Synthesis of 2,8-disubstituted imidazo[1,5-a]pyrimidines with potent antitumor activity

Seventeen 1,2,3,4-tetrahydroimidazo[1,5-a]pyrimidine derivatives bearing electron-withdrawing substituents were designed and synthesized by novel ring closure as potential antitumor agents. They were screened for their activities against mouse leukemia L1210 and human oral epidermoid carcinoma KB cell lines, and relationships of structure and antitumor activity in vitro are discussed. It was found that 8-thiocarbamoyl-1,2,3,4-tetrahydroimidazo[1, 5-a]pyrimidin-2(1H)-thione (8c) exhibited activity comparable to that of 5-fluorouracil against both L1210 and KB cells. The existence of both 2-thioxo and 8-substituent with a thioxo group in the molecule is crucial for the cytotoxicity against L1210 and KB cells. A novel procedure for introduction of a double bond between C-3 and C-4 in 8c was developed. Introduction of the 3,4-double bond increased the activity against L1210, but against KB cells the activity decreased by 4-fold. Cytotoxicity of compounds 8c and 8-thiocarbamoyl-1,2-dihydroimidazo[1,5-a]pyrimidin-2(1H)-thione (11c) against human solid tumor and leukemia cell lines was further evaluated. The saturation of the 3,4-double bond led to a significant increase in cytotoxicity against tumor cell lines tested.     

Potential applicability of clinical hyperthermia using a Thermotron-RF8 as assessed from thermal distribution in an agar phantom containing hydroxyapatite

We have already reported the antitumour effect of hydroxyapatite (HAP) containing anticancer drugs. In this study, we found an increased temperature effect around HAP particle(s) in an agar phantom in comparison with other areas when a Thermotron-RF8 (RF generator) was used for heating. Furthermore, it was revealed that the quantity of doxorubicin hydrochloride (DOX) released from HAP containing the drug (DOX-HAP complex) was increased by raising the temperature. These results indicated that the antitumor effect of the DOX-HAP complex + hyperthermia system was greater than that of either the DOX-HAP complex or hyperthermia system alone.     

A case of drowning linked to ingested sulfides — a report with animal experiments

An adult male was found dead beneath a pool of sewage in the pump room of a fish market. Autopsy revealed the cause of death to be suffocation after aspirating sewage into the respiratory tract. Since hydrogen sulfide gas was detected in the atmosphere at the scene of the accident, gas poisoning was suspected and toxicological analysis of sulfides in body tissues was performed. The concentrations of sulfides in the blood, lung and kidney were 0.95 mol/ml, 0.22 and 0.38 mol/g, respectively. These values were remarkably higher than those in previously reported cases involving exposure to hydrogen sulfide gas. Therefore, oral intake of sulfides was assumed and the distribution of sulfides in tissues following oral administration of sodium sulfide solution was examined by means of animal experiments using rats. The concentration of sulfides in the blood from rats following oral intake was much higher than that seen following gas exposure. Based on these results, we concluded that the victim had been exposed to hydrogen sulfide gas and had then collapse into a pool of sewage containing sulfides. The sulfides which were distributed throughout the body tissues had mainly issued from the alimentary tract prior to death by drowning.     

Intracranial adenoid cystic carcinoma mimicking meningioma: report of two cases

Two cases of intracranial adenoid cystic carcinoma mimicking meningioma are reported. In one, MRI showed not only a homogeneously enhancing extra-axial tumour attached to the dura mater of the posterior cranial fossa, but also surrounding dural enhancement, the dural tail sign. In the second, CT demonstrated a well-demarcated enhancing extra-axial tumour, indistinguishable from a sphenoid ridge meningioma extending into the orbit. The neuroradiological features of intracranial adenoid cystic carcinoma may thus closely resemble those of meningioma.     

Hand-arm vibration syndrome and its prevalence in the present status of private forestry enterprises in Japan

Summary Currently there are no limitations on age of employment on private forestries in Japan. Hence, it was hypothesized that in these kind of enterprises, elderly chain saw operators, or those with long-term exposure, might be at higher risk of developing hand-arm vibration syndrome (HAVS). We consequently investigated the prevalence of HAVS in 447 chain saw workers on private forestries in Gifu Prefecture, Japan, with particular reference to age and exposure period. Of this population, 43 (9.6%) had signs and symptoms of vibration-induced white finger (VWF), and among these workers the severity of finger blanching was significantly correlated (P < 0.01) with the exposure period. Classification of all subjects by exposure period showed that workers with 30 years' exposure had higher prevalences of VWF (20.9%) and numbness of the hands (25.4%) compared to other groups. Significant differences (P < 0.01) were found between the functional capacities of workers with VWF and those of control subjects. We concluded that (a) the elderly chain saw operators and those with longer exposure should be moved to other jobs with a lower or no risk of exposure to vibration, and (b) the results of screening tests, even without cold water immersion (which we did not employ, in order to protect workers' hands), could be helpful for the identification of workers with VWF.     

New three-dimensional moving field radiation therapy for brain tumors.

A new modified rotation radiation method called "three-dimensional moving field radiation therapy" is described. The new method uses rotation in many planes while maintaining the the same isocenter to achieve a good spatial dose distribution. This delivers a high dose to tumors and spares the surrounding normal structures. This easy method can be carried out using the equipment for conventional rotation radiation therapy. The new method was superior to the one plane rotation radiation therapy using a physical phantom with film, a chemical phantom using the iodine-starch reaction, and a new biological model using tumor cells. Treatment of six brain tumors irradiated with total air doses of 50-60 Gy caused no hair loss or radiation necrosis.     

Quantitative assessment of quality of digitized portal images: receiver operating characteristic analysis applied to imaging in radiation therapy

An objective and quantitative method for the evaluation of the quality of megavoltage portal images was developed by applying receiver operating characteristic analysis. On the basis of therapeutic use of portal images, setup errors were employed as "signals" in this experimental study that compared the original portal films with digitized images. Six readers observed 104 portal images of a chest phantom, half of which were "abnormal" (ie, had setup errors). Digital images (2,048 x 2,048 matrix) were enhanced by means of histogram equalization and then printed with a laser printer for observation. The readers showed a higher discrimination capacity with the digitally enhanced images, although a statistically significant improvement was not demonstrated. The present method of assessment of image quality proved to be both simple and clinically reasonable.     

Orthoses of ventilative plastics.

Plastics are extensively used as a material for orthoses. However, one remaining problem is the ventilation of the orthosis. This is a real problem in countries such as Japan, where it is hot and humid especially in summer. The authors have invented a new orthosis "POROPLAST", which is made of mesh plastic sheets, combined in a cross-like weave. These orthoses provide good ventilation and are very comfortable to wear. They have been fitted to seventy-four cases with satisfactory results.     

Thermological study of drilling bone tissue with a high-speed drill

OBJECTIVE: To perform a detailed quantitative analysis of the effect of intermittent drilling and irrigation to lower the temperature during high-speed drilling. METHODS: We examined the thermal changes for 15 bone flaps while drilling a 7- x 7-mm area for 18 seconds and a specific point for 9 seconds, under the following conditions: continuous or intermittent drilling; with a fluted steel or a diamond ball cutter; without or with irrigation, with room temperature or cold (8 degrees C) Ringer solution. RESULTS: The maximum temperature during continuous drilling with a diamond cutter (or steel cutter) was 82.4 +/- 1.3 degrees C (55.2 +/- 1.0 degrees C) without irrigation, 42.5 +/- 1.2 degrees C (35.4 +/- 0.9 degrees C) with room temperature Ringer irrigation, and 22.5 +/- 1.4 degrees C (21.6 +/- 0.3 degrees C) with cold Ringer irrigation, whereas that during intermittent drilling was 66.1 +/- 1.2 degrees C (35.6 +/- 0.8 degrees C), 35.0 +/- 0.8 degrees C (25.4 +/- 0.7 degrees C), and 21.5 +/- 0.6 degrees C (21.8 +/- 0.4 degrees C), respectively. During continuous drilling of a specific point, the radius of the concentric isothermal line for 43 degrees C (thermal threshold for neurons) was 3.6 +/- 0.8 mm with a steel cutter, and it was 8.1 +/- 0.3 mm with a diamond cutter. The radius was 4.2 +/- 0.8 mm during intermittent drilling with a diamond cutter, and it was 4.0 +/- 0.1 mm during continuous drilling with room temperature Ringer irrigation. Intermittent drilling with cold Ringer irrigation kept the temperature, even at the center of the drilled area, below 20 degrees C. CONCLUSION: Intentional intermittent drilling with irrigation reduces temperature elevation and its expansion. These procedures are necessary for safe drilling, especially with a diamond burr. Although cold irrigation can minimize temperature elevation, its substantial effect on nerves or other structures needs to be elucidated.     

Association of diet with the onset of menopause in Japanese women

A prospective study was conducted in Takayama, Gifu, Japan, to evaluate the association between diet and the onset of menopause. A total of 1,130 female residents aged 35-54 years who were premenopausal and completed a validated semiquantitative food frequency questionnaire in 1992 were contacted by mail with a follow-up questionnaire in 1998 to update information on menopause. Onset of menopause was defined as a woman's age at the last menstrual period prior to stopping menstruation for 12 months. During the 6-year study period, 296 women experienced natural menopause. The Cox proportional hazards model was used to estimate hazard ratios of the onset of menopause after controlling for age, total energy, body mass index, years of smoking, and age at which regular menstrual cycle began. The authors found that green and yellow vegetable intake was significantly inversely associated with the 6-year incidence of menopause (hazard ratio = 0.71, 95% confidence interval: 0.54, 0.95 for the highest vs. lowest tertile of intake, p for trend = 0.02). Association of carotene intake with the incidence of menopause was of borderline significance (hazard ratio = 0.78, 95% confidence interval: 0.59, 1.04, p for trend = 0.07).