Neonatal capsaicin treatment decreased substance P receptor immunoreactivity in lamina III neurons of the dorsal horn.

Using immunohistochemistry and in situ hybridization technique, the distribution of substance P (SP) and SP receptors was studied in the dorsal horn of the rat spinal cord after neonatal capsaicin treatment. Sprague-Dawley rats administered 100 mg/kg of capsaicin subcutaneously within 24 h after birth were examined at 8 weeks of age. In the capsaicin administered rats, slight reduction of SP immunoreactivities in lamina I, and severe decrease in lamina II were observed. In the control group, SP receptor-mRNA was observed in all laminae, and SP receptor-immunoreactivities were seen to be intense in laminae I and III. In contrast, in the capsaicin administered rats, the SP receptor-mRNA expression was low in laminae II-V, and SP receptor immunoreactivities decreased in laminae III-V. Furthermore, the density of the SP receptor immunoreactivities was considerably decreased in the nerve cells of lamina III. We concluded that elevation of the threshold to painful stimulation in rats was as a result of the decrease in SP immunoreactive afferent fibers in laminae I and II, decrease of the SP receptor-mRNA in the laminae II-V, or the decrease in SP receptor immunoreactive neurons in laminae III-V.

[Expired nitric oxide concentration derived from nasal cavity and that derived from airway and lung in Japanese cedar pollinosis].

AIM: Japanese cedar pollinosis (Type I allergy to Japanese cedar pollen) shows a high incidence in spring in Japan, demonstrating symptoms such as pituita, rhinostenosis, lacrimation and sometimes pharyngeal pain. The following study investigated whether expired nitric oxide (NO) concentration is increased in Japanese cedar pollinosis, and whether expired NO concentration can be used to discriminate from cold syndrome which symptoms are similar to Japanese cedar pollinosis. SUBJECTS AND METHODS: In 20 healthy subjects, 20 patients with Japanese cedar pollinosis and 20 patients with cold syndrome, expired NO concentrations derived from nasal cavity and those derived from airway and lung were measured. Expired NO concentrations derived from nasal cavity and those derived from airway and lung were compared among the groups. RESULTS: In patients with Japanese cedar pollinosis expired NO concentrations derived from nasal cavity and those derived from airway and lung markedly increased. In patients with cold syndrome there were no significant increases in these concentrations. DISCUSSION: It is considered that expired NO concentration is useful for discriminating Japanese cedar pollinosis from cold syndrome. It seems interesting that not only expired NO concentrations derived from nasal cavity but also those derived from airway and lung were clevated. Generalized airway inflammation may be present, even without clinical asthma, in patients with Japanese cedar pollinosis.

Analysis of localization of mutated tissue-nonspecific alkaline phosphatase proteins associated with neonatal hypophosphatasia using green fluorescent protein chimeras.

Hypophosphatasia is associated with a defect of the tissue-nonspecific alkaline phosphatase (TNSALP) gene. The onset and clinical severity are usually correlated in hypophosphatasia; patients with perinatal hypophosphatasia die approximately at the time of birth. In contrast, we describe a male neonatal patient with hypophosphatasia who had no respiratory problems and survived. He was compound heterozygous for the conversion of Phe to Leu at codon 310 (F310L) and the deletion of a nucleotide T at 1735 (delT1735), causing the frame shift with the result of the addition of 80 amino acids at the C-terminal of the protein. Because the C-terminal portion of TNSALP is known to be important for TNSALP to bind to the plasma membrane, the localization of wild-type and mutated TNSALP proteins was analyzed using green fluorescent protein chimeras. The expression vectors containing the complementary DNA of fusion proteins consisting of signal peptide, green fluorescent protein, and wild-type or mutated TNSALP, caused by delT1735 or F310L mutation, were introduced transiently or stably in Saos-2 cells. The delT1735 mutant failed to localize at the cell surface membrane, whereas the wild-type and the F310L mutants were located in the plasma membrane and cytoplasm. The assay for enzymatic activity of TNSALP revealed that the delT1735 mutant lost the activity and that the F310L mutant exhibited an enzymatic activity level that was 72% of the normal level. The F310L mutation was also detected in another neonatal patient with relatively mild (nonlethal) hypophosphatasia (reported in J Clin Endocrinol Metab, 81:4458-4461, 1996), suggesting that residual ALP activity of the F310L mutant contributes to the less severe phenotype. The patient is unique, with respect to a discrepancy between onset and clinical severity in hypophosphatasia.

Postoperative recurrence of solitary small hepatocellular carcinoma.

The prognosis of hepatocellular carcinoma after hepatic resection remains poor. The major cause is postoperative recurrence, most frequently intrahepatic. During the past 7 years, we conducted a detailed study of recurrence after hepatectomy in 34 patients with solitary small hepatocellular carcinoma measuring no larger than 4 cm in diameter, in which 13 cases had postoperative recurrent tumors, and two cases were considered multicentric. Eighty-five percent of recurrences were diagnosed at 6-18 months after the operation. The cumulative recurrence rates were 61% at 5 years after operation. When analyzing the factors affecting recurrence, a significant difference was observed regarding tumor diameter. After recurrence, most patients underwent percutaneous ethanol injection treatment and/or transcatheter arterial chemoembolization and lipiodolization. Four patients died of progressive disease within 1 year after recurrence; the treatment thus seemed to have no effect. The other patients with recurrence remain alive with the disease. The overall cumulative survival rates in this series were 76% at 3 years and 60% at 5 years after operation. To obtain better results after hepatectomy, even for small hepatocellular carcinoma, careful, long-term follow-up evaluation is therefore necessary for the multidisciplinary treatment of the postoperative recurrence, as well as the early diagnosis of tumors in high-risk patients.

Target-independent diversification and target-specific projection of chemically defined retinal ganglion cell subsets.

In diverse vertebrate species, defined subsets of retinal ganglion cells (RGCs, the neurons that project from retina to brain) are distinguishable on the basis of their dendritic morphology, physiological properties, neurotransmitter content and synaptic targets. Little is known about when this diversity arises, whether diversification requires target-derived signals, and how subtype-specific projection patterns are established. Here, we have used markers for two chemically defined RGC subsets in chick retina to address these issues. Antibodies to substance P (SP) and the nicotine acetylcholine receptor (AChR) beta 2 subunit label two small ( < 10%), mutually exclusive groups of RGCs in mature retina. SP and AChRs accumulate in distinct RGCs before retinotectal synapses have formed. Moreover, both populations of RGCs form in retinae that develop following tectal ablation or transplantation to the coelomic cavity. Thus, RGC subsets acquire distinct neurotransmitter phenotypes in the absence of extraretinal cues. In the mature optic tectum, SP- and AChR-positive RGC axonal arbors are confined to distinct retinorecipient (synaptic) laminae. In the developing tectum, SP- and AChR-positive axons are initially intermingled in a superficial fiber layer, but then enter and arborize in appropriate laminae soon after those laminae form. Importantly, SP-positive axons, which synapse in a superficial lamina, never extend into the deeper, AChR-positive lamina. Tectal interneurons rich in SP receptors are concentrated in the lamina to which SP-positive RGC axons project, and a set of cholinergic (choline acetyltransferase-positive) tectal projection neurons elaborate dendrites in the lamina to which AChR-positive RGC axons project. These populations of tectal neurons, which are likely targets of the RGC subsets, form in tecta that develop following enucleation. Thus, RGCs and their targets can diversify in each others absence. Accordingly, we propose that the lamina-selective connectivity we observe reflects the presence of complementary cues on RGC subsets and their laminar targets.

[The optimal period for orally administered fluoropyrimidines as an adjuvant chemotherapy for gastric cancer--a pilot study using 5-FU tablets compared with surgical operation alone].

Long-term oral administration of fluoropyrimidines such as 5-fluorouracil (5-FU) or tegafur is commonly used as an adjuvant chemotherapy for gastric cancer, but the optimal period or optimal total doses of fluoropyrimidines have not been studied. Two hundred cases of macroscopical Stage II and III curatively resected gastric cancer patients were entered in this study, and divided into three groups (6 months group: mitomycin C was given i.v. at day 0 and day 1 and 5-FU tablets were orally administered at a dose of 200 mg/day for 6 months. 12 months group: MMC was given the same as for the 6 months group and 5-FU tablets were administered for 12 months. Surgery alone group: No chemotherapy, operation only). As the result, 185 cases were eligible. There was no significant difference between the 6 months group and the 12 months group among Stage II patients. Although there was also no significant difference between the 2 groups in Stage III patients, the survival curve of 12 months group was always higher than in the 6 months group. When comparing with surgery alone group, 5-year survival of the 12 months group was always higher than in the surgery alone group of Stage III patients; however, the survival rate in the 6 months group was worse than in the surgery alone group at Stage II and III. These results suggest that MMC i.v. and 12 months or over administration of 5-FU tablets is useful for Stage III gastric cancer patients, and that cooperative study is required comparing with surgery alone in Stage II patients.

Parabolic flight experiments on physiological data acquisition and processing technologies using small jet aircraft (MU300).

The parabolic aircraft flight provides a short low gravity environment for approximately 20 seconds, which may not be sufficient for a research on the physiological phenomenon induced by actual weightlessness in space. However, the method is still useful to reveal essential and characteristic feature of physiological signs, and is available for testing hardware and also training of crew member during altered gravity. This paper reports the summary of parabolic flight experiments recently conducted as a NASDA program (1990-1992). The program is providing opportunities in low gravity research with small jet aircraft for researchers and agencies. The flight experiments in the life science area have been conducted mostly focused on a physiological changes and basic methodology which may be effective under the altered gravity condition. In this study, the following research team, NASDA, Research Institute of Environmental Medicine, Nagoya University, Toyohashi University of Technology, Tokyo Metropolitan Hospital, Torey Research Center and JSUP were involved and coordinated for the research.

A comparative study on effects of doxorubicin alone or mixed with lipiodol given through the hepatic artery or portal vein for liver tumors in rats.

Vascular feeding of metastatic liver tumors at early stage is uncertain. It is controversial whether anticancer agents should be given through the hepatic artery or portal vein. In order to clarify this point, a rat model of liver metastases generated by an intraportal injection of syngeneic tumor cells was used to determine the optimal regional chemotherapeutic modality for early hepatic metastases. The rats given the tumor cells through the portal vein were placed into 5 groups: In groups I and II, Adriamycin (ADR) 4 mg/kg alone was given either into the hepatic artery or into the portal vein, respectively, 24 h after the inoculation of tumor cells. In groups III and IV, ADR mixed with lipiodol (lipiodolized ADR) 4 mg/kg was given into the hepatic artery or into the portal vein, respectively, 24 h after inoculation. For the group V rats, no treatment was given after inoculation of the tumor. When a comparison was made with regard to the forms of anticancer drug administered, statistically significant differences in survival rates were recognized between groups I and III (p < 0.001), and groups II and IV (p < 0.05). The anticancer agent not mixed with lipiodol and given through the hepatic artery had a more preventive effect than that given through the portal vein. Thus, we conclude that administration of ADR not mixed with lipiodol and given through the hepatic artery is the preferred modality for treating early metastatic liver tumors.

Lipiodol drug targeting in the treatment of primary hepatocellular carcinoma.

When Lipiodol Ultra-Fluid (lipiodol) is administered through arteries feeding the tumor, lipiodol remains selectively in the neoplastic tissue for an extended period of time. This characteristic of the oily contrast medium has been utilized for regional targeting of chemotherapy in patients with hepatocellular carcinoma, which has been termed "lipiodolization". The current status of lipiodolization is reviewed herein.

Lipiodolization prolongs survival rates in postoperative patients with a recurrent hepatocellular carcinoma.

Curative resections were performed in 200 patients with primary hepatocellular carcinoma (HCC) during the period from 1971 to 1988, at Kyushu University Hospital. Patients seen before 1982 numbered 73 (group I), and the remaining 127 underwent hepatic resection after 1983 (group II). Thirty-nine (53.4%) of the 73 patients in group I had a recurrence during the follow-up period, as did 61 (48.0%) in group II. HCC resections done after 1983 (group II) were associated with (1) a low incidence of operative deaths (I 15.1% vs. II 2.4%) and hospital deaths (I 30.1% vs. II 5.5%), (2) relatively well-preserved hepatocellular function (indocyanine green test, I 24.5 +/- 12.6% vs. II 17.4 +/- 9.2%), (3) a low incidence of histologically verified concomitant cirrhosis (I 87.7% vs. II 68.5%) (4), and smaller HCC nodules (I 6.4 +/- 4.4 cm vs. II 4.1 +/- 3.1 cm). The survival rates of patients seen after 1983 were significantly better than those of patients resected prior to 1982. With respect of the recurrence-free rates achieved by curative hepatic resection, there was no statistically significant difference to be seen between the two groups. In the case of patients submitted of lipiodolization treatment for a recurrent HCC, the survival rates were better than in patients on systemic chemotherapy. Since lipiodolization prolongs survival time after a recurrence of HCC, this form of treatment should be given due consideration.

[Eight cases of non-resectable hepatocellular carcinoma surviving for more than 3 years after Lipiodol administration].

From December 1982 to February 1986, selective regional cancer chemotherapy using Lipiodol plus anticancer drug (Lipiodolization) was prescribed for 87 patients with non-resectable hepatocellular carcinoma (HCC). Eight out of 87 cases survived for more than 3 years. The mean age of the 8 long survivors was 52.6. In the liver function, 2 cases were in Child A, 5 cases in Child B, and 1 case in Child C. The largest diameter of HCCs was 5.3 cm, and the number of the tumors was one in 6 cases, two in one case, and three in one case. No vascular invasion was detected on hepatic angiography. These findings suggested that long survivors in lipiodolization are not in far advanced HCCs. For these 8 cases, lipiodolization was repeatedly prescribed from two to 6 times. The largest amount of adriamycin was 192 mg/case. The longest survivor has lived for 5 years and 6 months after first lipiodolization. After lipiodolization, one tumor vanished, and three tumors decreased in size. Although seven tumors increased in size after lipiodolization, the tumor doubling time of seven tumors were 64, 265, 313, 317, 350, and 1943 days (average 539 +/- 639 days). It is possible that lipiodolization remarkably inhibited tumor growth. Nevertheless, in 5 out of 7 cases, the daughter lesions increased in size and number, although the main tumors grew slowly. Lipiodolization was less effective for newly arising daughter lesions than main lesions.