alpha-sulfated TLCA is a crucial factor for protection against LCA-induced hepatotoxicity.

Theophylline chronotherapy of nocturnal asthma using bathyphase of circadian rhythm in peak expiratory flow rate.

We studied the efficacy of theophylline chronotherapy for nocturnal asthma using the changes of the circadian rhythms in peak expiratory flow rate (PEF). Eight patients with nocturnal asthma were evaluated for the periods with nocturnal symptoms and with an evening dose of theophylline administered daily. Patients recorded their PEF every 4 hours on one of the days (from 7:00 to 23:00 h) in each period. Circadian rhythms in PEF were examined using the single and group-mean cosinor method. Significant circadian rhythms in PEF were observed in the period with nocturnal symptoms. When nocturnal symptoms were present, the bathyphase of PEF was present between midnight and morning. A significant circadian rhythm disappeared or PEF amplitude decreased during theophylline chronotherapy. The circadian rhythm in PEF was altered according to the severity of the asthma. In patients with symptoms present between midnight and early morning, an evening dose of theophylline chronotherapy can be prophylactically used for nocturnal asthma attacks. Consideration of the circadian rhythm and bathyphase of PEF is useful in selecting appropriate chronotherapy for nocturnal asthma.

Midgut malrotation in adulthood.

A 29-year-old man was admitted to our hospital with a history of recurrent right upper quadrant abdominal pain and vomiting. These symptoms appeared intermittently for 7 years. Various examinations revealed a diagnosis of midgut malrotation. Laparotomy was performed and revealed reverse rotation of the duodenum with paraduodenal hernia and a normal rotating colon. This case suggests that recurrent abdominal complaints in an adult should arouse suspicion of midgut malrotation.

[A clinical study of inoperable head and neck cancers].

Thirty two patients with inoperable head and neck cancer seen at Jichi Medical School Hospital during the period 1978 to 1995 were analyzed. Distribution of the affected site was as follows: 15 cases of oropharynx, 12 of hypopharynx, and 3 of larynx. In order to study a better performance status, prognosis and side effects were compared between radiotherapy alone (17 patients) and combined radiochemotherapy (15 patients). Patients who received the combined therapy survived longer than those patients who received radiotherapy alone. Moreover, high QOL was obtained longer in the combined therapy. Therefore, we conclude that radiotherapy should be combined with chemotherapy for cases with inoperable head and neck cancer.

Down-regulation of 5-hydroxytryptamine7 receptors by dexamethasone in rat frontocortical astrocytes.

Astrocytes derived from rat frontal cortex contain 5-hydroxytryptamine7 (5-HT)7 receptors positively coupled to adenylyl cyclase. In the present study, we investigated the effects of glucocorticoids on adenylyl cyclase activity and 5-HT7 receptor gene expression in astrocytes. Addition of dexamethasone (0.01-100 nM, 12-72 h) to the culture medium decreased cyclic AMP formation induced by 5-HT in a time- and concentration-dependent manner. Dexamethasone treatment (10 nM, 48 h) reduced maximum responses of cyclic AMP formation induced by 5-HT and 5-carboxamidotryptamine without alterations in the EC50 value. In contrast, treatment with the mineralocorticoid aldosterone (48 h) had no significant effects on 5-HT-induced cyclic AMP formation with concentrations up to 10 nM. It was observed that dexamethasone treatment (1-100 nM, 3-72 h) also decreased the expression of 5-HT7 receptor mRNA, using reverse transcription and polymerase chain reaction analysis. A significant reduction in expression of 5-HT7 mRNA appeared at 3 h of dexamethasone treatment and reached a maximum at 6 h of treatment. On the other hand, dexamethasone treatment (10 nM, 48 h) did not affect basal levels of cyclic AMP and cyclic AMP synthesis stimulated by isoproterenol, N-ethylcarboxamidoadenosine, cholera toxin, and forskolin. These results suggest that dexamethasone decreases the expression of the 5-HT7 receptor gene and, consequently, 5-HT7 receptor-mediated signal transduction in frontocortical astrocytes.

[Continuous infusion high-dose leucovorin with cisplatin and 5-fluorouracil for a recurrent oropharynx carcinoma].

Cisplatin and leucovorin heighten the activity of 5-fluorouracil by increasing the intracellular concentration of reduced folates. Therefore, we treated the recurrent oropharynx carcinoma case, who had received concurrent chemotherapy with low-dose cisplatin and radiotherapy, with continuous infusion high-dose leucovorin with cisplatin and 5-fluorouracil. Chemotherapy included continuous intravenous infusion of cisplatin (25 mg/m2, days 1 through 5); 5-fluorouracil (600 mg/m2, days 2 through 6); and leucovorin (200 mg/m2, days 1 through 6) administered once about every 4 weeks. Three cycles were performed, and a complete response was achieved. Grade 3 to 4 mucositis, nausea-vomiting, anemia, neutropenia, and thrombocytopenia occurred. Continuous infusion high-dose leucovorin with cisplatin and 5-fluorouracil was effective for this recurrent head and neck carcinoma. However, one must be cautious when comparing this chemotherapy in terms of toxicity.

Induction of long-lasting potentiation in the secondary somatosensory cortex by thalamic stimulation requires cortico-cortical pathways from the primary somatosensory cortex.

We have investigated the role of cortico-cortical inputs from the primary somatosensory cortex in the induction of long-lasting potentiation in the secondary somatosensory cortex. Long-lasting potentiation of evoked potentials in the feline secondary somatosensory cortex is induced by high frequency stimulation of the ventral posterolateral thalamic nucleus. The secondary somatosensory cortex receives two projections from the ventral posterolateral thalamic nucleus; a direct pathway from the ventral posterolateral thalamic nucleus and a cortico-cortical pathway via the primary somatosensory cortex. The present study was designed to examine dominance of these pathways in the induction of long-lasting potentiation in the secondary somatosensory cortex. Long-lasting potentiation was evaluated by changes in the amplitude of field potentials and current source densities elicited by ventral posterolateral thalamic nucleus test stimulation (0.1 Hz) following conditioning stimulation. The conditioning stimulation, consisting of 20 trains of 200 Hz bursts, was delivered to the ventral posterolateral thalamic nucleus or the primary somatosensory cortex. Field potentials in the secondary somatosensory cortex were simultaneously recorded at 16 points placed vertically at 150 microns intervals from the cortical surface and current source density was computed using these field potentials. First, we blocked inputs from the primary somatosensory cortex to the secondary somatosensory cortex by intracortical injection of lidocaine into the primary somatosensory cortex. The amplitudes of the field potentials recorded in the secondary somatosensory cortex diminished within 5 min after lidocaine injection. Current source density analysis showed a marked decrease in the sink currents in layers II/III (at depths of 450-600 microns).(ABSTRACT TRUNCATED AT 250 WORDS)

Manifestations of cancer cachexia induced by colon 26 adenocarcinoma are not fully ascribable to interleukin-6.

In order to further clarify the role of interleukin 6 (IL-6) in the pathogenesis of cachexia, recombinant human IL-6 (hIL-6) was administered s.c. by osmotic pump for 9 days at a dose of 1 or 10 micrograms/day into CDF1 mice inoculated with a non-cachexia-inducing subclone of colon 26 adenocarcinoma (clone 5), or with a cachexia-inducing subclone (clone 20) of this malignancy. The serum level of IL-6 in non-cachectic mice with clone-5 tumors was 35% lower than in cachectic mice bearing clone 20 of colon 26 adenocarcinoma on the 19th day after tumor inoculation. IL-6 administration induced anemia, thrombocytosis and visceral organ hypertrophy not only in mice with clone-5 tumors but also in control mice with no tumor burden. Lipolysis and proteolysis became conspicuous when a large dose (10 micrograms/day) of IL-6 was infused into mice with clone-5 tumors. However, IL-6 supplementation did not induce loss of body weight, a decline in food intake or lymphocytopenia, which were characteristically observed in cachectic mice with clone-20 tumors. In conclusion, IL-6 appears to be a permissive factor for the development of cachexia but, while it can induce some of the symptoms typical of cachexia, it cannot in itself induce the full cachectic syndrome.

Secretion of gastric inhibitory polypeptide in patients with bile duct obstruction.

BACKGROUND: The direct contribution of bile to gastric inhibitory polypeptide (GIP) release and the role of bile in regulating GIP secretion in response to fat ingestion are still obscure. The present study was aimed to clarify the influence of bile on GIP release. METHODS: Seven patients with obstruction of the common bile duct and nine volunteers participated in the study. Fifty milliliters of Lipomul was ingested, and GIP was measured serially for 180 min. After intraduodenal instillation of pooled autologous bile for 2 days, the same study was carried out. RESULTS: The fat-stimulated GIP response was significantly lower in the patients than in the controls. The basal GIP level did not change on bile instillation, but the GIP response to fat ingestion was significantly increased on bile instillation compared with that in the absence of bile. CONCLUSIONS: Intraluminal bile alone does not stimulate the secretion of GIP, but it promotes GIP secretion in response to fat ingestion.

The antitumor effect of hyperthermia combined with fluorouracil and its analogues.

The effectiveness of 5-fluorouracil (5-FU), FT-207 and FT-207 + uracil in combination with two repetitions of 43 degrees C hyperthermia in the treatment of the Meth-A-Fibrosarcoma and Sarcoma-180 was examined in vivo in BALB/c mice. The antitumor effect was evaluated in terms of inhibition of tumor growth by measuring the tumor for 7 days. The 5-FU concentration in each tumor was also monitored. Hyperthermia combined with FT-207 or FT-207 + uracil showed a synergistic effect for the inhibition of growth of both tumors which was not observed with 5-FU. There were no significant differences in the intratumoral concentration of 5-FU in unheated or heated Sarcoma-180 for any drug treatment after the first hyperthermia treatment, except for significant decreases in the group given 5-FU with the first hyperthermia treatment. After the second hyperthermia treatment, significant decreases in the concentration of 5-FU and FT-207 + uracil were observed. In the Meth-A-Fibrosarcoma, the intratumoral concentration of 5-FU decreased significantly in the group given 5-FU and increased significantly in the group given FT-207 + uracil after the first hyperthermia treatment, while there were significant decreases in 5-FU, FT-207 and FT-207 + uracil administered with the second hyperthermia treatment. Hyperthermia combined with FT-207 or FT-207 + uracil is considered to be effective.

Serum lidocaine and MEGX concentrations after pharyngeal anesthesia for gastroscopy.

In 20 patients undergoing topical anesthesia for gastroscopic examination, serum concentrations of lidocaine and its metabolite, monomethylglycinexylidide (MEGX), were measured. Patients were divided randomly into two groups: a gel group, in which 5 ml of 2% lidocaine gel was applied to the throat for 20 minutes; and a solution group, in which 40 ml of 2% lidocaine solution was administered by gargling for five minutes. The effect of oropharyngeal anesthesia was comparable in both groups. In the gel group, the serum levels of lidocaine and MEGX were not elevated at 15 minutes after application of the anesthetic. However, in the solution group, a rise in both serum lidocaine and MEGX at 15 minutes after anesthesia was detected in some of the patients (40%). Increased serum MEGX concentrations, which correlated well with serum lidocaine concentrations, were associated with the age of the patient (r = 0.606; p < 0.05), but not with height or weight. As a topical anesthetic for endoscopic examination, we prefer lidocaine gel to lidocaine solution, because the latter might be absorbed more rapidly and unpredictably in some, especially aged patients.

Aggravation of experimental allergic conjunctivitis by environmental chemical and physical factors.

The effects of trichlorfon (DEP, Dipterex, anticholinesterase pesticide) and paraquat dichloride (Gramoxon, inhibitor of superoxide dismutase) on passive anaphylactic reaction in guinea pig conjunctiva using Japanese cedar pollen were quantitatively studied. For estimation of allergic conjunctivitis, Evans blue after i.v. injection was extracted from conjunctiva and measured spectrophotometrically. Allergic conjunctivitis was apparently aggravated by extremely low dosages of organophosphorus pesticide (10(-5) mg/kg) and organochlorine herbicide (10(-4) mg/kg). The aggravation of allergic conjunctivitis was also observed after exposure to cathode ray tubes used in commercial television, possibly due to electromagnetic waves. IgE-mediated allergic reaction could be non-specifically potentiated by such environmental factors.

Reaction of two heads of gizzard myosin with ATP.

The reaction intermediates formed by the two heads of smooth muscle myosin were studied. The amount of myosin-phosphate-ADP complex, MPADP, formed was measured from the Pi-burst size over a wide range of ATP concentrations. At low concentrations of ATP, the Pi-burst size was 0.5 mol/mol myosin head, and the apparent Kd value was about 0.15 microM. However, at high ATP concentrations, the Pi burst size increased from 0.5 to 0.75 mol/mol myosin head with an observed Kd value of 15 microM. The binding of nucleotides to gizzard myosin during the ATPase reaction was directly measured by a centrifugation method. Myosin bound 0.5 mol of nucleotides (ATP and ADP) with high affinity (Kd congruent to 1 microM) and 0.35 mol of nucleotides with low affinity (Kd = 24 microM) for ATP. These results indicate that gizzard myosin has two kinds of nucleotide binding sites, one of which forms MPADP with high affinity for ATP while the other forms MPADP and MATP with low affinity for ATP. We studied the correlation between the formation of MPADP and the dissociation of actomyosin. The amount of Pi-burst size was not affected by the existence of F-actin, and when 0.5 mol of ATP per mol of myosin head was added to actomyosin (1 mg/ml F-actin, 5 microM myosin at 0 degrees C) most (93%) of the added ATP was hydrolyzed in the Pi-burst phase. All gizzard actomyosin dissociated when 1 mol of ATP per mol myosin head was added to actomyosin.(ABSTRACT TRUNCATED AT 250 WORDS)

[A resected case of recurrent carcinoma of the right colon ten years after the initial operation].

A 59 year-old female complained of right lower abdominal mass. She underwent radical operation 10 years ago for the right colonic cancer staged Dukes C. She had passed 10 years without any sign or symptom of recurrence. She noticed a egg-sized tumor in the right lower abdomen unexpectedly one month ago when she got a bruise on that region, and then the tumor grew rapidly. Preoperative examinations, including barium enema, abdominal computerized tomography and so on, suggested a extraluminal tumor with infiltration to the colon. Laparotomy revealed that the tumor originated from the right paracolic gutter. The tumor sized 18 X 11 X 8 cm was resected and histological diagnosis was adenocarcinoma with the similar structural pattern to the initial specimen. On the basis of both operations and histological findings, we concluded that free tumor cells might be implanted in the large raw surface of the right dorsolateral abdominal wall, which was created by surgical incision at the initial operation, and subsequently appeared as a local recurrence after 10 years interval.

Studies of a brain polypeptide functioning as a putative endogenous ligand to benzodiazepine recognition sites in rats selectively bred for alcohol related behavior.

The brain content of Diazepam Binding Inhibitor (DBI), its cell location and that of its specific mRNA were studied immunohistochemically and by in situ hybridization. Various strains of rats were genetically selected for their alcohol tolerance and the above mentioned brain parameters were studied before and after chronic ethanol consumption. The DBI like immunoreactivity (DBI-LI) was found to be located in selected neuronal population and in non-neuronal cells. The DBI-mRNA was located in brain areas where DBI is abundant. It was immunochemically determined that the DBI content was increased in cerebellum and in hypothalamus of alcohol preferring rats after chronic ethanol consumption. DBI content was compared in the cerebellum of rats genetically selected for different alcohol sensitivity and it was significantly higher on the ethanol sensitive (ANT) rat strain.