Carnitine palmitoyltransferase deficiency in a patient with severe psychomotor retardation

A 13-year-old girl who had severe brain damage due to unknown prenatal cause presented rhabdomyolysis triggered by a mild viral infection. Her muscle biopsy revealed mild variation in fiber size and type 2 fiber atrophy without excess lipid storage. Biochemical analysis of the biopsied material showed decreased carnitine palmitoyltransferase (CPT) activity (15% of the control). Serum and urinary carnitine levels were normal. Skeletal muscle CT scanning showed multiple low density spots. The patient was diagnosed as having CPT deficiency. She recovered from rhabdomyolysis without renal failure after a month with conservative therapy. CPT deficiency is usually found in young healthy persons. This is the first case report of CPT deficiency which presented severe psychomotor retardation since neonatal period.     

Alterations of nuclear pores in preneoplastic and neoplastic rat liver lesions induced by 2-acetylaminofluorene

The nuclear pore density and area were measured on freeze-fracturednuclei of ACI/N rat liver altered foci, adenomas and carcinomasinduced by 2-acetylaminofluorene, and compared with those ofnormal hepatocytes. The pore density of nuclei from these preneoplasticand neoplastic lesions was significantly higher than that ofhepatocytes, but there was no difference between lesions. Thearea of nuclear pores of the focus cells did not differ fromnormal hepatocytes, whereas the areas of pores of adenoma andcarcinoma cells were increased. Moreover, the nuclear pore areaof carcinomas was significantly greater than that of adenomas.These results suggest that some changes may occur in nuclearpores in the progress of tumorigenesis.     

Bacteriological, pharmacokinetic and clinical studies on clarithromycin in the pediatric field. Pediatric Study Group of Clarithromycin

Clarithromycin (TE-031, A-56268), a new macrolide antibiotic agent, was evaluated bacteriologically and clinically for its efficacy and safety in pediatrics by a study group organized with pediatricians from all over the country. A summary of the results of the evaluation is as follows. 1. Absorption and excretion Pharmacokinetics of TE-031 was examined by single oral administration of 10% granules and 50 mg tablets at doses of 1, 5, 10 and 15 mg/kg. There were no significant differences between 10% granules and 50 mg tablets, and between administrations before and after meal. Peaks and half-life periods of blood level of TE-031 given once at doses of 5, 10 and 15 mg/kg (10% granules) before meal were 1.58, 4.37 and 3.79 micrograms/ml, and 2.53, 3.17 and 2.20 hours, respectively, and the urinary excretion in 6 hours after the administration were about 20-30%. 2. Antibacterial effects TE-031 was proved to have excellent antibacterial effect, i.e., inhibiting growth over 80% of strains of Streptococcus pneumoniae and Streptococcus pyogenes at 0.10 micrograms/ml, Branhamella catarrhalis at 0.39 micrograms/ml, and Campylobacter jejuni at 0.78 micrograms/ml. Against Staphylococcus aureus, TE-031 showed very similar activity spectrum to EM, and EM resistant strains were also resistant to TE-031. 3. Clinical results A total of 764 cases was studied. Clinical effects of TE-031 were evaluated in 717 cases out of the 764, excluding drop-outs and cases which did not meet specified protocols. Clinically, efficacies of TE-031 were "excellent" in 265 cases and "good" in 161 cases out of 453 cases of Group A in which causal agents were identified, with an efficacy rate of 94.0%, and out of 264 cases of Group B in which pathogens were not detected, clinical effects of TE-031 were "excellent" in 115 cases and "good" in 124 cases, with an efficacy rate of 90.5%. In terms of clinical effects of TE-031 classified by diseases when Group A and B were combined, efficacy rates were 91.6% for upper respiratory tract infection (217/237), 90.0% for bacterial pneumonia (108/120), 97.4% for Mycoplasma pneumonia (111/114), 100% for Chlamydia pneumonia (4/4), 85.0% for pertussis (34/40), 100% for scarlet fever (16/16), 83.9% for skin and soft tissue infection (26/31), and 98.9% for Campylobacter enteritis (87/88).(ABSTRACT TRUNCATED AT 400 WORDS)     

Reduction of tumorigenicity by an interferon-γ-gene-transduced tumor on another syngeneic tumor in a murine model

To evaluate the effect of interferon-γ-genetransduced cells, DS mice were inoculated into their footpads with syngeneic mammary adenocarcinoma SC42 admixed with interferon-γ producing mammary adenocarcinoma SC115Kγ, which had been established by an interferon-γ-gene transduction in another syngeneic mammary adenocarcinoma SC115 using retroviral vectors. These mice rejected both tumor cells and developed resistance to subsequent challenges with either SC115 or SC42 cells inoculated into their opposite posterior footpads. These results thus indicate that systemic immunological memory to each of the independent tumor cell lines developed in these mice. Although the SC42 cells admixed with irradiated SC115Kγ cells were rejected by these mice, the SC42 cells admixed with irradiated SC115neoR, in which the neo-gene had been transduced, were observed to proliferate. Tumor rejection was reversed by an in vivo administration of anti-interferon-γ antibody, thus suggesting that locally produced interferon-γ plays an important role in tumor elimination and immunological memory induction. In conclusion, interferon-γ-gene-transduced tumor cells are therefore considered to have a therapeutic potential for other types of malignant tumor cell lines.     

Roles of human CYP2A6 and 2B6 and rat CYP2C11 and 2B1 in the 10-hydroxylation of (-)-verbenone by liver microsomes.

(-)-Verbenone, a monoterpene bicyclic ketone, is a component of the essential oil from rosemary species such as Rosmarinus officinalis L., Verbena triphylla, and Eucalyptus globulus and is used for an herb tea, a spice, and a perfume. In this study, (-)-verbenone was found to be converted to 10-hydroxyverbenone by rat and human liver microsomal cytochrome p450 (p450) enzymes. The product formation was determined by high-performance liquid chromatography with UV detection at 251 nm. There was a good correlation between activities of coumarin 7-hydroxylation and (-)-verbenone 10-hydroxylation catalyzed by liver microsomes of 16 human samples, indicating that CYP2A6 is a principal enzyme in (-)-verbenone 10-hydroxylation in humans. Human recombinant CYP2A6 and CYP2B6 catalyzed (-)verbenone 10-hydroxylation at Vmax values of 15 and 21 nmol/min/nmol p450 with apparent Km values of 16 and 91 microM, respectively. In contrast, rat CYP2A1 and 2A2 did not catalyze (-)-verbenone 10-hydroxylation at all, suggesting that there were species-related differences in the catalytic properties of human and rat CYP2A enzymes in the metabolism of (-)-verbenone. In the rat, recombinant CYP2C11, CYP2B1, and CYP3A2 catalyzed (-)-verbenone 10-hydroxylation with Vmax and Km ratios (ml/min/nmol p450) of 0.73, 0.20, and 0.03, respectively. Male-specific CYP2C11 was a major enzyme in (-)-verbenone 10-hydroxylation by untreated rat livers, and CYP2B1 catalyzed this reaction in liver microsomes of phenobarbital-treated rats. Rat CYP2C12, a female-specific enzyme, did not catalyze (-)verbenone 10-hydroxylation. These results suggest that human CYP2A6 and rat CYP2C11 are the major catalysts in the metabolism of (-)-verbenone by liver microsomes and that there are species-related differences in human and rat CYP2A enzymes and sex-related differences in male and female rats in the metabolism of (-)-verbenone.     

Effects of skyrin, a receptor-selective glucagon antagonist, in rat and human hepatocytes

Peptidic glucagon antagonists have been shown to lower blood glucose levels in diabetic models (1-3), but attempts to identify small molecular weight glucagon receptor-binding antagonists have met with little success. Skyrin, a fungal bisanthroquinone, exhibits functional glucagon antagonism by uncoupling the glucagon receptor from adenylate cyclase activation in rat liver membranes (1). We have examined the effects of skyrin on cells transfected with the human glucagon receptor and on isolated rat and human hepatocytes. The skyrin used was isolated from Talaromyces wortmanni American Type Culture Collection 10517. In rat hepatocytes, skyrin (30 micromol/l) inhibited glucagon-stimulated cAMP production (53%) and glucose output (IC50 56 micromol/l). There was no detectable effect on epinephrine or glucagon-like peptide 1 (GLP-1) stimulation of these parameters, which demonstrates skyrin's selective activity. Skyrin was also evaluated in primary cultures of human hepatocytes. Unlike cell lines, which are largely unresponsive to glucagon, primary human hepatocytes exhibited glucagon-dependent cAMP production for 14 days in culture (EC50 10 nmol/l). Skyrin (10 micromol/l) markedly reduced glucagon-stimulated cAMP production (55%) and glycogenolysis (27%) in human hepatocytes. The inhibition of glucagon stimulation was a specific property displayed by skyrin and oxyskyrin but not shared by other bisanthroquinones. Skyrin is the first small molecular weight nonpeptidic agent demonstrated to interfere with the coupling of glucagon to adenylate cyclase independent of binding to the glucagon receptor. The data presented in this study indicate that functional uncoupling of the human glucagon receptor from cAMP production results in metabolic effects that could reduce hepatocyte glucose production and hence alleviate diabetic hyperglycemia.     

Mitogenicity and down-regulation of high-affinity interleukin 2 receptor by YTA-1 and YTA-2, monoclonal antibodies that recognize 75-kDa molecules on human large granular lymphocytes.

A large number of interleukin 2 receptors lacking the Tac epitope (IL-2R/p75) were found to be constitutively expressed on the human large granular lymphocyte/natural killer cell line YT, which bears inducible IL-2R/p55 associated with Tac antigen. Two anti-YT IgG1 monoclonal antibodies, YTA-1 and YTA-2, recognizing different epitopes of the same 75- to 80-kDa molecule, were established. The 75-kDa antigen recognized by these monoclonal antibodies was strongly expressed on the large granular lymphocytes of normal peripheral blood mononuclear cells and on various lymphoid cell lines bearing IL-2R/p75. The YTA-1 and YTA-2 antibodies were mitogenic and were different from other mitogenic monoclonal antibodies such as anti-T3 (CD3), anti-T11 (CD2), and KOLT-2 (CD28). Further, they down-regulated the high-affinity IL-2R of peripheral blood mononuclear cells within 24 hr in culture. The relationship between the YTA-1/2 antigen and the IL-2R system is discussed.