Differential antinociceptive effects induced by intrathecally administered endomorphin-1 and endomorphin-2 in the mouse.

Two highly selective mu-opioid receptor agonists, endomorphin-1 and endomorphin-2, have been identified and postulated to be endogenous ligands for mu-opioid receptors. Intrathecal (i.t.) administration of endomorphin-1 and endomorphin-2 at doses from 0.039 to 5 nmol dose-dependently produced antinociception with the paw-withdrawal test. The paw-withdrawal inhibition rapidly reached its peak at 1 min, rapidly declined and returned to the pre-injection levels in 20 min. The inhibition of the paw-withdrawal responses to endomorphin-1 and endomorphin-2 at a dose of 5 nmol observed at 1 and 5 min after injection was blocked by pretreatment with a non-selective opioid receptor antagonist naloxone (1 mg/kg, s.c.). The antinociceptive effect of endomorphin-2 was more sensitive to the mu (1)-opioid receptor antagonist, naloxonazine than that of endomorphin-1. The endomorphin-2-induced paw-withdrawal inhibition at both 1 and 5 min after injection was blocked by pretreatment with kappa-opioid receptor antagonist nor-binaltorphimine (10 mg/kg, s.c.) or the delta(2)-opioid receptor antagonist naltriben (0.6 mg/kg, s.c.) but not the delta(1)-opioid receptor antagonist 7-benzylidine naltrexone (BNTX) (0.6 mg/kg s.c.). In contrast, the paw-withdrawal inhibition induced by endomorphin-1 observed at both 1 and 5 min after injection was not blocked by naloxonazine (35 mg/kg, s.c.), nor-binaltorphimine (10 mg/kg, s.c.), naltriben (0.6 mg/kg, s.c.) or BNTX (0.6 mg/kg s.c.). The endomorphin-2-induced paw-withdrawal inhibition was blocked by the pretreatment with an antiserum against dynorphin A-(1-17) or [Met(5)]enkephalin, but not by antiserum against dynorphin B-(1-13). Pretreatment with these antisera did not affect the endomorphin-1-induced paw-withdrawal inhibition. Our results indicate that endomorphin-2 given i.t. produces its antinociceptive effects via the stimulation of mu (1)-opioid receptors (naloxonazine-sensitive site) in the spinal cord. The antinociception induced by endomophin-2 contains additional components, which are mediated by the release of dynorphin A-(1-17) and [Met(5)]enkephalin which subsequently act on kappa-opioid receptors and delta(2)-opioid receptors to produce antinociception.

Heterogeneity of keratin expression in epithelial tumor cells of adenolymphoma in paraffin sections.

Immunohistochemical expressions of keratin polypeptides detected by monoclonal antibodies were described in tumor cells of adenolymphoma, and the possibility of intercalated duct and ductal basal cells in the salivary glands being the progenitors was discussed. Basal cells in the tumor showed positive staining for keratin nos. 8, 13, 16, 18 and 19 detecting for monoclonal keratin antibodies (PKK 1, K 4.62, K 8.12, K 8.13), columnar tumor cells displayed strongly positive reactions with RPN 1164 and K4.62 suggesting keratin nos. 8 and 19. Great heterogeneity of distribution for keratin polypeptides was displayed by epithelial cells of adenolymphoma. Intercalated duct cells of normal salivary glands reacted with RPN 1164, RPN 1165, K 4.62 and K 8.13 monoclonal antibodies, which indicates the presence of keratins 8 and 19; and ductal basal cells reacted with PKK 1, K 4.62 and K 8.12, suggesting nos. 8, 13, 16, 18 and 19 keratins. Distribution of involucrin was variable in tumor epithelium of adenolymphoma, and was negative in the normal gland. The immunohistochemical distribution of keratin types between basal tumor cells of adenolymphoma and ductal basal cells of the normal salivary gland was compared.

Immunohistochemical localization of carbonic anhydrase I and II in submandibular salivary glands of the mouse, rat, hamster and guinea pig.

Tissues were fixed in Bouin and Carnoy solutions, and the peroxidase, anti-peroxidase (PAP) method was used. Serous acinar cells of the guinea pig were positive for carbonic anhydrase (CA), but acinar cells of rodents were negative. Granular convoluted tubule (GCT) cells of the mouse, rat and hamster had varying degrees of staining for CA isoenzyme I and II. Striated and excretory ducts from all four species were usually positive for CA. Scattered cells containing a high concentration of CA I and CA II were present in striated ducts and GCT of the hamster, GCT of the rat and striated and excretory ducts of the guinea pig.

Immunoreactive prolactin in lesions and tumours of salivary glands.

The prolactin binding in obstructive lesions and tumours of salivary glands was described by use of the immunohistochemical PAP technique. Normal salivary glands had prolactin binding cells in the striated ducts only. Chronic obstructive lesions of submandibular glands showed negative immunoreaction for prolactin binding in ductal cells, but positive staining of the luminal surface of ductal segments. In pleomorphic adenomas, occasional neoplastic cells located along the luminal borders of tubular, ductal, or of duct-like epithelial structures were strongly reactive with anti-prolactin and 26.5% of cases pleomorphic adenoma were positive for anti-prolactin. Adenoid cystic carcinoma exhibited positive prolactin binding on the luminal surface of some of tumour foci, but not in the rest of the tumour. Warthin's tumour was devoid of detectable prolactin binding.

Heterogeneous expression of S-100 protein subunits alpha and beta in cystadenolymphomas of salivary glands.

Immunohistochemical expression of S-100 protein and its subunits alpha and beta in a total of 27 cases of cystadenolymphomas of the parotid gland is described by means of polyclonal anti-S-100 protein antiserum and monoclonal antibodies against S-100 alpha and beta. Normal salivary glands showed strongly positive staining for S-100 alpha in acinic cells and a negative or slightly positive reaction in ductal cells; however, they were usually negative for S-100 beta staining. Neoplastic epithelial cells of cystadenolymphomas showed slightly positive staining for S-100 alpha in their cytoplasm, and there was a strongly positive reaction in a limited number of tumour cells. The S-100 beta subunit was expressed as a fine granular deposition in the apical cytoplasm of tumour cells. S-100 protein staining with the polyclonal reagent was usually negative or slightly positive in the tumour epithelia, but a small number of strongly positive cells were scattered throughout the tumour epithelia, suggesting the presence of Langerhan's cells. Interdigitating cells in lymphoid tissue reacted positively to monoclonal S-100 alpha as well as to the polyclonal antiserum.

[Levels for discharge to home and return to general ward of patients who received therapeutic dose of 131I based on external exposure dose].

This paper describes levels for discharge from hospital and return to general ward of patients treated with 131I. The level was determined by comparing the possible exposure dose to those individuals whom the patients are in daily contact with the annual dose limit for the public. The external exposure dose was calculated by using the data on the distance between the patient and individuals, length of the time spent at each distance, and each individual's age. The following levels were obtained: (1) For the patient to be discharged from the hospital, the maximum residual radioactivity should be less than 0.51 GBq if the distance from the patient in bedroom is 50 cm or more and the ages of her children are all over one year. No restriction is needed for the patient with residual radioactivity of 0.20 GBq. (2) For the patient to be returned to the general ward, the maximum residual radioactivities should be 28 MBq and 41 MBq, corresponding to the distance from the patient of 2.0 m and 2.5 m respectively. We established a method to analyze the factors affecting the level.

[Adjuvant chemotherapy for osteosarcoma in Japan--past, present and future].

The therapeutic results for osteosarcoma were very discouraging before 1970 in Japan despite many modes of treatment. In 1960, Miki introduced the regional perfusion technique into the treatment of osteosarcoma, and in 1963, Akaboshi pioneered the intraarterial infusion technique. By these methods, a five-year survival rate about 30% was achieved during the period from 1971 to 1976. In Japan, the five-year disease-free survival rate will soon exceed 50% thanks to intensive multi-drug adjuvant chemotherapy, considering the therapeutic results of 117 cases of JOOG treated during 6 years from 1975 to 1980 and 114 cases included in the Group Study of Osteosarcoma treated during 8 years from 1973 to 1981. In most cases, ablative surgery must still be considered the standard method of treatment. However, the importance of preoperative adjuvant chemotherapy is emphasized because limb-saving operations have become an increasingly common feature in the management of osteosarcoma as a result of the recent advances achieved by intensive multi-drug adjuvant chemotherapy.

[Preoperative adjuvant chemotherapy of skeletal and soft tissue sarcomas].

Preoperative adjuvant chemotherapy for skeletal and soft tissue sarcomas requires: (1) correct identification of the effective postoperative adjuvant chemotherapy, (2) eradication of any of the micrometastatic foci that may have already occurred in many of the patients with these sarcomas, (3) easier and safer limb-salvage procedure, being clearly defined, with shrinkage of the primary lesion. For this purpose, a preoperative adjuvant chemotherapy regimen making practical use of intra-arterial CDDP (cis-dichlorodiammineplatinum II) infusion is desired in multi-drug combined chemotherapeutic treatment, including HDMTX (high-dose methotrexate), ADR (adriamycin) and CDDP. In this paper, the clinical application of preoperative adjuvant chemotherapy to skeletal and soft tissue sarcomas with combination of HDMTX and CDDP is presented in the light of the observations of tumor response to these anticancer agents, and the possibility of to establishing a new preoperative adjuvant protocol is discussed.

[Application of preoperative chemotherapy to postoperative chemotherapy in malignant bone and soft tissue tumors].

We analyzed the effectiveness of preoperative chemotherapy mainly with radiographic images in 9 patients with osteosarcoma, 5 patients with other malignant bone tumor and 14 patients with malignant soft tissue tumor. Judging from the application of preoperative to postoperative chemotherapy and outcome, its evaluation was useful in osteosarcoma and malignant soft tissue tumors. Changes in radiographic images by preoperative chemotherapy were the same in malignant bone and soft tissue tumors, but the reactivity of the latter was more evident. In malignant bone and soft tissue tumors, the effects of preoperative chemotherapy should be evaluated for the cases with resection of primary tumor. Malignant bone tumors excepting osteosarcoma also should be assessed through further accumulation of many more cases.

[Rationale of preoperative chemotherapy of osteosarcoma].

The rationale of preoperative chemotherapy for osteosarcoma requires: eradication of microscopic metastatic foci which have already occurred in many patients with osteosarcoma, determination of a more effective form of postoperative adjuvant chemotherapy and easier and safer limb-salvage procedures through clearer marginal definition with reduction of primary lesions. In this paper, chemotherapeutic effects on the 5-year survival rate were analyzed for 49 patients with primary non-metastatic osteosarcoma of the extremities treated with radical surgery. The efficacy of preoperative chemotherapy was assessed in 11 cases of osteosarcomas treated with systemic chemotherapy as a preliminary study. As to the 5-year cumulative survival rate, the systemic group (20 cases) showed a level of 56.7%, which was significantly higher (p less than 0.05) than the figure of 13.8% in a historical retrospective group (29 cases). In assessing the effective tumor response to preoperative chemotherapy, a close correlation between the tumor necrotic ratio and the ratio of decrease of serum alkaline phosphatase was revealed. Seven (63.6%) of 11 cases showed correlation of the tumor necrotic ratio with the ratio of decrease of serum alkaline phosphatase. The tumor necrotic ratios calculated were relatively definite (50-60%) in the CDDP group (3 cases), varied (10-70%) in the HDMTX group (4 cases), and low (less than 40%) in the ADR group (4 cases), regarded as a control group in further studies.

Improvement of Quality of Life (QOL) in Osteoporotic Patients by Elcatonin Treatment: A Trial Taking the Participants' Preference into Account.

Osteoporosis is associated with compromised quality of life (QOL), to which pain has the most important contribution. Elcatonin, a derivative of calcitonin, is widely used in the treatment of osteoporosis in two ways. One is as the inhibitor of osteoclastic bone resorption. The other is for osteoporosis-related pain based on the unique analgesic effects of elcatonin. Since pain is subjective in nature, and QOL is the only clinical outcome representing the patients' subjective perception of health status, pain associated with osteoporosis would be best evaluated based on QOL assessment. Evidence based medicine gives the highest remarks to the double-blinded, randomized controlled trial, which, however, cannot be free from methodological problems on some occasions. For example, it is practically impossible to remain blinded in the trial of a potent analgesia, which in turn causes biases. Thus, the significance of taking the patients' preference into account is increasingly acknowledged. In this study, 45 osteoporotic patients were given brochures describing the pros and cons on the three treatment choices; calcium and alfacalcidol, additional use of elcatonin, and additional use of bisphosphonate. Those who favored elcatonin were older, had more vertebral fractures, and lower QOL scores. QOL was evaluated before and three months after the treatment using SF-8; the most widely used generic questionnaire, and RDQ; a lumbago-specific measure. Elcatonin treatment improved physical function, general health, and vitality of SF-8, and RDQ score. Although this is a preliminary study, our results suggest that patients with vertebral fracture(s) have impaired QOL and more likely to favor elcatonin treatment expecting analgesia.

Immunohistochemical evaluation of factor VIII related antigen, filament proteins and lectin binding in haemangiomas.

Immunohistochemical identification of factor VIII related antigen (F VIII RAG) filament proteins (actin, myosin, filamin, vimentin and desmin) and lectin binding patterns of Con A, PNA, SBA, WGA, RCA-1, UEA-1 and DBA in the endothelial cells and the muscular layers of haemangiomas and normal blood vessels are reported, using paraffin sections with the HRP method. The endothelial cells of haemangiomas were usually strongly positive to F VIII RAG as were those from capillary vessels and other small vessels. Some of the endothelium from haemangiomas and angiokeratomas was negative for factor VIII. The vessel walls of hemangiomas showed staining slightly positive for microfilaments (actin, myosin, filamin). The smooth muscle layer in small vessels showed a more marked staining with actin. Vimentin and desmin reactions in the vessel walls of haemangioma and in normal vessels were slight or moderate. UEA-1 lectin binding was constantly positive in endothelial cells from hemangiomas and in blood vessels. SBA and WGA binding appeared in the border layer of endothelium in haemangiomas and normal vessels.