Impact of various intensities and frequencies of non-occupational physical activity on the risk of dementia among physically independent older adults: the Japan Gerontological Evaluation Study.

OBJECTIVES: The aim of this study was to investigate the association between different intensities and frequencies of non-occupational physical activity (PA) and the risk of dementia among Japanese older adults. STUDY DESIGN: This was a prospective cohort study. METHODS: A total of 2194 participants aged ≥65 years from the Japan Gerontological Evaluation Study were followed up between 2010 and 2016. The standardised dementia scale of the long-term care insurance system was used to identify incident dementia, whereas non-occupational PA (<2 or ≥2 times/week on each intensity: light, moderate and vigorous) was assessed using a questionnaire. Cox regression was used to compute the hazard ratios (HRs) and 95% confidence intervals (CIs) for incident dementia. RESULTS: After adjustment for sociodemographic and medical characteristics, the following frequencies and intensities of non-occupational PA, compared with no non-occupational PA at all, were associated with a reduced risk of dementia: light PA ≥2 times/week (HR = 0.61, 95% CI: 0.38-0.97), moderate PA <2 times/week (HR = 0.46, 95% CI: 0.28-0.76), moderate PA ≥2 times/week (HR = 0.57, 95% CI: 0.36-0.91), vigorous PA <2 times/week (HR = 0.40, 95% CI: 0.21-0.74) and vigorous PA ≥2 times/week (HR = 0.29, 95% CI: 0.15-0.57). In the sex-specific analysis, moderate PA <2 times/week and vigorous PA ≥2 times/week were associated with a reduced risk of dementia in men, whereas light and moderate PA ≥2 times/week and all frequencies of vigorous PA were associated with a reduced risk of dementia in women. CONCLUSIONS: Practicing non-occupational PA was associated with a reduced risk of dementia among Japanese older adults.

Selective localization of Bcl-2 to the inner mitochondrial and smooth endoplasmic reticulum membranes in mammalian cells.

Bcl-2, an anti-apoptotic protein, is believed to be localized in the outer mitochondrial membrane, endoplasmic reticulum, and nuclear envelope. However, Bcl-2 has also been suggested as playing a role in the maintenance of mitochondrial membrane potential, indicating its possible association with the inner mitochondrial membrane. We therefore further examined the exact localization of Bcl-2 in mitochondria purified from wild-type and bcl-2-transfected PC12 cells and pre- and postnatal rat brains. Double immunostaining demonstrated that Bcl-2 was co-localized with subunit beta of F1F0ATPase in the inner mitochondrial membrane. Biochemical analysis of isolated mitochondria using digitonin and trypsin suggests an association of Bcl-2 with the inner mitochondrial membrane. More interestingly, the majority of Bcl-2 disappeared from the inner membrane of mitochondria when cultured under serum deprivation. These results suggest that Bcl-2 acts as an anti-apoptotic regulator by localizing mainly to the inner mitochondrial and smooth ER membranes.

The effects of KNK437, a novel inhibitor of heat shock protein synthesis, on the acquisition of thermotolerance in a murine transplantable tumor in vivo.

A newly synthesized reagent, KNK437, has been found specifically to inhibit the synthesis of heat shock proteins in vitro. In this study, we investigated the effects of KNK437 on the synthesis of heat shock proteins and the induction of thermotolerance in transplantable tumors in vivo. SCC VII cells were grown in vivo and transplanted into C3H/He mice. The concentrations of KNK437 in the tumors and the sera of the mice were examined by high-performance liquid chromatography. Hsp72 synthesis was examined by Western immunoblot analysis. The response to hyperthermia was evaluated in terms of the delay in tumor growth. KNK437 had low toxicity in vivo. The concentration of KNK437 in the tumors gradually increased and reached a peak 6 h after i.p. injection. Hsp72 were synthesized 8 h after hyperthermia at 44 degrees C for 10 min, and their synthesis was inhibited by administration of KNK437 6 h before hyperthermia. At a concentration of 200 mg/kg, KNK437 alone showed no antitumor effects and did not increase the thermosensitivity of nontolerant tumors. The same dose of KNK437 enhanced the antitumor effects of fractionated heat treatment at 44 degrees C in a synergistic manner. This study strongly suggests the inhibition of thermotolerance via the inhibition of HSP72 in vivo. The inhibition of thermotolerance by KNK437 may help to improve the efficacy of clinical fractionated hyperthermia.

Analysis of the clinical benefit of intraoperative radiotherapy in patients undergoing macroscopically curative resection for pancreatic cancer.

PURPOSE: To determine the survival of pancreatic cancer patients treated with intraoperative radiotherapy (IORT) and/or external beam radiation therapy (EBRT) following macroscopically curative resection. METHODS AND MATERIALS: One hundred and thirty-eight patients with pancreatic cancer who had undergone potentially curative total or regional pancreatectomy between 1980 and 1997 were retrospectively analyzed. Among the 138 patients, 98 had a pathologically negative surgical margin and the remaining 40 patients had a positive surgical margin. The usual EBRT dose was 45-55 Gy with a daily fraction of 1.5-2.0 Gy. The median IORT dose was 25 Gy in a single fraction. RESULTS: The 2-year cause-specific survival rate of patients with pathologically negative surgical margins was 19%, and that of patients with positive margins was 4% (p < 0.005). Although the median survival time (MST) of patients with negative margins treated with IORT and EBRT was significantly longer than that of those treated with operation alone (17 vs. 11 months), no significant difference in survival curves was observed. In patients with positive surgical margins in peripancreatic soft tissue, the difference between the survival curve of patients treated with surgery alone and that of those treated with surgery and radiation therapy was borderline significant (p < 0.10). Patients receiving intraarterial or intraportal infusion chemotherapy had significantly improved survival rates compared with those who did not receive it (p < 0.05). CONCLUSION: Although the MST was longer in patients with negative margins receiving IORT and EBRT than in those receiving no radiation, improved long-term survival by IORT and/or EBRT was not suggested. In patients with positive margins, our results obtained by IORT/EBRT were encouraging. Randomized studies with much higher patient numbers are necessary to define the role of IORT in curatively resected pancreatic cancer.

Impact of neoadjuvant chemotherapy on Ki-67 and PCNA labeling indices for esophageal squamous cell carcinomas.

PURPOSE: The effects of neoadjuvant chemotherapy (CT) on Ki-67 and proliferating cell nuclear antigen (PCNA) labeling index (LI) were analyzed, using biopsy and surgical specimens of esophageal cancer. METHOD AND MATERIALS: Immunohistochemical staining for Ki-67 and PCNA was performed for biopsy and surgical specimens of 35 patients with esophageal squamous cell carcinoma. Seventeen patients were treated with neoadjuvant CT (CT group), while no preoperative treatment was performed for the remaining 18 patients (control group). As neoadjuvant CT, cisplatin of 50 mg/body/week was administered 2-5 times (100-250 mg in total) until 7-10 days before subtotal esophagectomy. RESULT: Significant correlation between the LIs of biopsy and surgical specimens was observed for the control group (p = 0.006 for Ki-67 and p = 0.005 for PCNA), although both LIs of surgical specimens were significantly higher than those of biopsy specimens (p < 0.05). However, no significant correlation between LIs of biopsy specimens and those of surgical specimens was observed for the CT group. In addition, the LIs of the surgical specimens of the CT group were significantly lower than the LIs of the control group (p < 0.005 for Ki-67 and p < 0.05 for PCNA). Significant decrease in Ki-67 LI after neoadjuvant CT was noted especially for well or moderately differentiated squamous cell carcinomas and/or tumors treated with high-dose cisplatin (150-250 mg). CONCLUSION: Significant correlation of Ki-67 and PCNA LIs between biopsy and surgical specimens was demonstrated for the control group. Neoadjuvant CT decreased the percentage of cycling and proliferative tumor cells of esophageal cancer.

Combined effects of tirapazamine and mild hyperthermia on anti-angiogenic agent (TNP-470) treated tumors-reference to the effect on intratumor quiescent cells.

PURPOSE: To evaluate the efficacy of the use of tirapazamine (TPZ), especially combined with mild hyperthermia (40 degrees C, 60 min), in the treatment of solid tumors following an anti-angiogenic treatment with TNP-470. In addition, we assessed the effect of TPZ and/or mild hyperthermia (MHT) combined with conventional radiotherapy or chemotherapy on TNP-470 treated tumors. MATERIALS AND METHODS: C3H/He mice bearing SCC VII tumors subcutaneously received TNP-470 at two doses of 100 mg/kg after tumor cell inoculation. At the same time, the tumor-bearing mice received 5-bromo-2'-deoxyuridine (BrdU) continuously for 5 days via implanted mini-osmotic pumps to label all proliferating (P) cells. The mice then received TPZ administration combined with or without MHT, gamma-ray irradiation combined with or without TPZ and/or MHT, or cisplatin injection with or without TPZ and/or MHT. Another group of mice received a series of test doses of gamma-rays while alive or after being killed to obtain hypoxic fractions (HFs) in the tumors at various time points after the above-mentioned cytotoxic treatment point. After each treatment, the tumors were excised, minced, and trypsinized. The tumor cell suspensions thus obtained were incubated with cytochalasin-B (a cytokinesis blocker), and the micronucleus (MN) frequency in cells without BrdU labeling (or quiescent [Q] cells) was determined using immunofluorescence staining for BrdU. The MN frequency in the total (P + Q) tumor cells was determined from the tumors that were not pretreated with BrdU. For the measurement of the HFs, the MN frequency of BrdU-unlabeled cells was then used to calculate the surviving fraction of the unlabeled cells from the regression line for the relationship between the MN frequency and the surviving fraction of total tumor cells. RESULTS: TPZ administration combined with TNP-470 treatment and MHT increased the MN frequency more markedly than treatment with TPZ alone, and this tendency was more remarkable in Q cells than total cells. In both total and Q cells, combined treatment with TPZ and MHT produced significant increases in MN frequencies whether gamma-rays were delivered to TNP-470 treated tumors or cisplatin was injected into the TNP-470 administered mice. Although not significantly, the HFs of total and Q cell populations within solid tumors increased after TNP-470 treatment. CONCLUSION: Combined treatment with TPZ and MHT, whether other cytotoxic treatments such as gamma-ray irradiation or chemotherapy using cisplatin were combined or not, was useful for sensitizing tumor cells in vivo including Q cells even after TNP-470 treatment.

External and intraoperative radiotherapy for resectable and unresectable pancreatic cancer: analysis of survival rates and complications.

PURPOSE: Clinical results of intraoperative radiotherapy (IORT) and/or external beam radiotherapy (EBRT) for both resectable and unresectable pancreatic cancer were analyzed. METHODS AND MATERIALS: Between 1980 and 1995, 332 patients with pancreatic cancer were treated with surgery and/or radiation therapy (RT). Of the 332 patients, 157 patients were treated with surgical resection of pancreatic tumor, and the remaining 175 patients had unresectable pancreatic tumors. Among the 157 patients with resected pancreatic cancer, 62 patients were not treated with RT, while 40 patients were treated with EBRT alone (mean RT dose; 46.3 Gy) and 55 patients with IORT (25.2 Gy) +/- EBRT (44.0 Gy). On the other hand, among the 175 patients with unresectable pancreatic cancer, 58 patients were not treated with RT, 46 patients were treated with EBRT alone (39.2 Gy), and the remaining 71 patients with IORT (29.3 Gy) +/- EBRT (41.2 Gy). RESULTS: For 87 patients with curative resection, the median survival times (MSTs) of the no-RT, the EBRT, and the IORT +/- EBRT groups were 10.4, 13.0, and 15.5 months, respectively, without significant difference. For 70 patients with noncurative resection, the MSTs of the no-RT, the EBRT, and the IORT +/- EBRT groups were 5.3, 8.7, and 6.5 months, respectively. When the EBRT and the IORT +/- EBRT groups were combined, the survival rate was significantly higher than that of the no RT group for noncuratively resected pancreatic cancers (log rank test; p = 0.028). The 2-year survival probability of the IORT +/- EBRT group (16%) was higher than that of the EBRT group (0%). For unresectable pancreatic cancer, the MSTs of 52 patients without distant metastases were 6.7 months for palliative surgery alone, 7.6 months for EBRT alone, and 8.2 months for IORT +/- EBRT. The survival curve of the IORT +/- EBRT group was significantly better than that of the no-RT group (p < 0.05), and the difference between the IORT +/- EBRT and the EBRT alone groups was marginally significant (p = 0.056). In addition, the 2-year survival probability for the IORT +/- EBRT group was 14%, while no 2-year survival was observed in the no RT or the EBRT groups. Multivariate analysis using the Cox proportional hazards model revealed that tumor size, stage (Stages 1, 2 vs. Stages 3, 4), and curability of resection were significant variables for resectable pancreatic cancer, while distant metastases and performance of IORT were significant variables for unresectable pancreatic cancer. The dose of EBRT was a marginally significant factor for both resectable and unresectable tumors (both p = 0.06). In terms of complications, ulcers of gastrointestinal tract were noted in 14% of the 126 patients treated with IORT. CONCLUSION: Although prolongation of the MST by IORT was not remarkable, long survivals (>2 years) were obtained by IORT +/- EBRT for noncuratively resected and unresectable pancreatic cancer. IORT combined with EBRT is indicated for noncurative resected or unresectable pancreatic cancer without distant metastases.

Clinical results of radiofrequency hyperthermia for malignant liver tumors.

PURPOSE: To evaluate thermometry and the clinical results of radiofrequency (RF) hyperthermia for advanced malignant liver tumors. METHODS AND MATERIALS: One hundred seventy-three patients with malignant liver tumors treated between 1983 and 1995 underwent hyperthermia. The 173 tumors consisted of 114 hepatocellular carcinomas (HCCs) and 59 non-HCCs (47 metastatic liver tumors and 12 cholangiocarcinomas). Eight-megahertz RF capacitive heating equipment was used for the hyperthermia. Two opposing 25-cm electrodes were generally used for heating the liver tumors. Our standard protocol was to administer hyperthermia 40-50 min twice a week for a total of eight sessions. The liver tumor temperature was measured by microthermocouples when possible. Transcatheter arterial embolization, radiotherapy, immunotherapy, and chemotherapy were combined with hyperthermia treatment in accordance with each patient's liver function. RESULTS: One hundred forty (81%) of the 173 patients who underwent more than four sessions of hyperthermia were evaluated in this study. Thermometry was performed in 77 (55%) of these 140 patients. The maximum tumor temperature, average tumor temperature, and minimum tumor temperature in the HCC were (mean +/- standard error) 41.2 +/- 0.2 degrees C, 40.3 +/- 1.3 degrees C, and 40.1 +/- 0.2 degrees C, respectively. The same thermometry results for non-HCC were 42.3 +/- 0.2 degrees C, 41.2 +/- 0.2 degrees C, and 40.9 +/- 0.2 degrees C, respectively. The maximum and minimum temperatures (41.8 +/- 0.2 degrees C and 40.3 +/- 0.4 degrees C) in the patients with a complete or partial response (CR or PR) were higher than those in the patients with no response or progressive disease (NR or PD) (41.3 +/- 0.5 degrees C and 39.8 +/- 0.4 degrees C), but the difference was not significant. Of the 73 cases with HCC who were evaluated by computed tomography (CT), CR was achieved in 7 (10%), PR in 15 (21%), NR in 37 (51%), and PD in 14 (19%). Of the 45 cases involving liver metastases evaluated by CT, CR was achieved in 3 (7%), PR in 17 (38%), NR in 12 (27%), and PD in 13 (29%). The 1-year cumulative survival rate for HCC patients was 30.0%, and the 5-year survival rate was 17.5%. The 1-year survival of non-HCC patients was 32.5%, and the longest survival was 30 months. The sequelae of hyperthermia included focal fat necrosis in 20 patients (12%), gastric ulceration in 4 (2%), and liver necrosis in 1 (1%). The sequelae of thermometry were severe peritoneal pain in seven patients (11%), intraperitoneal hematoma in one (1%), and pneumothorax in one (1%). CONCLUSION: Even though the thermometry results for liver tumors were not satisfactory, the treatment results are promising. Further clinical trials of RF capacitive hyperthermia for the treatment of advanced liver tumors should be encouraged.

Regulation of a novel pathway for cell death by lysosomal aspartic and cysteine proteinases.

PC12 cells undergo apoptosis when cultured under conditions of serum deprivation. In this situation, the activity of caspase-3-like proteinases was elevated, and the survival rate could be maintained by treatment with acetyl-DEVD-cho, a specific inhibitor of caspase-3. In a culture of PC12 cells treated with acetyl-DEVD-cho, where caspase-3-like proteinases are not activated, CA074, a specific inhibitor of cathepsin B induced active death of the cells. Cathepsin B antisense oligonucleotides showed a similar effect to CA074 on the induction of active cell death. By double staining of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling and activated caspase-3, the dying cells treated with CA074 were positive for terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling staining but negative for activated caspase-3. Ultrastructurally, the cells were relatively large and had nuclei with chromatin condensation. The initiation of cell death by CA074 or the cathepsin B antisense were inhibited by the addition of pepstatin A, a lysosomal aspartic proteinase inhibitor, or by cathepsin D antisense. To examine whether this cell death pathway was present in cell types other than PC12 cells, we analysed dorsal root ganglion neurons obtained from rat embryos on the 15th gestational day, a time when they require nerve growth factor for survival and differentiation in culture. When cultured in the absence of nerve growth factor, the neurons survived in the presence of acetyl-DEVD-cho or acetyl-YVAD-cho. Under these conditions, CA074 reduced the survival rate of the neurons, which was subsequently restored by the further addition of pepstain A. These results suggest that a novel pathway for initiating cell death exists which is regulated by lysosomal cathepsins, and in which cathepsin D acts as a death factor. We speculate that this death-inducing activity is normally suppressed by cathepsin B.

Different distribution patterns of the two mannose 6-phosphate receptors in rat liver.

Two mannose 6-phosphate receptors, cation-dependent and -independent receptors (CDMPR and CIMPR), play an important role in the intracellular transport of lysosomal enzymes. To investigate functional differences between the two in vivo, their distribution was examined in the rat liver using immunohistochemical techniques. Positive signals corresponding to CIMPR were detected intensely in hepatocytes and weakly in sinusoidal Kupffer cells and interstitial cells in Glisson's capsule. In the liver acinus, hepatocytes in the perivenous region showed a more intense immunoreactivity than those in the periportal region. On the other hand, positive staining of CDMPR was detected at a high level in Kupffer cells, epithelial cells of interlobular bile ducts, and fibroblast-like cells, but the corresponding signal was rather weak in hepatocytes. In situ hybridization analysis also revealed a high level of expression of CIMPR mRNAs in hepatocytes and of CDMPR mRNA in Kupffer cells. By double immunostaining, OX6-positive antigen-presenting cells in Glisson's capsule were co-labeled with the CDMPR signal but were only faintly stained with anti-CIMPR. These different distribution patterns of the two MPRs suggest distinct functional properties of each receptor in liver tissue.

Evaluation of intraoperative radiation therapy for unresectable pancreatic cancer with FDG PET.

UNLABELLED: This investigation was undertaken to evaluate 18F-labeled fluorodeoxyglucose (FDG) PET in monitoring patients after intraoperative radiotherapy (IORT) for unresectable pancreatic cancer and to compare its usefulness with CT. METHODS: FDG PET was performed in 12 consecutive unresectable ductal adenocarcinoma patients before (n = 12) and after IORT (0.7-11.9 mo, n = 14). In the follow-up period, FDG PET results after IORT were divided into three groups: early (0-2.0 mo after IORT, n = 7), intermediate (2.1-4.0 mo, n = 5) and delayed period (4.1 mo or later, n = 2). FDG uptake at 60 min after injection of 185 MBq FDG under fasting conditions was analyzed with standardized uptake value (SUV). Three parameters, the highest SUV in the tumor, the area of tumor showing SUV of more than 2.0 and the average SUV in the tumor area were calculated. Ratios of each parameter after IORT to that before IORT were defined as residual uptake ratio (RUR)-1, -2 and -3, respectively. Tumor regression after IORT was evaluated with CT as tumor size ratio (TSR) every 2 mo. RESULTS: Results of RUR-1 and -3 were consistent with tumor size measured by CT. They decreased in 10 patients with partial response and increased in 2 patients with no change, although these 2 patients had abscesses. RUR-3 decreased consistently as 0.65+/-0.33 in 2 mo, 0.51+/-0.39 in 4 mo and 0.24 in 4 mo or later after IORT, respectively. RUR-1 decreased in early period, but demonstrated no change through the remaining periods. There were discrepancies between the results of RUR-2 and those of the other RURs. CT results revealed a slow decrease in tumor size, because TSR was 0.91 +/-0.10, 0.76+/-0.11 and 0.70+/-0.18 in 2, 4 and 6 mo after IORT, respectively. RUR-3 was smaller than TSR at 2 mo (P < 0.05) and 4 mo (P = 0.056). These results indicate that the measurement of the average SUV in the tumor area with FDG PET could evaluate the local response of pancreatic cancer after IORT earlier and more markedly than with CT. CONCLUSION: FDG PET was useful in monitoring patients after IORT, because the decrease of metabolism in pancreatic tumor could be detected earlier than the decrease in tumor size.

Longitudinal study of macrophages in prostatic fluid from nonbacterial prostatitis patients.

Longitudinal study of percentage of macrophages among leukocytes in prostatic fluid from 10 patients with nonbacterial prostatitis did not show correlation between percentage of macrophages and severity of clinical symptoms.

Renal cell carcinoma with solitary contralateral adrenal metastasis.

We report on 2 cases of renal cell carcinoma with solitary contralateral adrenal metastasis which was demonstrated six months and one year, respectively, after radical nephrectomy. Pulmonary metastases developed six months after adrenalectomy in 1 patient; the other patient is alive without any evidence of disease twenty-two months after adrenalectomy.

Papilloma of renal pelvis in childhood.

A papilloma in the renal pelvis of a five-year-old girl is reported. The transitional cell tumors of the renal pelvis in the pediatric age group are reviewed, and this is found to be the first case of a benign papilloma in childhood. We believe this pathologic entity should be included in the differential diagnosis of hematuria in a child.

Percutaneous nephrolithotomy. With emphasis on large renal stones.

With utilization of safety guide wire, dilator (up to 36F), and Mazzariello-Caprini forceps, percutaneous removal of renal stone was successfully performed in 18 cases, including 5 cases with staghorn calculus, although parts of the staghorn calculus were left in 4 cases. Attempts at stone extraction were performed on the day nephrostomy was made. All of the renal stones excluding staghorn calculi were removed without disruption followed by satisfactory postoperative renal function. Unexpectedly Kocher forceps was found to be a useful and relatively safe instrument for quick fragmentation and removal of staghorn calculi.

Aggressive non-Hodgkin's lymphoma after successful eradication of Helicobacter pylori and regression of gastric lymphoma of mucosa-associated lymphoid tissue.

A 57-year-old woman presented to our clinic with low-grade gastric lymphoma of mucosa-associated lymphoid tissue (stage IE) and Helicobacter pylori infection. She received a 2-week course of omeprazole and clarithromycin, resulting in eradication of H. pylori and histological disappearance of the lymphoma. However, 9 months later (May 1996), multiple mass lesions were found around the pancreas and hepato-duodenal ligament on abdominal computed tomography. Inguinal lymph node biopsy revealed aggressive nodal type B-cell non-Hodgkin's lymphoma, diffuse large cell type. She received chemotherapy with cyclophosphamide, adriamycin, vincristine, and prednisolone, but failed to achieve remission and died in December 1996. There was no evidence of recurrent gastric lymphoma. This case emphasizes the importance of performing follow-up examinations to detect other neoplasms in patients with gastric lymphoma of mucosa-associated lymphoid tissue.

Hyperphalangeal bones induced in rat pups by maternal treatment with nifedipine.

Hyperphalangeal bones were found in postnatal rat pups of mothers treated with nifedipine during pregnancy. The anomaly occurred only at the region between the middle and distal phalanges of the 3rd and 4th fingers and toes. The critical periods of the anomaly were days 13 and 14 of pregnancy for the fingers, and days 14 and 15 of pregnancy for the toes. The incidences were dose-related, being more than 90% in both fingers and toes at a single dose of 150 mg/kg, and even more marked at the 4th digits than at the 3rd digits. Neither right/left difference nor sex difference was manifested in the incidence of the anomaly.

Epididymal sperm motion as a parameter of male reproductive toxicity: sperm motion, fertility, and histopathology in ethinylestradiol-treated rats.

The present study was designed to characterize the effect of ethinylestradiol (EE) on epididymal sperm motion using a computer-assisted sperm analysis system (CASA), and to elucidate the correlation between sperm motion endpoints and other measures including fertility, histopathologic, and endocrinologic endpoints. EE was orally given to adult male rats at a daily dosage of 10 mg/kg for 3 and 5 d, and at daily dosages of I and 10 mg/kg for 1, 2, 3, and 4 weeks. Changes in sperm motion were first detected after one week of treatment. Of nine sperm motion parameters, the percentage of motile sperm, velocity, and amplitude of the lateral head displacement (ALH) were decreased in the 10 mg/kg dosing group. Accompanying the decreases in those parameters, the male fertility indices in the 10 mg/kg dosing group were reduced after one week of treatment, and no males in this group could impregnate intact females after 2 weeks or more of treatment. The number of sperm heads in the cauda epididymis in the 10 mg/kg dosing group was reduced to about one-half that in the control group after one week of treatment, whereas the total number of homogenization-resistant advanced spermatids in the testis was not altered and only a slight change was detected in the number and morphology of germ cells in the testis. These results suggest that reduction in the number of epididymal sperm and in sperm motion are not secondary to testicular alteration. However, after 3 weeks of treatment, the number of sperm heads in the testis was drastically reduced with severe atrophy of the seminiferous tubules both in the 1 and 10 mg/kg dosing groups. The profiling of epididymal luminal fluid proteins indicated that two major bands that migrated with molecular weights of about 22 and 23 kDa were weakened and their density was reduced to approximately 70% of the control after 5-d and one week treatments in the 10 mg/kg dosing group. Circulating testosterone declined drastically after 3 d of treatment and remained at undetectable levels with a concomitant decline of circulating LH and FSH, suggesting that EE inhibits testosterone secretion immediately via a negative feedback system, and there follow changes in the accessory reproductive organs including the epididymis. These results indicate that EE affects epididymal spermatozoa before testicular germ cells via a testosterone deficiency, when it is administered at extremely high dosages. The reduction in the sperm motion manifested as decreases in the percentage of motile sperm, ALH, and velocity, is considered to be responsible for the onset of infertility. Sperm motion analysis could be particularly useful for detecting the toxic effects of chemicals that act through the endocrinologic system on the epididymis.

Clinical results of transcatheter arterial infusion for uterine cervical cancer.

The effects of transcatheter intraarterial infusion of anticancer drugs on the prognosis of cervical cancer were retrospectively studied. Two or three sessions of transcatheter arterial infusion therapy were performed for 68 patients with primary uterine cervical cancer. The number of patients with stage I, II, III, or IV disease were 13, 22, 24, and 9, respectively. Patients with squamous cell carcinoma comprised 3, 17, 17, and 5 of the respective groups, and the patients with stage I and II disease had either adenocarcinoma or adenosquamous carcinoma, or bulky tumor (>4 cm). The drugs infused were cisplatin (60-70 mg/m2), doxorubicin hydrochloride (30-40 mg/m2), mitomycin (15 mg/m2), and 5-fluorouracil (500 mg/body). They were infused via the bilateral internal iliac arteries. Fifty-eight of the 68 patients (85%) received a radical hysterectomy after transcatheter arterial infusion: 12 of 13 with stage I disease, 21 of 22 with stage II disease, 20 of 24 with stage III disease, and five of nine with stage IV disease. Two patients with stage III disease received radical radiotherapy. The other eight patients (one with stage I disease, one with stage II disease, two with stage III disease, and four with stage IV disease) did not receive an operation after transcatheter arterial infusion because they had distant metastases at the time of operation. Thirty-two of 58 patients (56%) received postoperative radiotherapy. The complete histologic response rates (no active cancer cells) after transcatheter arterial infusion were: 2 of 12 patients with stage I disease, 3 of 21 patients with stage II disease, 5 of 20 patients with stage III disease, and one of five patients with stage IV disease. Tumors with squamous cell carcinoma disappeared at a significantly better rate (10/36, 28%) than did tumors with adenocarcinoma or adenosquamous cell carcinoma (1/22, 5%; p < 0.05). The overall 5-year survival rates of the patients with stages I, II, and III disease were 92.3%, 62.2%, and 71%, respectively. The 5-year survival rates of the patients who underwent surgery with stage I, II, and III disease were 100%, 66.3%, and 71.5%, respectively. Leukocytopenia and thrombocytopenia occurred as an acute complication in 75% and 79% of the patients, respectively. As a late complication, ileus occurred in 7%. Transcatheter arterial infusion may improve the prognosis of patients with cervical cancer without increasing the incidence of late complications.

Characterization of epididymal sperm motion and its correlation with stages of target cells in rats given alpha-chlorohydrin, cyclophosphamide or nitrazepam.

Epididymal sperm motion in rats was characterized by computer-aided sperm motion analysis (CASA) with its correlation to testicular lesions in the 2-week treatment study, using three compounds which are known to affect different stages of germ cells. Mature male rats were treated daily for 2 weeks with alpha-chlorohydrin (alpha-CH, 5 mg/kg), cyclophosphamide (CP, 20 mg/kg) or nitrazepam (NZ, 20, 40, 60 mg/kg). Changes in sperm motion were detected only in the alpha-CH and 60-mg/kg NZ-treated groups. Of the sperm motion parameters, velocity and amplitude of lateral head displacement (ALH) were concomitantly reduced in these two groups with good correlation. With respect to the distribution of the values in parameters, however, alpha-CH shifted the values down within a small range with high percentages of motile sperm, while NZ distributed them over a wide range with low percentages of motile sperm. CP treatment showed no histopathological changes in advanced germ cells, though it showed a decrease in the number of early germ cells. NZ treatment affected round and elongating spermatids (approximately step 14) at doses of 20 and 40 mg/kg, and affected also more advanced spermatids (approximately step 19) at the dose of 60 mg/kg. alpha-CH treatment did not affect testicular histopathology. These findings indicate that 60-mg/kg NZ treatment reduced sperm motion as a result of lesions affected in elongated spermatids and alpha-CH reduced it by direct effects on epididymal spermatozoa. The present study indicates that in addition to percentage of motile sperm, the velocity and ALH can be useful to detect the changes in sperm motion caused by different actions of NZ and alpha-CH, though each compound showed a distinct distribution pattern of these parameters.