Overtime work,insufficient sleep,and risk of non-fatal acute myocardial infarction in Japanese men

Objectives: To examine the relation between working hours and hours of sleep and the risk of acute myocardial infarction (AMI), with special reference to the joint effect of these two factors.

Method: Case-control study in Japan. Cases were 260 men aged 40–79 admitted to hospitals with AMI during 1996–8. Controls were 445 men free from AMI matched for age and residence who were recruited from the resident registers. Odds ratios of AMI relative to mean weekly working hours and daily hours of sleep in the past year or in the recent past were calculated.

Results: Weekly working hours were related to progressively increased odds ratios of AMI in the past year as well as in the past month, with a twofold increased risk for overtime work (weekly working hours ≥61) compared with working hours ≤40. Short time sleep (daily hours of sleep ≤5) and frequent lack of sleep (2 or more days/week with <5 hours of sleep) were also associated with a two to threefold increased risk. Frequent lack of sleep and few days off in the recent past showed greater odds ratios than those in the past year.

Conclusions: Overtime work and insufficient sleep may be related to increased risk of AMI.

     

Surgical treatment of the rheumatoid cervical spine in patients aged 70 years or older

OBJECTIVE: To investigate whether surgery is appropriate for elderly rheumatoid arthritis patients who are already approaching their statistical life expectancy. PATIENTS AND METHODS: The subjects were 10 patients who underwent cervical spine surgery for rheumatoid arthritis at an age of over 70 yr. The pain grade and neurological deficit class according to Ranawat, peri-operative complications, causes of death and pre-operative cardiopulmonary function were assessed. RESULTS: Good pain relief was achieved. Relief of pain enabled the patients, who could not sit up even in bed because of intolerable neck pain, to ride in a wheel chair without using a neck collar. Only one death was related to surgery. Pre-operative cardiopulmonary function was not significantly different compared with that of elderly patients undergoing other surgical procedures. CONCLUSION: Surgery is a valuable option for the management of elderly patients with rheumatoid cervical spine since it can improve the quality of life.     

Effect of long-term atrial-demand ventricular pacing on cardiac sympathetic activity

It has been shown that either dual-chamber or atrial pacing may be better than ventricular single-chamber pacing, but the long-term effect of dual-chamber pacing on cardiac sympathetic activity is unclear. The aim of this study was to assess the effect of long-term dual-chamber pacing on cardiac sympathetic activity, compared with atrial pacing and unpaced individuals. We studied 11 patients with dual-chamber pacemakers (Group D), nine with atrial single-chamber pacemakers (Group A) over the long term (mean 44 +/- 36 months) and 10 normal individuals without cardiac pacing. All underwent myocardial 123I-metaiodobenzylguanidine (MIBG) imaging to assess cardiac sympathetic activity. The heart-to-mediastinum (H/M) MIBG uptake ratio and the MIBG washout rate from the myocardium were calculated. Echocardiography was performed in all patients with cardiac pacing to assess left ventricular function. In Group D, the H/M ratio on delayed images was significantly lower than that of Group A (1.82 +/- 0.51 vs 2.56 +/- 0.50, P < 0.001) and normal individuals (2.65 +/- 0.35, P < 0.05). The myocardial MIBG washout rate of Group D was significantly higher than that of either Group A (52 +/- 13% vs 36 +/- 8%, P < 0.01) or normal individuals (31 +/- 7%, P < 0.05). Neither the H/M ratio nor MIBG washout rate differed significantly between patients in Group A and normal individuals. Furthermore, the echocardiographic parameters did not differ significantly between the two pacing groups. We conclude that long-term ventricular pacing, even in the presence of atrioventricular synchrony, accelerates cardiac sympathetic activity without deteriorating left ventricular function.     

Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group Study 9104.

PURPOSE: To evaluate the optimal timing for thoracic radiotherapy (TRT) in limited-stage small-cell lung cancer (LS-SCLC), the Lung Cancer Study Group of the Japan Clinical Oncology Group conducted a phase III study in which patients were randomized to sequential TRT or concurrent TRT. PATIENTS AND METHODS: We treated 231 patients with LS-SCLC. TRT consisted of 45 Gy over 3 weeks (1.5 Gy twice daily), and the patients were randomly assigned to receive either sequential or concurrent TRT. All patients received four cycles of cisplatin plus etoposide every 3 weeks (sequential arm) or 4 weeks (concurrent arm). TRT was begun on day 2 of the first cycle of chemotherapy in the concurrent arm and after the fourth cycle in the sequential arm. RESULTS: Concurrent radiotherapy yielded better survival than sequential radiotherapy (P =.097 by log-rank test). The median survival time was 19.7 months in the sequential arm versus 27.2 months in the concurrent arm. The 2-, 3-, and 5-year survival rates for patients who received sequential radiotherapy were 35.1%, 20.2%, and 18.3%, respectively, as opposed to 54.4%, 29.8% and 23.7%, respectively, for the patients who received concurrent radiotherapy. Hematologic toxicity was more severe in the concurrent arm. However, severe esophagitis was infrequent in both arms, occurring in 9% of the patients in the concurrent arm and 4% in the sequential arm. CONCLUSION: This study strongly suggests that cisplatin plus etoposide and concurrent radiotherapy is more effective for the treatment of LS-SCLC than cisplatin plus etoposide and sequential radiotherapy.     

Expression of brain specific chondroitin sulfate proteoglycans, neurocan and phosphacan, in the developing and adult hippocampus of Ihara's epileptic rats

Ihara's epileptic rats (IER) is an animal model of temporal lobe epilepsy with mycrodysgenesis, that exhibit abnormal migration of hippocampal neurons and recurrent spontaneous seizures. As an attempt to elucidate the roles of extracellular matrix molecules in the epileptogenecity and mossy fiber sprouting, immunohistochemical localization of brain specific chondroitin sulfate proteoglycans (CSPGs), neurocan and phosphacan, was examined in the hippocampus of postnatal IER and Sprague-Dawley (SD) rats using monoclonal antibodies 1G2 against neurocan and 6B4 against phosphacan. There was no difference in the expression of these two CSPGs between IER and SD rats in the 1st postnatal week. However, the expression of neurocan was poor in the hippocampus of IER in the 2nd and 3rd weeks whereas intense labeling of neurocan was present throughout the hippocampus of SD rats. Labeling of neurocan was almost absent in the hippocampus, while phosphacan was diffusely expressed in the stratum oriens and radiatum of Ammon's horn, and in the hilus and inner one-third molecular layer of the dentate gyrus at the 2nd month after birth. There was no difference in the expression of neurocan and phosphacan between IER and SD rats at the 2nd month after birth. By contrast, phosphacan was reduced in the inner molecular layer of the dentate gyrus in 8-month-old IER, while neurocan was reexpressed in the outer molecular layer and hilus in 3- and 8-month-old IER. It was suggested that the insufficient expression of neurocan may affect the development of neuronal organization in the hippocampus, and that the remodeling of extracellular matrix in the dentate gyrus may contribute to the mossy fiber sprouting into the inner molecular layer.     

Enhanced Antitumor Efficacy of a Combination of CPT-11, a New Derivative of Camptothecin, and Cisplatin against Human Lung Tumor Xenografts

The objective of this study was to evaluate the antitumor efficacy of combined use of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carhonyloxycamptothecin (CPT-11) and cisplatin (CDDP). The antitumor activities of CPT-11, CDDP and their combination against 3 human lung tumor xenografts were estimated using congenitally athymic BALB/c ( nu/nu ) mice. The doses were 47 mg/kg for CPT-11 and 6 mg/kg for CDDP on days 1, 5 and 9. In combination therapy, half of the single dosage of each agent was used. The doses were administered intraperitoneally. The antitumor activity and toxicity were evaluated in terms of the tumor volume and body weight change of mice, respectively. The combination therapy resulted in a statistically significant tumor regression compared to the use of only CPT-11 or CDDP in two tumor xenografts out of three. The toxicity of the combination therapy was no higher than that of CPT-11 or CDDP alone. These results suggest that the antitumor activity of the combination of CPT-11 and CDDP is superior to that of CPT-11 or CDDP alone.     

Molecular determinants of UCN-01-induced growth inhibition in human lung cancer cells

UCN-01 (7-hydroxystaurosporine) inhibits the growth of various malignant cell lines in vitro and in vivo. In this study, a human small cell lung carcinoma subline resistant to UCN-01, SBC-3/UCN, was established and characterized. SBC-3/UCN cells showed 8-fold greater resistance to the UCN-01-induced growth-inhibitory effect than the parent cells, SBC-3. No UCN-01-induced G1 accumulation in SBC-3 cells was observed in SBC-3/UCN cells and decreased expression of phosphorylated RB protein was found in SBC-3 cells. Neither basal expression nor induction of p21(Cip1) by UCN-01 treatment was detected in the SBC-3/UCN cell line. An inhibitory effect of UCN-01 on CDK2 activity, which is mediated by p21(Cip1)/CDK2 complex formation upon UCN-01 treatment, was observed in SBC-3 but not in SBC-3/UCN cells. SBC-3/UCN showed higher CDK6 activity than SBC-3 cells. UCN-01 did not inhibit the CDK4 and CDK6 activities in both cells. We screened the cell cycle regulatory molecules associated with G(1)/S progression and found a remarked decrease in interferon regulatory factor 1 (IRF-1), which is known to cooperate with p53 in p21(Cip1) induction. Our results suggest that p21(Cip1) regulation via the IRF-1-associated pathway may represent a major determinant of UCN-01-induced growth inhibition in human lung cancer cells.     

Phase II study of concurrent chemotherapy and radiotherapy for unresectable stage III non-small-cell lung cancer: Long-term follow-up results. Japan Clinical Oncology Group Protocol 8902

Background:Although chemoradiotherapy is standard treatment forunresectable stage III non-small-cell lung cancer (NSCLC), few long-termsurvival data exist. Patients and methods:Between October 1989 and December 1991, 74patients with histologically or cytologically proven NSCLC, unresectable stageIIIA or IIIB, were entered into this study. Seventy patients were eligible andevaluable for response, toxicity, and survival analysis. Chemotherapyconsisted of cisplatin (100 mg/m² on days 1, 29, and 57) andvindesine (3 mg/m² on days 1, 8, 29, 36, 57, and 64). Thoracicradiotherapy was administered for two weeks (2 Gy given 10 times, fivefractions per week), and after a 14-day rest period, the previous schedule ofradiotherapy was repeated for two weeks. A 10-Gy to 20-Gy dose of radiotherapywas administered during the third cycle of chemotherapy. Results:Of the 70 evaluable patients, 1 (1.4%) hada complete response (CR) and 51 (72.9%) had a partial response (PR).The median survival time was 14.8 months, and the five-year survival rate was14.8%. The major toxicity was leukopenia ( grade 3, 93%).Other toxicities grade 3 included anemia (34%),nausea/vomiting (27%), alopecia (7%), thrombocytopenia(4%), and serum creatinine elevation (1%). Treatment relateddeath occurred in two patients (2.8%). One patient died of pneumoniaand pneumothorax, and the other of hemoptysis. Conclusions:Concurrent chemotherapy and radiotherapy has thepotential to provide long-term survival with acceptable toxicities.     

Pharmacokinetic and pharmacodynamic analysis of bis-acetato-ammine-dichloro-cyclohexylamine-platinum(IV) (JM216) administered once a day for five consecutive days: a phase I study

BACKGROUND: Bis-acetato-ammine-dichloro-cyclohexylamine-platinum(IV) (JM216) is the first orally given platinum complex that shows in vitro cytotoxicity comparable to that of cisplatin and in vivo cytotoxicity superior to those of cisplatin and carboplatin. METHODS: We conducted an escalating-dose (50, 75, 100, 120 mg/m2) phase I study of JM216 administered orally once a day for five consecutive days in patients with solid tumors to establish the toxicity profile, maximum tolerated dose (MTD) and pharmacokinetic profile. Twenty-three patients were enrolled and all were assessable for toxicity. RESULTS: The MTD was 120 mg/m2/day and the dose-limiting toxicities were leukopenia, thrombocytopenia, anemia and diarrhea. Because of the delayed hematological toxicities, it was difficult to repeat cycles every 26 days in some patients. Tumor shrinkage was observed in two patients with breast cancer, both of whom were resistant to doxorubicin. A pharmacokinetic study showed that the areas under the concentration-time curve (AUC) and peak plasma concentrations (Cmax) for total platinum (Pt) on days 1 and 5 and ultrafiltered Pt (UF-Pt) on day 1 increased in proportion to the dose of JM216. The AUCs for both total and UF-Pt on day 5 were higher than the AUCs on day 1. The AUC for UF-Pt on day 5 showed the best correlation with percentage reduction in leukocyte count and in absolute neutrophil count. CONCLUSION: The recommended dose for phase II studies is 100 mg/m2/day every 4-6 weeks. The observation of tumor shrinkage in previously heavily treated breast cancer patients supports a phase II investigation.