Enhanced Tumor Delivery and Antitumor Activity of Palmitoyl Rhizoxin Using Stable Lipid Emulsions in Mice

Purpose. A highly lipophilic antitumor agent, 13-O-palmitoyl-rhizoxin (RS-1541), was incorporated into lipid emulsions of various sizes consisting of triglyceride ODO and surfactant HCO-60. Pharmacokinetics, toxicities, and antitumor activities were evaluated after intravenous administration to mice bearing subcutaneously inoculated M5076 sarcoma cells. Methods. The levels of RS-1541 in the plasma and tissues including tumor, were determined by HPLC. The maximum tolerated dose (MTD) was estimated by toxic death and change in body weight. The decrease in tumor diameter was measured for antitumor activity. Results. There existed large variations in pharmacokinetics of RS-1541, depending on the size of emulsion particles. Compared with a colloidal solution (reference solution), the small (110nm) and medium (230nm) size emulsions showed high concentrations of RS-1541 in the tumor, while the large emulsions (350nm–630nm) exhibited low concentrations. The MTD of RS-1541 was reduced, when incorporated in the emulsions larger than 220nm in size. At MTD, each size of emulsions (70nm–380nm) effectively retarded the tumor growth and increased survival time. The maximum effect was achieved for the 220 nm emulsions. Conclusions. When particle size is properly selected, these emulsions could be promising and effective as an injectable carrier for lipophilic antitumor agents in order to enhance the tumor delivery and efficacies while reducing toxicities.     

Regional magnetic resonance spectroscopy of the brain in autistic individuals

We studied the variations in the concentration of metabolites with brain region and age in autistic individuals and normal controls using multiple analysis of covariance. We examined 55 autistic individuals (2–21 years old, 47 male and eight female) and 51 normal children (3 months–15 years old, 26 boys and 25 girls). Single volumes of interest were placed in the frontal, parietal and temporal region on both sides, the brain stem and cingulate gyrus. The concentration of each metabolite was quantified by the water reference method. The concentration of N-acetylaspartate in the temporal regions (Brodmann's areas 41 and 42 ) in the autistic individuals were significantly lower than those in the controls (P < 0.05), but concentrations in other regions were not significantly different between the autistic individuals and controls. This suggests low density or dysfunction of neurones in Brodmann's areas 41 and 42 in autistic individual, which might be related to the disturbances of the sensory speech centre (Wernicke's area) in autism. Received: 3 July 2000 Accepted: 21 November 2000     

Juvenile granulosa cell tumor in a three-year-old infant. An immunohistochemical and ultrastructural study

A three-year-old female infant with a juvenile granulosa cell tumor of the ovary and precocious pseudopuberty is presented. Laboratory tests revealed elevated levels of serum and urinary estrogen. Histological examinations showed an immature follicular pattern surrounded by theca-like stromal tissue. The immunohistochemical localization of estradiol, estriol, progesterone and testosterone was studied by indirect immunoperoxidase staining of cryostat sections. All of these steroid hormones were localized mainly in stromal cells and in some follicular cells. Electron microscopic examination revealed three types of tumor cell, i.e. polygonal cells, spindle cells and transitional cells. Well developed smooth endoplasmic reticulum, mitochondria with tubulovesicular cristae, and lipid droplets in the cytoplasm, which are typical features of steroid synthesis, were conspicuous mainly in the last type of cell. Such transitional cells almost corresponded to steroid-positive cells. These cells were considered to have a close relationship to theca gland cells of developed ovarian follicles and to have mainly participated in steroid synthesis in the present tumor. In addition, some spindle cells showed features of myofibroblasts, such as intracytoplasmic filaments, dense body-like structures, and pinocytotic vesicles. These features suggest that the cells might all be derived from the same progenitor of ovarian mesenchyme.     

Effect of pregnancy on ethanol concentrations at onset of loss of righting reflex in rats

To determine if the pharmacodynamics of ethanol are altered in advanced pregnancy, 20-days pregnant Lewis rats and nonpregnant rats of the same age received an i.v. infusion of ethanol, 96 mg/min/kg, until they lost their righting reflex. The concentrations of ethanol at that time in adult and fetal serum, and in the cerebrospinal fluid (CSF) and brain of the adult animals were determined. Ethanol concentrations in the pregnant rats were only slightly (less than 10%) but statistically significantly lower than in nonpregnant controls. Brain/serum, CSF/serum, and CSF/brain concentration ratios of ethanol were essentially identical in pregnant and nonpregnant rats, indicating no apparent effect of pregnancy on the distribution kinetics of ethanol. The serum concentrations of ethanol in mothers and their fetuses were similar and significantly correlated. The results of this investigation show that the central nervous system depressant effect of ethanol is not appreciably altered by pregnancy.     

Dermatofibrosarcoma protuberans with fibrosarcomatous areas

 Fibrosarcomatous (FS) change in a rare, but well-known phenomenon encountered in dermatofibrosarcoma protuberans (DFSP), and an increased chance in an adverse outcome has been suggested in patients with DFSP having FS areas (DFSP-FS). As altered p53 pathway has been suggested as having a potential role in tumour progression, we analysed the p53 gene and p53 protein together with the p53-related protein mdm2 and p21^Wafl in 5 cases of DFSP-FS and 13 of DFSP to ascertain whether the p53 pathway correlates to the fibrosarcomatous transformation of DFSP. Three of the five DFSP-FSs overexpressed p53 protein immunohistochemically, and one of them had a ”missense” mutation of the p53 gene without immunohistochemical overexpression of mdm2 or p21^Wafl. The other two DFSP-FSs with p53 overexpression demonstrated increased labelling indices of both mdm2 and p21^Wafl. The three DFSP-FS patients with overexpression of p53 protein had frequent local recurrences, ranging from 3 to 5 in number with increasingly short intervals (mean 4.5 years), while one of the other two had no recurrences and the other, only one. None of the 13 DFSPs showed any alterations in the p53 gene or overexpressions of p53, mdm2 and p21^Wafl, except for one DFSP having a ”silent” mutation of the p53 gene. Three DFSPs had local recurrences once or twice with longer intervals to recurrence (mean 10.3 years). Although the number of cases examined is limited, the results suggest that alterations in the p53 pathway, such as overexpression of p53 protein by a mutated gene and mdm2 overexpression, are involved in fibrosarcomatous transformation in a subset of fibrohistiocytic tumours and possibly correlated with its more locally aggressive behaviour than that without p53 alterations or ordinary DFSP. Received: 21 January 1998 / Accepted: 25 March 1998     

Association between serum uric acid levels and achievement of target blood pressure among Japanese community residents with hypertension

The authors examined the sex-specific association between serum uric acid (SUA) levels and achievement of target blood pressure among Japanese patients with hypertension. This cross-sectional study was conducted between January 2012 and December 2015 and examined 17 113 eligible participants (6499 men; 10 614 women) with hypertension among 66 874 Japanese community residents who underwent voluntary health checkups. Multivariate analysis was used to estimate the association between high SUA level (≥7.0 mg/dL for men and ≥6.0 mg/dL for women) and “therapeutic failure” in achieving target blood pressure (BP) of 140/90 and 130/80 mmHg in both sexes. Multivariate analysis revealed that high SUA level was significantly associated with failure to achieve the 130/80 mmHg treatment goal among men (AOR = 1.24, 95% CI = 1.03–1.50, p = .03). Among women, high SUA level was significantly associated with failure to achieve both the 130/80 and 140/90 mmHg treatment goals (AOR = 1.33, 95% CI = 1.20–1.47, p < .01 and AOR = 1.17, 95% CI = 1.04–1.32, p < .01, respectively). Each increase in SUA quartile was positively associated with increases in systolic BP (SBP) and diastolic BP (DBP) (p < .01 for trend) in both sexes. SBP and DBP in each quartile (Q2–Q4) were also significantly higher compared with those of Q1 in both sexes (p < .01). Our data confirms the difficulties in maintain goal BP control in those with elevated SUA.