Cloning and characterization of cDNAs encoding two normal isoforms of bovine stem cell factor.

The cDNA clones encoding two isoforms of bovine stem cell factor (bSCF) were obtained using reverse transcriptase-polymerase chain reaction, and their sequences were determined. The deduced amino acid sequences of the longer and shorter isoforms of bSCF consist, respectively, of 274 and 246 residues and show a high degree of identity to those of SCFs of different animal species. Northern blot analysis with the cDNA revealed the expression of a 5.8 kilobase bSCF RNA in fetal bovine tissues.

Sequence of a cDNA encoding chicken stem cell factor.

Stem cell factor (SCF) is a polypeptide growth factor and the ligand for the c-kit proto-oncogene product. We cloned a chicken cDNA encoding a protein homologous to the mouse and human SCFs. The deduced amino acid (aa) sequence shows 53 and 52% identity to the mouse and human SCFs, respectively.

A nonparametric method for estimating interaction effect of age and period on mortality.

In this paper we introduce a new model and develop an estimation strategy to analyze mortality data. The model we dealt with has the specific structure E[log qij] = mu + alpha i + beta j + rho ij subject to the linear restrictions sigma i alpha i/sigma 2i = sigma j beta j = sigma i pij/sigma 2i = sigma j rho ij = 0 for any i and j; here, qij denotes the mortality for the jth period category and ith age category, mu denotes the overall mean, alpha i denotes the ith age effect in antichronological order, beta j the jth period effect, rho ij the general interaction effect; and sigma 2i is the common error variance of log qij for the ith age group. We propose a combined technique of ANOVA and nonparametric smoothing for estimating these parameters. The methods described are illustrated by mortality data on rectum cancer in Japanese males and females between 1950-1986.

Application of log-linear model in inference on karyotypic evolution in chronic myelocytic leukemia.

Relationships among additional chromosome abnormalities in chronic myelocytic leukemia (CML) with translocation 9;22 [Philadelphia chromosome (Ph1)-positive CML] were analyzed by log-linear models on 709 karyotypes reported in the literature. Additional abnormalities, such as the gain of chromosome 8 (+8), gain of Philadelphia chromosome (+Ph1), isochromosome of the long arm (q) of chromosome 17 [i(17q)], and the gain of chromosome 19 (+19), were frequently observed. A four-way 2 x 2 x 2 x 2 contingency table was considered with respect to the appearance of these four abnormalities, then the hierarchical log-linear models having at least four main effects were fitted to the observed contingency table. Akaike's information criteria of the models reflected the fitness of the model very well. Parameter estimates of the interaction terms indicated that the combinations of two abnormalities, '+8 and +19', '+Ph1 and +19', and '+8 and i(17q)' were positively associated, while '+Ph1 and i(17q)', and '+19 and i(17q)' were negatively associated. Based on the results of the data analysis, an inference was made on the route of karyotypic evolution in Ph1-positive CML; it statistically supports the hypothesis presented by Heim and Mitelman.

Evaluation of cancer prevention strategies by computerized simulation model: methodological issues.

A computerized simulation model developed to evaluate the potential impact of primary and secondary prevention is discussed from methodologic perspectives. In the simulation model, named CANSAVE (Cancer Strategy Analysis and Validation of Effect), the natural history of cancer was modeled as a Markovian stochastic process from cancer-free state to death. The lung cancer death rate among Japanese males was projected for 50 years to the year 2041. The simulation showed that the age-adjusted death rate would increase and reach a peak of 166 per 100,000 in 1989 and then decrease to 148 in 2003. It then shows a tendency to increase again, up to 255 in 2028. This change may be attributed to a lower smoking initiation rate among those born in the 1930s. Promotion of mass screening programs exhibits a more prompt effect than antismoking efforts, but the reduction in annual deaths is expected to be only 11%, even if a 100% participation is realized by the year 2000. The reduction in smoking initiation rate, on the other hand, begins to show a visible effect very slowly. It was predicted that a 1% annual reduction in smoking initiation rate would result in a 20% decrease in the number of deaths in 2041. The smoking cessation program is in the middle with regard to promptness. The predicted reductions in lung cancer deaths in 2041 were 13, 47, and 66%, respectively, when the annual smoking cessation rate was increased from 0.46% (present status) to 1, 3, and 5%. The combined application of all three preventive measures seems essential to realize the most effective reduction in lung cancer deaths.

A mathematical model of radiation carcinogenesis with induction of genomic instability and cell death.

We developed a mathematical model of carcinogenesis that incorporates genomic instability, a feature characterized by long-term destabilization of the genome in irradiated cells that leads to an increase in cancer risk in the exposed individuals at the cancer-prone age. This model also considers the induction of cell death, another important effect of radiation on cells. It is assumed that cell killing by radiation may occur at all stages of the carcinogenic process. The resulting model can explain not only the paradoxical relationship between low mutation rates and high cancer incidence but also the low-order dose-response relationship of cancer risk.

Estimation of chronic phase duration in Ph-positive chronic myelocytic leukemia treated with busulfan: statistical analysis on Japanese patients.

Chronic phase duration was analyzed in 148 Japanese patients with Ph-positive chronic myelocytic leukemia (CML) treated only with busulfan, and multivariate proportional hazard models were constructed to infer the prognosis of a given patient, and to evaluate the prognostic importance of the clinical findings. To make an accurate estimation of an individual patient's prognosis, we introduced a piecewise linear model for describing a hazard function in each prognostic variable. Of the 11 prognostic variables initially analyzed, the absolute count of peripheral basophils was revealed as the most important prognostic factor. A high basophil count was clearly a factor in cases with poor prognosis. The statistical model selection based on the criteria of model approximation finally suggested a model with three covariates; absolute count of peripheral basophils, platelet count, and presence or absence of additional chromosome abnormalities superimposed on the translocation of 9;22. By analyses based on the above model, we estimated that the median of the chronic phase duration for the patients with poor and good prognosis was 12 and 75 months, respectively. The piecewise linear model was well suited for an accurate estimation of an individual patient's prognosis. Thus, the model constructed here would become a reliable control to evaluate investigational approaches, such as hydroxyurea, interferons, and/or bone marrow transplantation.

Analysis and rearrangement of human karyotypes by computer.

A system useful for the collection and analysis of a large number of abnormal karyotypes and for studies on the relationship between cytogenetic abnormalities and clinical features of diseases is reported. The program is based on the disintegration and rearrangement of abnormal karyotypes recorded according to the 1978 International System for Human Cytogenetic Nomenclature (ISCN).

Use of the Weibull hazard model to estimate age-specific probability of permanent tooth loss.

In analysis of the probability of tooth loss with age, the exact time of tooth loss is often unknown, although it is clear whether a tooth remains or has been lost. That is, left censoring is inevitable during data sampling. This may provide a biased estimate if such data are dealt with by the product-limit method, which is a common method of survival analysis. To reduce such a bias in estimating the age-specific probability of tooth loss, we developed a survival analysis method taking left censoring into consideration. Four hundred and forty-six panoramic radiographs obtained in a daily clinical practice were used. The frequency of tooth loss with age was assumed to follow the Weibull hazard model, and a likelihood function taking left censoring into consideration was defined to estimate the probability of tooth loss. The estimate obtained from our method was compared with that from the product-limit method to examine whether the effect of left censoring was reduced. We found that the probability of tooth loss estimated by the product-limit method was biased by left-censored data, and that the bias was reduced when our method was used. A Monte Carlo simulation study, in which the true tooth loss time was given, also showed that our method provided an estimate closer to the true value. Our method is considered to be more accurate in estimating the probability of tooth loss, since it reduces the bias caused by left-censored data.

Strain differences in the induction of intestinal metaplasia by X-irradiation in rats.

Strain differences in the susceptibility of rats to induction of intestinal metaplasia by X-irradiation were examined. The gastric regions of 5-week-old males of five inbred strains of rats (F344/NSlc, Copenhagen, Buffalo/NacJcl, and ACI/NHos) and three strains of randomly bred rats (HOS:Donryu, Slc:Wistar, Slc:SD) were irradiated with a total dose of 20 Gy X-ray given in two equal fractions at 3-day interrals. When examined after the rats were killed, 6 months after the last irradiation, the number of intestinal metaplastic crypts positive for alkaline phosphatase (ALP) was highest in the Donryu and lowest in the Copenhagen rats. Morphologically, the number of crypts with intestinal metaplasia in the glandular stomachs of Donryu, Wistar, SD, and Buffalo rats was higher than the number in ACI, F344, and Copenhagen rats. Intestinal metaplasia was more frequently observed in the pyloric than in the fundic glands. These results demonstrate that the induction of intestinal metaplasia by X-irradiation in rats is greatly influenced by the rat strain.

Isotonic mannitol and the prevention of local heat generation and tissue adherence to bipolar diathermy forceps tips during electrical coagulation. Technical note.

The authors observed temperature levels of saline and mannitol on the tips of bipolar diathermy forceps during application of power to the forceps and compared the effects of irrigation with saline and isotonic mannitol on electrical coagulation of vessels during neurosurgical operations. There was a marked rise in the temperature of saline corresponding to increased output power of the coagulator; there was no rise in the temperature of the mannitol. Irrigation with isotonic mannitol during surgery resulted in a considerable reduction of adherence of burned tissue and blood clots to forceps tips during coagulation of both arteries and veins compared with that which occurred during irrigation with saline. These results demonstrate that irrigation with an isotonic mannitol surpasses that with conventional ionic fluids, such as a saline, for prevention of both tissue adherence to bipolar diathermy forceps and removal of heat generated during electrical coagulation.

Lymphoplasmacyte-rich meningioma with clinical resemblance to inflammatory pseudotumor. Report of two cases.

Two cases of lymphoplasmacyte-rich meningioma manifesting clinical and radiological characteristics unusual for a meningioma are reported. The patient in Case 1 was a 22-year-old man with a 9-year history of bilateral visual disturbances and recent dyspnea. An en plaque skull base mass, which was partially resected, was found at surgery to extend down from the planum sphenoidale into the spinal canal to C-5. Seven years later most of the residual mass in the spinal canal had disappeared, although a localized round tumor recurred at C2-3. The patient in Case 2 was a 24-year-old woman with an original diagnosis of clival meningioma, which recurred as multiple skull base lesions that spontaneously regressed in 10 months. These two cases and others reported in the literature indicate that lymphoplasmacyte-rich meningiomas may manifest peculiar biological behavior more typical of intracranial granulomas than of meningiomas.

Effects of trimebutine on intestinal motility after massive small bowel resection.

Effects of trimebutine maleate (TM) on intestinal motility in short bowel syndrome (SBS) were studied in conscious canines in both acute and chronic phases following 80% massive distal small bowel resection (MSBR). TM was administered orally to beagles with MSBR or as controls in the postprandial and fasting states, and given simultaneously with meals. Intestinal motility was measured using bipolar electrodes for approximately 1 month after the electrodes were implanted in each beagle and the data compared between treatment groups. When TM was given with meals, the postprandial period without duodenal migrating myoelectric (or motor) complexes (MMCs) was shorter than in those given meals only. When TM was given in the postprandial state in short bowel beagles, the initial duodenal MMCs occurred earlier, i.e. the postprandial period was shorter. Diarrhea did not occur in these beagles. When TM was given in the fasting state, duodenal MMCs occurred and propagated to the distal intestine. In conclusion, oral TM administration can produce a more appropriate intestinal condition for the next food intake and make enteral nutrition possible even in the acute phase after MSBR. Such feeding can be carried out without overloading gut function as a result of the modulation of gastrointestinal motility by TM.

Effects of intestinal muscular wrapping on remnant intestinal motility after massive small bowel resection in conscious canines.

We searched the effect of the muscular valve on the management of short bowel syndrome. The motility of the remnant intestine with a special muscular valve after 80% massive distal small bowel resection (MSBR) was evaluated in conscious dogs. The valve (muscular ring) was made by the autointestinal muscle layer holding vascular pedicle. Interdigestive and postprandial bowel motility using bipolar electrodes and/or contractile strain gauge force transducers 2-4 weeks after the surgery, and data of this group (Group I) were compared to the motility in dogs after MSBR without valve construction (Group II) and in controls (Control). Results; Fasting duodenal migrating myoelectric (or motor) complexes (MMCs) in Group I occurred at longer intervals than in Control and almost similarly to those in Group II. MMCs arising from the duodenum were often interrupted before the jejunum above the valve and the anastomosis. The velocity of duodenal MMC propagation was slowed in every intestinal segment including that from the duodenum to the proximal jejunum, and to the jejunum above the anastomosis. Transit time in MSBR group (I and II) from the duodenum to the terminal ileum was extremely shorter than in Control, but there were no differences between in Groups I and II. The duration of the postprandial period without duodenal MMCs in Group I was significantly prolonged than in Control, but was shorter than that in Group II. The muscular valve was frequently activated, and the jejunum covered with the valve was contracted frequently which synchronized with the valve activity. It seemed the valve worked as sphincter. However, intestinal obstruction was not occurred through the jejunum covered by the valve. In conclusion, changes in gut motility after MSBR with the valve construction compensate for the shortened intestine and maintain the bowel content earlier postoperatively in comparison with the MSBR alone, and also contribute to the adaptive increase in the remnant intestinal absorption.

Analysis of cancer mortality among atomic bomb survivors registered at Hiroshima University.

The aim of this study was to investigate the late effect on cancer mortality risk of the radiation exposure of atomic bomb survivors who comprised a study population different from that previously studied by the Radiation Effects Research Foundation (RERF). We examined survivors residing in Hiroshima Prefecture, who were followed up between 1968 and 1989 by the Research Institute for Radiation Biology and Medicine (RIRBM) at Hiroshima University. We used the dose-evaluation system known as Atomic Bomb Survivors 1993 Dose (ABS93D), which was based on the Dosimetry System 1986 for the survivors registered with RERF. The dose estimation was applied in a total of 35,123 subjects. Among survivors who had been alive for > 20 years after the bombing, the relative mortality risk of leukaemia at 1 Gy of organ dose was 2.37 (90% confidence interval: 1.36-3.39), which was significantly higher than the zero dose control group. Similarly, significantly higher risks were observed for all cancers except leukaemia, including cancers of the lung, colon and female breast. Comparison is made with RERF results regarding temporal changes in the relative risk. Although we observed slightly lower relative risks than RERF values for the cancer of the stomach and lung, and for all cancer except leukaemia, no marked trends for any cancer were observed in this study. Though there were some differences in population between RERF and RIRBM, no marked discrepancies were observed.

Effect of tritiated water on female germ cells: mouse oocyte killing and RBE.

The relative biological effectiveness (RBE) of tritiated water (HTO) was investigated using mouse immature oocytes. Juvenile mice, having immature oocytes that are highly sensitive to radiation killing, were exposed to HTO, 137Cs gamma rays, 60Co gamma rays, or 252Cf fission neutrons. The 137Cs gamma rays were used to simulate the changing dose rate (but not the radiation quality) received from HTO (see section 2). On the 14th day after birth, female ICR strain mice were injected once in the abdominal cavity with HTO at levels of 1.70, 3.40, 6.81, or 10.21 MBq/10g body weight, and their ovaries were removed 2 weeks after the injection. (The cumulative doses are equivalent to 0.039, 0.077, 0.159 and 0.246 Gy, respectively.) The survival rate of oocytes was determined by light microscopy inspection of serial sections, and the results of the different exposures were compared. The number of surviving oocytes decreased exponentially with increasing dose of HTO or 137Cs, and RBEs of HTO compared to 137Cs gamma rays ranged from 1.1 to 3.5. The relative effectiveness of the different types of radiations was compared, and the results of the comparison, in order of increasing effectiveness, was 137Cs, 60Co, HTO, and 252Cf. The RBE of 252Cf compared to 60Co gamma rays ranged from 1.6 to 3.5.

Estimation of dose absorbed fraction for 131I-beta rays in rat thyroid.

The dose absorbed fraction of rat thyroid by internal deposit of 131I has been calculated as a function of effective diameter of thyroid. The calculations were done using two types of Monte Carlo simulations: one was by a simple energy-loss calculation in spherical volume according to the electron stopping power, and another by a more realistic simulation using Monte Carlo N-Particle Transport code system Version 4A (MCNP). These two calculations were consistent with each other within a deviation of 5%. The absorbed fractions in spherical thyroid were drastically changed up to 5 mm diameter, and then almost all energy was deposited within 10 mm diameter. For the practical application to the animal experiment, the absorbed fractions of ellipsoid-shaped thyroids were also calculated for 1-, 4- and 9-week-old rats, where the fractions were estimated to be 0.61, 0.67 and 0.68, respectively. It was also found that the absorbed fraction of the ellipsoid with various dimensions can be simulated by a calculation for spherical volume with a comparable effective diameter.

Role of hypervolemic hemodilution in focal cerebral ischemia of rats.

This study was designed to better define a protocol for hypervolemic hemodilution in acute cerebral ischemia and investigate the mechanism of action of this therapy. Anesthetized rats (n = 40) were subjected to 6 h of middle cerebral artery (MCA) occlusion. At 45 min after MCA occlusion, each rat received one of the following treatment modalities: (1) control, (2) isovolemic hemodilution, (3) hypervolemic nonhemodilution (whole blood), (4) hypervolemic hemodilution (normal saline), and (5) hypervolemic hemodilution (hetastarch). Local cerebral blood flow (CBF) was determined with hydrogen clearance technique, and cardiac output was assessed by measuring the descending aorta blood flow (DAF). Infarction volume was estimated by 2,3,5-triphenyltetrazolium chloride staining method. Hetastarch infusion increased both DAF and local CBF more than the other treatments, by 98% and by 89%, respectively. Hetastarch also reduced infarction volume the most to 71 +/- 19 mm3 (p < 0.01 versus control 117 +/- 32 mm3). A significant correlation between percent (%) changes in local CBF and % changes in DAF existed in ischemic brain regions, and the hetastarch infusion improved local CBF more prominently in profoundly ischemic regions in contrast to isovolemic hemodilution. These data demonstrated the superiority of hypervolemic hemodilution with hetastarch as compared to other similar treatment modalities for acute cerebral ischemia, and indicate that cardiac output augmentation may be more responsible than decreased blood viscosity for the beneficial effect of hypervolemic hemodilution on local CBF in profoundly ischemic regions, as such ischemic brain tissue can severely lose its regulatory control of CBF to alterations in cardiac output.

Hyperdynamic therapy for focal cerebral ischemia of rats: use of colloidal volume expansion and dobutamine.

The effects of hyperdynamic therapy with colloidal volume expansion and pharmacological augmentation of cardiac function with dobutamine on local cerebral blood flow (CBF) and the size of ischemic injury were investigated in rats subjected to 6 h of middle cerebral artery (MCA) occlusion. At 45 min after MCA occlusion, each rat was randomly assigned to one of the following treatment groups: (1) control; (2) hetastarch infusion (HES); and (3) hetastarch plus dobutamine (12 micrograms/kg/min) infusion (HES/DOB). In both the HES and HES/DOB groups, cardiac output and local CBF in ischemic brain markedly increased after treatment and infarction volumes were significantly reduced as compared to the control group. There were, however, no significant differences between both groups apart from a dobutamine-induced tachycardia. Colloidal volume expansion augmented cardiac output, increased CBF in ischemic brain, and substantially modified the extent of ischemic injury. However, the addition of dobutamine did not bring about adjunctive beneficial effects of cardiac performance, CBF, or the degree of ischemic brain damage in the rat focal ischemic model.

Intracranial facial nerve neurinoma: surgical strategy of tumor removal and functional reconstruction.

BACKGROUND: Three cases with intracranial facial neurinoma underwent tumor removal and facial nerve reconstruction with or without tympanoplasty. Surgical strategy for each case was tailored to: (1) the site of main tumor mass, (2) its extension along the facial nerve, and (3) involvement of the auditory organs. METHODS: Surgeries adopted in the three cases were: transpetrosal approach with intracranial-intratemporal facial nerve anastomosis, middle fossa and transmastoid approach with intratemporal facial nerve anstomosis and tympanoplasty, and middle fossa and transmastoid approach with intracranial-intratemporal facial nerve anastomosis and tympanoplasty. The greater auricular nerve was used as the nerve graft for all three cases. RESULTS: In the follow-up period of 8-13 months there was no tumor recurrence; facial function was scored 20/90 in modified May's scoring system in each case, but two are still in the process of functional recovery. One of the two cases who underwent tympanoplasty showed complete recovery of hearing within 1 month, and the other showed worsened hearing, which was not serviceable at 3 months postoperatively. CONCLUSION: Systematic surgical approach for tumor removal, facial nerve reconstruction, and auditory reconstruction should be considered in cases with intracranial facial neurinoma due to its varied clinical features.