Feeding suppression by fibroblast growth factor-1 is accompanied by selective induction of heat shock protein 27 in hypothalamic astrocytes.

It has been suggested that fibroblast growth factor (FGF)-1 serves as a physiological satiety factor in the hypothalamus, although the molecular mechanism underlying such a function is poorly understood. To gain additional insight into this issue, we used a Sendai virus (SeV) gene expression system in rats to explore genes differentially expressed subsequent to expression of FGF-1. Using cDNA arrays, we determined that infusion of FGF-1/SeV into one lateral ventricle induced selective expression of heat shock protein (HSP) 27 in the hypothalamus. Whereas FGF-1 expression was restricted to the ependymal cell layer of the cerebral ventricles, HSP27 was more widely expressed in astrocytes residing in the surrounding periventricular region. Similarly, infusion of FGF-1 polypeptide into a lateral ventricle induced dose-dependent HSP27 expression in periventricular astrocytes surrounding the third ventricle, with maximum mRNA levels being attained 6 h after infusion. This induction of HSP27 was accompanied by a significant suppression of feeding behaviour. Interestingly, suppression of feeding caused by intracerebro ventricular infusion of ciliary neurotrophic factor was also accompanied by induction of HSP27 in periventricular astrocytes, but suppression of feeding caused by infusion of leptin was not. It therefore appears that suppression of feeding by FGF-1 is accompanied by selective induction of HSP27 expression in hypothalamic astrocytes surrounding the third ventricle, and that this response may be a key component of the mechanism by which appetite is regulated by FGF-1.

Hyperthermic isolated regional perfusion for the treatment of osteosarcoma in the lower extremity.

BACKGROUND: In order to reduce the systemic toxity of cisplatin and to increase the effect on the local tumor, facilitating limb-preserving procedures, we have been using hyperthermic isolated regional perfusion (HIRP) for the treatment of osteosarcoma in addition to preoperative chemotherapy. MATERIALS AND METHODS: Twenty patients with an osteosarcoma in a lower extremity were treated with both preoperative chemotherapy and HIRP. RESULTS: The chemotherapeutic effects of preoperative chemotherapy with HIRP was grade III in 6, and grade IV (no viable cell areas observed) in 7. The surgical margins could be reduced in these 13 cases of good responders showing over 90% necrosis (grade III or grade IV), which mainly involved postnecrotic fibrosis and osteosclerosis. CONCLUSION: HIRP can help to control the tumor locally. A more conservative operation was then possible in cases of good responders to preoperative chemotherapy with HIRP.

Molecular characterization of 6-pyruvoyl-tetrahydropterin synthase deficiency in Japanese patients.

We identified three mutations in four Japanese patients with central type 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency. One missense mutation was a C-to-T transition, resulting in the substitution of Pro by Ser at codon 87 (P87S) in exon 5. Another missense mutation was a G-to-A transition, resulting in the substitution of Asp by Asn at codon 96 (D96N) in exon 5. A splicing mutation was found by skipping of exon 4 on PTPS mRNA analysis, and a G-to-A transition at the third base of codon 81 (E81E) and at the terminal base in exon 4 were detected on genomic PTPS DNA analysis. The E81E mutation affected the splice donor site of exon 4 and caused the splicing error. In COS cell expression analysis, the P87S and D96N mutant constructs revealed, respectively, 52% and 10% of wild-type activity. Patients with P87S/P87S (52%/52% in-vitro PTPS activity) exhibited 0.11 and 0 microU/g hemoglobin [Hb] in erythrocyte PTPS activity (wild-type control: 11-29 microU/gHb) erythrocyte PTPS activity, and the patient with P87S/D96N mutations (52%/10%) had 0.97 microU/gHb in PTPS erythrocyte activity. The PTPS erythrocyte activity did not coincide with the in-vitro PTPS activity based on patient genotype.

Distribution of fibroblast growth factor-5 in rat hypothalamus, and its possible role as a regulator of feeding behaviour.

We previously reported that a transcript of fibroblast growth factor-5 (FGF-5) was more abundant in the brain of postnatal and adult mice than in the embryonic brain. This suggested that FGF-5 plays some role in the mature brain. Here, we have investigated the spatiotemporal expression and function of FGF-5 in the adult rat hypothalamus with the emphasis on feeding behaviour. In situ hybridization experiments demonstrated that, in both adequately fed and fasted (20 h) rats, FGF-5 transcripts were present within several nuclei in the hypothalamus (viz. the magnocellular part of the paraventricular nucleus, supraoptic nucleus, arcuate nucleus, median eminence, and ventromedial hypothalamic nucleus), but not in the lateral hypothalamic area. Quantitative detection of FGF-5 mRNA in the hypothalamus (especially in the paraventricular nucleus) indicated that food deprivation (20 h) reduced the expression of this gene to almost one-half of that seen in the control (fed) rats. The expression recovered to the control level after 1 h re-feeding, and this recovery persisted for several hours. Furthermore, FGF-5, when infused into the third ventricle, consistently reduced food intake, water intake and body weight gain, all in a dose-dependent manner. These results suggest that FGF-5 in the hypothalamus acts as a physiological regulator of feeding behaviour, and that its decreased expression during food deprivation may be important in stimulating appetite.

Hereditary sensory neuropathy with deafness and dementia: a clinical and neuroimaging study.

We describe three sibling patients with autosomal dominantly inherited sensory neuropathy, sensorineural hearing loss and dementia. The features of cognitive-behavioral deficits in the patients, including executive dysfunction, apathy, indifference and inattention, were consistent with a frontal lobe dysfunction. Magnetic resonance imaging showed a diffuse brain atrophy. A fluorodeoxyglucose positron emission tomography in one patient and a single photon emission computed tomography in another demonstrated a glucose hypometabolism or a hypoperfusion in the medial frontal and thalamic regions. Primary frontal involvement or frontal dysfunction secondary to thalamic lesions may contribute to the nature of dementia in these patients.

Diffuse bilateral thalamic astrocytomas as examined serially by MRI.

We report the case of a 13-year-old girl with diffuse bilateral thalamic astrocytomas. Incoordination was observed at the onset. Cranial computed tomography (CT) showed enlarged thalami, and magnetic resonance imaging (MRI) revealed these lesions to be symmetrically enlarged with high intensity on the T2-weighted image. Owing to these atypical findings in the neuroimaging studies, we had difficulty in making the correct diagnosis of a brain tumor. After the diagnosis of diffuse bilateral thalamic astrocytomas was obtained, we performed hyperfractionated radiotherapy followed by chemotherapy. Radiation therapy was effective for a while, but the girl's condition deteriorated again and she died 8 months after admission. Although diffuse bilateral thalamic astrocytomas are difficult to diagnose because they do not resemble most other neoplasms on neuroimaging studies, pediatricians should keep this entity in mind in order to arrive at a precise and prompt diagnosis.

Identification of beverages and beverage stains by GC/MS using aroma components as indicators.

A method to identify brown coloured beverages or beverage stains for criminological purposes was devised using aroma components as indicators. The examined beverages comprised three brands each of beer, coffee, cola and black tea, two brands of oolong tea, and four brands of green tea. Aroma components in each sample were efficiently concentrated with a porous polymer beads column (Porapak Q) and were analyzed by gas chromatography/mass spectrometry (GC/MS) using n-octyl alcohol as the internal standard. Specific aroma components were found in each beverage and beverage stain, for example cis-terpin hydrate in cola, and thus identification of beverages or beverage stains became feasible through the detection of these specific components. The present method was applied efficiently to two practical criminological cases.

Induction of histamine release from non-immunized guinea pigs: a possible involvement of lectin-like factor(s) in pollinosis.

To investigate nonimmune pathogenic functions of pollens, vascular permeability enhancement (VPE) activity of pollen extracts was examined using guinea pigs nonimmunized against pollens. Ryegrass, ragweed, mesquite and almond, but not common cattail and sumac, induced VPE which was inhibited primarily by an anti-histamine drug. Ryegrass pollen VPE activity was extracted more at pH 7.3 than at pH 6.5 or 8.0 and the maximal activity was extracted in 30 min. Interestingly, more than 60% of the maximal activity was extracted in 5 min. The maximal VPE activity had a dose-dependency similar to histamine (3 x 10(-5) M) but lasted longer than the histamine activity. The VPE activity was inhibited by oligomannose-glycosylated ovalbumin or avidin, as well as the oligosaccharides but not by the deglycosylated proteins. These results indicate that some pollens contain lectin-like, histamine-releasing factor(s), which may be involved in part in pollinosis, by inducing mast cell degranulation through a nonimmune mechanism and resulting in allergy-like symptoms.

Screening of antipsychotic drugs by wide-bore capillary gas chromatography with nitrogen phosphorus detection--detection levels in plasma.

The detection levels of 12 antipsychotic drugs as ascertained from drug screening were examined in order to use the screening results effectively for treatment of patients or medico-legal examinations in cases of poisoning. Wide-bore capillary gas chromatography with nitrogen phosphorus detection was used for the analysis. The detection limits of drugs in plasma using 3 extraction procedures, single-solvent, 3-step solvent and solid-phase extractions were 50-100 ng/ml, 10-200 ng/ml and 5-50 ng/ml, respectively. The detection limits were compared with blood levels previously reported in the literature. Only 4 drugs were detected at the therapeutic level, thioridazine, floropipamide, sultopride and oxypertine using the single-solvent extraction procedure. Using the 3-step solvent extraction procedure, chlorpromazine, levomepromazine and zotepine in addition to the above 4 drugs were detected. Using the solid-phase extraction procedure, 8 of 12 drugs were able to be detected at the therapeutic level, with the exception of perphenazine, haloperidol, bromperidol and nemonapride. These data were proved to be useful for a rapid forensic diagnosis.

Long-acting nicardipine for elderly hypertensive patients: effect on diurnal variation of blood pressure.

The effect of long-acting nicardipine tablets on diurnal variation of blood pressure was compared with that of standard nicardipine tablets and long-acting nifedipine tablets by 24-hour ambulatory blood pressure monitoring in 35 patients with hypertension. Long-acting nicardipine decreased systolic blood pressure in each age group, and there was no difference in its anti-hypertensive effect when compared with the other two drugs. All three drugs had no effect on the amplitude of daily blood pressure variation, and all three drugs decreased the baseline blood pressure in each age group when compared with untreated patients. In addition, no change was observed in the decrement of baseline blood pressure after switching from the other two drugs to long-acting nicardipine. Long-acting nicardipine had less effect on diurnal blood pressure variation than standard nicardipine tablets, which are administered three times daily. In each age group, long-acting nicardipine also more effectively inhibited the increase in cardiac work resulting from the morning rise phenomenon when compared with standard nicardipine tablets. These findings suggest that long-acting nicardipine may be a more useful preparation for the treatment of essential hypertension, particularly in elderly patients.

How to diagnose polysulphide poisoning from tissue samples.

We carried out animal experiments to toxicologically verify polysulphide poisoning by analyzing tissue samples. A bathing agent containing calcium polysulphides was administered orally to rats, and then polysulphides and sulphide, the decomposed product of polysulphides, were analyzed by GC and GC/MS. The concentrations of polysulphides (mumol/ml or g) were found to be highest in blood (0.196), followed by the liver (0.051), the lungs (0.018) and kidneys (0.013), but were below the detection limit (0.005 mumol/g) in the other tissues tested. Sulphide was detected in all the tissue samples and was found to be highest in the blood (0.518 mumol/ml), this being 40 times higher than that required for fatal poisoning in the case of hydrogen sulphide. Polysulphide poisoning was considered to be confirmatively diagnosed by detecting and measuring polysuphides and supplementarily sulphide in body tissues, most pertinently in the blood. Two practical cases of suspected poisoning by polysulphides are briefly described.

[The significance of preoperative chemotherapy for thermopreservation of limbs].

Preoperative chemotherapeutic effects on 42 osteosarcomas treated with CDDP intra-arterial infusion protocol were compared with the effects of treatment of same by local perfusion only, following administration of adriamycin (ADR) or high doses methotrexate and leucovorin (HD-MTX). Thirteen cases were further given local hyperthermic perfusion (LHP) treatment. The preoperative local treatment resulted in a poor response in cases in which the serum ALP failed to fall down the normal range, those with angiographically demonstrated tumor stains remaining, and those with reactive zones remaining as indicated by T2 MR imaging. The ratios of necrotic areas were significantly higher in the LHP group, while those of viable areas were significantly lower in the LHP group compared to other groups. Total tumor cell killing was possible in six of 13 cases in the LHP group. Post-necrotic fibrosis and post-necrotic osteosclerosis were significantly higher in the LPH group. The results suggested that, in selected cases treated with LHP, conservative surgery may well be possible so as to preserve all functional activity.

Elimination of unstable angina by diltiazem under temporary pacing.

We describe two patients in whom spontaneous angina following acute myocardial infarction (postinfarction angina caused by coronary artery spasm) and worsening angina were successfully eliminated after clinical dosage of oral diltiazem, while marked sinus node suppression developed and temporary pacing was performed. The patients were females (one was 67 years and one was 64 years old), and had no history of sinus node dysfunction. The occurrence of the adverse effect was not during angina, and the intervals between the initiation of diltiazem and the occurrence were 6 days after 120 mg/day in one patient, and 4 h after a single administration of 60 mg in the other. Diltiazem is also efficacious in the elimination of unstable angina, however one should note that diltiazem may remarkably suppress not only atrioventricular node activity but also sinus node activity in some patients.

A new family with beta-thalassemia intermedia.

In a Japanese family several members in three generations had, on hemoglobin analysis, typical findings of heterozygous beta-thalassemia. However, hemoglobin concentrations, red cell morphology, splenic size and clinical histories indicated that the disorder was more severe than in the usual beta-thalassemia trait. From the previous and the present studies folic acid supplements appeared to be beneficial in ameliorating the anemia. The findings may provide an apparent pathophysiologic and genetic explanations for the more severe anemia and red-cell abnormalities present in a small proportion of families with beta-thalassemia trait.