Total Esophagectomy versus Proximal Esophagectomy for Esophageal Cancer at the Cervicothoracic Junction

To investigate the adequate extent of esophagectomy and lymphadenectomy for an esophageal cancer localized at the cervicothoracic junction, the mortality and morbidity rates, survival rates, and patterns of recurrence were retrospectively analyzed in two groups—14 patients who underwent total esophagectomy with or without laryngectomy and 15 patients who underwent proximal esophagectomy with or without laryngectomy—at Kurume University Hospital from 1981 to 1996. Proximal esophagectomy with or without laryngectomy resulted in a lower hospital mortality rate and better overall survival for patients who underwent curative esophagectomy compared with total esophagectomy with or without laryngectomy. Multivariate analysis indicated that the extent of esophagectomy (total esophagectomy versus proximal esophagectomy) was not a prognostic factor. The incidence of recurrence was not different between the two groups. Lymph node metastasis or recurrence from such esophageal cancers was localized to the neck and upper mediastinum. For an esophageal cancer localized at the cervicothoracic junction, therefore, proximal esophagectomy with or without laryngectomy and with cervical and upper mediastinal lymphadenectomy could be better indicated for preselected patients.     

Impaired glucose tolerance, diabetes mellitus, and gallstone disease: An extended study of male self-defense officials in Japan

Few studies have investigated the relation between glucose tolerance status and ultrasonographically determined gallstone disease. Using a 75-g oral glucose tolerance test, we examined the association of impaired glucose tolerance (IGT) and non-insulin-dependent diabetes mellitus (NIDDM) with gallstone disease in Japanese men. Subjects were men aged 48 to 59 of the Japan Self-Defense Forces who received a preretirement health examination between October 1986 to December 1994. After exclusion of 12 men under insulin treatment in the consecutive series of 7637 men, 174 were found to have gallstones; 103 were at the state of postcholecystectomy, and 6899 had normal gallbladder. IGT and NIDDM were associated with a modestly increased risk of gallstone disease; adjusted odds ratios were 1.3 (95% confidence interval [CI]: 0.9–1.8) for IGT and 1.3 (95% CI: 0.8–2.0) for NIDDM after adjustment for hospital, rank, smoking, alcohol use, and body mass index. Adjusted odds ratio for IGT and NIDDM combined was 1.3 (95% CI: 1.0–1.7, p=0.08). When prevalent gallstones and postcholecystectomy were considered separately, NIDDM showed a significant, positive association with postcholecystectomy, but not with prevalent gallstones. The findings add to evidence that glucose intolerance is associated with a modest increase in the risk of gallstone disease.     

Functional regulation by dopamine receptors of serotonin release from the rat hippocampus: in vivo microdialysis study

The functional regulation by dopamine (DA) receptors of serotonin (5-HT) release from the rat hippocampus was investigated by use of in vivo microdialysis. Dialysate 5-HT levels were reduced by co-perfusion of 10 M tetrodotoxin (TTX) and were elicited by K⁺ (60 and 120 mM) stimulation in a concentration-dependent manner. Local perfusion (10 M) and peripheral administration (20 mg/kg, i.p.) of fluoxetine produced increases in 5-HT levels. These results indicate that the spontaneous 5-HT levels in the rat hippocampus can be used as indices of neuronal origin from the serotonergic nerve terminals. The nonselective dopamine (DA) receptor agonist apomorphine (1, 10 and 100 M), when perfused through the probe over a period of 40 min, increased 5-HT release in a concentration-dependent manner. Apomorphine-induced (100 M) increases in 5-HT release was abolished by pretreatment with the selective D₂ receptor antagonist, S(–)-sulphide (1 and 10 M), but not prevented by pretreatment with the selective D₁ receptor antagonist, R(+)-SCH-23390 (R(+)-7-chloro-8-hydroxy-3-methyl-l-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) (1 M). S(–)-Sulpiride and R(+)-SCH-23390 by themselves did not alter the spontaneous 5-HT levels. The 5-HT release was elevated by perfusion of the selective DA reuptake inhibitor GBR 12909 (1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[3-phenylpropyl]piperazine)(1, 10 and 100 M), indicating the possibility of not only exogenous but also endogenous DA-mediated facilitatory effects on 5-HT release in vivo. The 5-HT release was also elevated by perfused (±)-PPHT ((±)-2-(N-phenylethyl-N-propyl)-amino-5-hydroxytetralin)(1, 10 and 100 M), the selective D₂ receptor agonist, in a concentration-dependent manner. On the other hand, (±)-PPHT (100 M) failed to increase 5-HT release in catecholamine (CA)-lesioned rats pretreated with 6-hydroxydopamine (6-OHDA)(200 g/rat, i.c.v.). The (±)-PPHT-induced (100 M) increase in 5-HT release was prevented not only by pretreatment with 10 M S(–)-sulphide but also by pretreatment with the ₂-adrenoceptor antagonist idazoxan (10 M). These findings suggest that the functional regulation of 5-HT release via D₂ receptors exists in the rat hippocampus. Furthermore our results indicate that the facilitatory effect of 5-HT release via D₂ receptors may be mediated indirectly by noradrenergic neurons, but not mediated directly through D₂ receptors located on serotonergic nerve terminals.     

Effects of cholecalciferol and calcium on experimental hepatic osteodystrophy in rats

To investigate cholecalciferol (vitamin D) metabolism disorders in hepatic osteodystrophy (HOD) and the effects of vitamin D, its metabolites, and calcium (Ca) on HOD, an experimental HOD model in rats was developed using carbon tetrachloride. In the serum level of 25-hydroxycholecalciferol, 1,25-dihydroxycholecalciferol, and 24R,25-dihydroxycholecalciferol, there were no significant differences between normal and control cirrhotic rats. Vitamin D supplementation significantly inhibited the atrophy of intestinal villi, reduction of bone calcium content, elevation of bone resorption, reduction of osteoid volume, and reduction of bone volume. Ca supplementation significantly increased the serum free Ca index and inhibited the elevation of bone resorption, the reduction of bone ash and Ca content, and the reduction of bone volume. This experimental study demonstrates that: (1) no marked vitamin D hydroxylation disorder was found in HOD; (2) vitamin D supplementation was effective in inhibiting HOD; and (3) sufficient Ca supplementation was also effective in inhibiting HOD.A portion of this work was presented at the 13th Annual Meeting of the Japanese Society for Bone and Mineral Research, July 1995, Fukuoka, Japan.     

Urinaryβ 2-microglobulin and renal functions in elderly people in an area with no known cadmium pollution (Japan)

Urinary ₂-microglobulin (MG) was determined in 99 elderly people above 50 years of age from an area with no known cadmium pollution. With advancing age, the urinary MG increased as well as the urinary protein, urinary retinol-binding protein (RBP), and plasma urea nitrogen. Nevertheless, age effects were not observed in renal functions such as creatinine clearance or tubular reabsorption of phosphorus. Analysis of the relationship between urinary MG and parameters of the renal functions suggested 2-step increases in urinary MG: a slight increase between 160 and 1600g/L and a remarkable increase above 1600g/L. The latter strong increase in urinary MG was closely related with depressed tubular reabsorption of MG, but was independent of tubular reabsorption of phosphorus. The screening level of urinary MG for renal tubular dysfunction is suggested at 1600g/L.     

Exposure to 1-bromopropane causes ovarian dysfunction in rats.

Although 1-bromopropane has been used in chemical and electronic industries as an alternative to ozone layer-depleting solvents, its toxicity on female reproductive organs has not been fully elucidated. The aim of this experiment was to determine the effect of 1-bromopropane on female reproductive function in rats. Forty female Wistar rats were divided into four equal groups. Each group was exposed daily to 0, 200, 400, or 800 ppm of 1-bromopropane for eight h a day. After exposure for 7 weeks, all rats in the 800-ppm group became seriously ill and were sacrificed during the 8th week. The other dose groups were exposed for 12 weeks. In the 800-ppm group, but not in the other two exposed groups, body weight was significantly less than the control at each time point from 2 to 7 weeks after the beginning of exposure. Tests of vaginal smears showed a significant increase in the number of irregular estrous cycles with extended diestrus in the 400- and 800-ppm groups. Histopathological examination of the ovary showed a significant dose-dependent reduction of the number of normal antral follicles and a decrease in the number of normal growing follicles in the 400-ppm group. No significant change was found in plasma concentrations of LH or FSH in any group when compared with the control. Our results indicate that 1-bromopropane can induce a dose-dependent ovarian dysfunction in nonpregnant female rats associated with disruption in follicular growth process.     

Behavioral and pharmacological studies of juvenile stroke-prone spontaneously hypertensive rats as an animal model of attention-deficit/hyperactivity disorder]

The present study was undertaken to evaluate juvenile stroke-prone spontaneously hypertensive rats (SHRSP) as an animal model of attention-deficit/hyperactivity disorder (AD/HD). Juvenile SHRSP showed significant increases in horizontal ambulatory activity and vertical rearing activity in the open field as compared with genetic control Wistar-Kyoto rats (WKY). Anxiety-related behavior assessed by elevated plus-maze as an index of impulsivity, the entries into open arms and the spent time in the open arms of SHRSP were significantly higher than those of WKY. Spontaneous alternation behavior requiring attention and working memory in the Y-maze was significantly impaired in male, but not female, SHRSP when compared with sex-matched WKY. Hippocampal long-term potentiation formation, a cellular model of learning and memory, was not impaired in SHRSP. Methylphenidate, a first choice psychostimulant for AD/HD, significantly alleviated the hyperactivity in SHRSP. However, intense impulsivity of SHRSP was not improved by methylphenidate. Methylphenidate dose-dependently and significantly ameliorated the impaired spontaneous alteration behavior in male SHRSP. These results suggest that juvenile male SHRSP manifest problematic behavior resembling ADHD, namely inattention, hyperactivity and impulsivity. Methylphenidate alleviates the behavioral symptoms of hyperactivity and inattention. Thus, juvenile male SHRSP might be a useful behavioral animal model of AD/HD, from behavioral and pharmacological perspectives.     

Increased Sensitivity to Long-term 5-Fluorouracil Exposure of Human Colon Cancer HT-29 Cells Resistant to Short-term Exposure

A 5-fluorouracil (5-FU)-resistant subline of human colon cancer HT-29 cells was developed by repeated 1-h exposure in vitro to 5-FU. This subline (HT-29/5-FU/S) had 8-fold resistance to 5-FU in a 1-h exposure assay. However, it had rather increased sensitivity to 5-FU when assayed after a continuous 96-h exposure to it. Significantly less 5-fluorouridine-5'-triphosphate was produced in the resistant cells, leading to a lower level of 5-FU incorporation into the cellular RNA. The reduced activity of orotate phosphoribosyltransferase might explain these results. In contrast, the HT-29/5-FU/S cells were more sensitive to the inhibition of in situ thymidylate synthase (TS) by 5-FU than were the parent cells. The lower in situ TS activity may have made HT-29/5-FU/S cells more sensitive to TS inhibition by 5-FU as compared with the parent cells. The fact that HT-29/5-FU/S was more resistant to short-term 5-FU exposure but more sensitive to long-term exposure than the parent line confirmed the existence of different modes of action of 5-FU, depending on the exposure time.     

Targeting of nuclear factor kappaB Pathways by dehydroxymethylepoxyquinomicin, a novel inhibitor of breast carcinomas: antitumor and antiangiogenic potential in vivo.

We previously designed and synthesized the new nuclear factor kappaB (NF-kappaB) inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) derived from the structure of the antibiotic epoxyquinomicin C. We looked into the effect of DHMEQ on cellular phenotypes and tumor growth in mice injected with human breast carcinoma cell line MDA-MB-231 or MCF-7. In estrogen-independent breast adenocarcinoma cell line MDA-MB-231, NF-kappaB is constitutively activated. The addition of DHMEQ (10 microg/mL) completely inhibited the activated NF-kappaB for at least 8 hours. On the other hand, NF-kappaB is not activated in estrogen-dependent MCF-7 cells. In this cell line, DHMEQ completely inhibited the tumor necrosis factor-alpha-induced activation of NF-kappaB. DHMEQ did not inhibit the degradation of IkappaB but inhibited the nuclear translocation of NF-kappaB by both p65/p50 and RelB/p52 pathways. MDA-MB-231 cells secrete interleukin (IL)-6 and IL-8 without stimulation, and DHMEQ decreased the secretion levels of both cytokines. When MDA-MB-231 or MCF-7 cells were stimulated by tumor necrosis factor-alpha, the inhibitory effects of DHMEQ were still maintained. I.p. administration of DHMEQ (thrice a week) significantly inhibited the tumor growth of MDA-MB-231 (12 mg/kg) or MCF-7 (4 mg/kg) in severe combined immunodeficiency mice. No toxicity was observed during the experiment, including the loss of body weight. An immunohistological study on resected MCF-7 tumors showed that DHMEQ inhibited angiogenesis and promoted apoptosis. Furthermore, in Adriamycin-resistant MCF-7 cells highly expressing multidrug resistance gene-1, DHMEQ also exhibited the above capability, including down-regulation of IL-8. Thus, DHMEQ might be a potent drug for the treatment of various breast carcinomas by inhibiting the NF-kappaB activity.