Persistent supersensitivity of sigma receptors develops during repeated methamphetamine treatment.

Functional changes in sigma receptors were examined after behavioral sensitization induced by repeated methamphetamine treatment. Rats received either saline or 4 mg/kg methamphetamine for 14 days. (+)3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP), a sigma receptor agonist, was given as challenge after various periods of abstinence. (+)-3-PPP at doses greater than 6 mg/kg stimulated several forms of behavior in naive rats. (+)-3-PPP at 12 and 24 mg/kg produced more frequent rearing and more intense stereotyped sniffing and repetitive head movements in rats previously sensitized with methamphetamine than in saline-pretreated rats. The augmented response to (+)-3-PPP in methamphetamine-treated rats was maintained for at least one month. The augmented response to (+)-3-PPP was reversed by the combined administration of 100 mg/kg (+/-)-sulpiride, a D2 dopamine receptor antagonist, and 30 mg/kg BMY 14802, a sigma receptor antagonist. These results suggest that repeated methamphetamine treatment induces persistent supersensitivity in sigma receptors and that it may subsequently activate the dopamine system.     

Case of Heerfordt's syndrome with prolonged peripheral nerve involvement]

A 28-year-old man complaining of myiodesopsia was given a diagnosis of uveitis. Subsequently he complained facial nerve palsy and enlargement of parotid gland. Heerfordt's syndrome was diagnosed based on the results of several examinations. Facial nerve palsy, enlargement of the parotid gland and uveitis were improved by systemic corticosteroid therapy. At present he is receiving systemic corticosteroid therapy, but numbness in the mouth, thought to be the involvement of the trigeminal nerve, remains. Systemic corticosteroid therapy is usually effective for most cases with Heerford's syndrome. On the other hand, there are some cases with the prolonged peripheral nerve involvement despite systemic corticosteroid therapy, as seen in this case. If peripheral nerve involvement is prolonged, it is necessary to consider small-fibre neuropathy as one possible cause.     

Serum Levels of Free Insulin-Like Growth Factor (IGF)-I in Normal Children

Serum levels of free insulin-like growth factor (IGF)-I were measured by immunoradiometric assay (IRMA) in fasting sera of 137 normal boys and 120 normal girls aged from 8 to 15 yr to study relationships between free IGF-I levels and ages, total IGF-I, IGF binding protein (IGFBP)-1, IGFBP-3, and acid-labile subunit (ALS) levels. In both sexes, serum free IGF-I levels and the ratios of free IGF-I to total IGF-I were significantly higher in the pubertal age groups than in the prepubertal age groups. Serum levels of free IGF-I showed a significant positive correlation with those of total IGF-I, IGFBP-3 and ALS, while they showed a significant negative correlation with those of IGFBP-1. These observations suggest that increase in serum free IGF-I levels during puberty is caused by a dramatic increase in total IGF-I, rather than IGFBP-3, and a decrease in IGFBP-1. Also, high free IGF-I levels may play an important role in pubertal growth spurt.     

Antiproliferative effects of NKH477, a forskolin derivative, on cytokine profile in rat lung allografts.

OBJECTIVE: NKH477 was recently identified as a water-soluble forskolin derivative and was reported to prolong survival of murine cardiac allografts. However, the mechanism of the efficacy is not clear in vivo. The aim of this study was to investigate the immunosuppressive effects of NKH477 on acute lung allograft rejection in the rat model and its mechanism of action in vivo. METHODS: Left lungs were transplanted orthotopically from Brown-Norway donors to Lewis recipients. Recipient rats were untreated or treated daily with different doses of NKH477. Grafts were excised on Day 3 or Day 5 to determine histopathological rejection and expressions of interleukin (IL)-2, IL-4, IL-10, and interferon (IFN)-gamma by enzyme-linked immunosorbent assay. The cytokine expression at Day 3 or Day 5 was also evaluated in recipient spleens by immunohistochemistry. Furthermore, mesenteric lymph node cells from recipients at Day 5 were cultured alone or stimulated with donor antigens for 72 hours to determine cell proliferation by means of thymidine incorporation. RESULTS: NKH477 significantly extended allograft survival time in a dose-dependent manner and reduced histopathological rejection. Treatment with NKH477 inhibited IFN-gamma and IL-10 expression, whereas expression of these cytokines were markedly upregulated in the untreated allografts. Expression of IL-2 and IL-10 also increased in the spleen of untreated allorecipients. NKH477 suppressed expression of both cytokines in the spleen. In addition, lymphocyte proliferation was inhibited in NKH477-treated recipients as compared with untreated recipients. CONCLUSION: These results suggest that NKH477 exerts an antiproliferative effect on lymphocytes in vivo with an altered cytokine profile in rat recipients of lung allografts.     

Role of proteasomes in the formation of neurofilamentous inclusions in spinal motor neurons of aluminum‐treated rabbits

We examined the role of the 20S proteasome in pathologic changes, including abnormal aggregation of phosphorylated neurofilaments, of spinal motor nerve cells from aluminum‐treated rabbits. Immunohistochemistry for the 20S proteasome revealed that many lumbar spinal motor neurons without intracytoplasmic neurofilamentous inclusions or with small inclusions were more intensely stained in aluminum‐treated rabbits than in controls, whereas the immunoreactivity was greatly decreased in some enlarged neurons containing large neurofilamentous inclusions. Proteasome activity in whole spinal cord extracts was significantly increased in aluminum‐treated rabbits compared with controls. Furthermore, Western blot analysis indicated that the 20S proteasome degraded non‐phosphorylated high molecular weight neurofilament (neurofilament‐H) protein in vitro. These results suggest that aluminum does not inhibit 20S proteasome activity, and the 20S proteasome degrades neurofilament‐H protein. We propose that abnormal aggregation of phosphorylated neurofilaments is induced directly by aluminum, and is not induced by the proteasome inhibition in the aluminum‐treated rabbits. Proteasome activation might be involved in intracellular proteolysis, especially in the earlier stages of motor neuron degeneration in aluminum‐treated rabbits.     

Simulation for population analysis of Michaelis-Menten elimination kinetics

A simulation study was conducted to compare the cost and performance of various models for population analysis of the steady state pharmacokinetic data arising from a one-compartment model with Michaelis-Menten elimination. The usual Michaelis-Menten model (MM) and its variants provide no estimate of the volume of distribution, and generally give poor estimates of the maximal elimination rate and the Michaelis-Menten constant. The exact solution to the Michaelis-Menten differential equation (TRUE) requires a precise analysis method designed for estimation of population pharmacokinetic parameters (the first-order conditional estimation method) and also considerable computational time to estimate population mean parameters accurately. The one-compartment model with dose-dependent clearance (DDCL), in conjunction with the first-order conditional estimation or Laplacian method, ran approximately 20-fold faster than TRUE and gave accurate population mean parameters for a drug having a long biological half-life relative to the dosing interval. These findings suggest that the well-known MM and its variants should be used carefully for the analysis of blood concentrations of a drug with Michaelis-Menten elimination kinetics, and that TRUE, in conjunction with a precise analysis method, should be considered for estimating population pharmacokinetic parameters. In addition, DDCL is a promising alternative to TRUE with respect to computation time, when the dosing interval is short relative to the biological half-life of a drug. This work was supported in part by the Epilepsy Research Foundation, the Nakatomi Foundation, and a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan.     

The relation between EEG and mental development following cardiac surgery performed under simple deep hypothermia in children

In order to assess the accuracy of electroencephalography (EEG), in children who have undergone cardiac surgery under simple deep hypothermia, the relation between IQ or schoolwork achievement and the duration of circulatory arrest was investigated in 75 such children. Abnormal preoperative EEG's were found in 16 per cent of the children while abnormal postoperative EEG's were found in 17 per cent. The children were divided into 4 groups, according to pre- and postoperative EEG results. Schoolwork achievement scores ranged between 3.0 and 3.2, the difference among the groups being insignificant. Moreover, no significant shift in IQ was found among the groups. Finally, regarding the number of children who were able to go on to a higher level of education, including high school the college or university, again no significant differences were found among the 4 groups. In a comparison with the number of such children in neighboring Nagasaki prefecture able to continue on to a higher level of education, no significant differences were seen either. The findings and statistics of this investigation therefore indicate that pre- and postoperative EEG's are not always a reliable reference for assessing the prognosis of cerebral activity.     

Anaplastic ganglioglioma with sarcomatous component: An immunohistochemical study and molecular analysis of p53 tumor suppressor gene

The present case report describes a case of ganglioglioma with a distinct sarcomatous component in the left temporal lobe of a 59‐year‐old Japanese man. Neoplastic neuroglial tissue contained both benign and anaplastic glial components with a MIB‐1 labeling index of 0.1% and 12.0%, respectively. Sarcomatous tissue adjacent to the anaplastic glial tissue was dominated by pleomorphic fibroblastic cells with a MIB‐1 labeling index of 10.8%. They were immunoreactive for smooth muscle actin, type IV collagen, and alpha 1 antitrypsin, but not for desmin and CD34. Interestingly, some of the sarcomatous cells were double‐positive for smooth muscle actin and GFAP. The p53 protein had accumulated in the anaplastic astrocytes and sarcomatous cells, but direct DNA sequencing of PCR products failed to detect any mutation in the p53 gene (from exon 4 to exon 10).     

A Combination of Speckled Lentiginous Nevus with Patch-type Blue Nevus

A peculiar case of “nevus on nevus” was reported. A 67-year-old man had had a pigmented lesion in the left hypochondrial area since birth. The clinicopathologic findings of the pigmented lesion revealed a combination of speckled lentiginous nevus and patch-type blue nevus. This case of “nevus on nevus” is not described under the term of combined nevus as is current in the literature; it was considered to be a subtype of the type II atypical blue nevus described by Kawamura.     

A common FGFR3 mutation functions as a diagnostic marker for achondroplasia-group disorders in the Japanese population

Recent DNA studies performed by several groups have detected mutations of the gene encoding fibroblast growth factor receptor 3 (FGFR3) in patients with achondroplasia-group disorders, including achondroplasia (ACH), hypochondroplasia (HCH), and thanatophoric dysplasia (TD). For this study, we analyzed theFGFR3 gene in 31 Japanese patients with typical ACH, four with HCH, three with a condition intermediate between ACH and HCH (ACH/HCH-intermediate), and one with TD. Of the 31 typical ACH patients, 29 showed a G1138 to A transition and the other two a G1138 to C transversion, both resulting in a common Gly380Arg substitution in the transmembrane domain of FGFR3. The one TD and the four HCH patients did not display any mutations in the transmembrane domain of FGFR3. Of the three ACH/HCH-intermediate cases, one patient showed the Gly380Arg substitution and one did not, and further analysis of the second patient revealed the presence of Asn540Lys substitution. The first patient was, therefore, genotypically diagnosed as ACH and the second as HCH. Peripheral blood leukocyte DNA analysis in the remaining ACH/HCH-intermediate patient indicated an unequal ratio of mutant to normal PCR products, possibly representing a somatic mosaic for the Gly380Arg mutation. Analysis of the common FGFR3 mutation thus appears to help in the molecular diagnosis of patients with achondroplasia-group disorders.