A case of primary hypothyroidism with repeated episodes of respiratory failure

A case of repeated episodes of hypoventilatory respiratory failure accompanied with primary hypothyroidism was reported. A 76-year-old woman was admitted to our hospital due to both disturbance of consciousness and respiratory failure. A diagnosis of primary hypothyroidism complicated with hypoventilatory respiratory failure deterioration due to respiratory infection was made. Supplemental therapy of thyroid hormones improved her general condition, but respiratory failure recurred after interruption of a replacement drug. Cases of unexplained respiratory failure should be differentiated from respiratory failure induced by hypothyroidism.     

Induction of rat liver drug-metabolizing enzymes by tetrachloroethylene

The effect of tetrachloroethylene on Phase I and II drug-metabolizing enzymes in rat liver was examined. Rats were treated orally with tetrachloroethylene daily for five days, at doses of 125, 250, 500, 1,000 and 2,000 mg/kg. The higher doses (>500 mg/kg) of tetrachloroethylene induced the hepatic microsomal 7-pentoxyresorufin O-depentylase and 7-benzyloxyresorufin O-debenzylase activities associated with the CYP2B subfamily. 7-ethoxyresorufin O-deethylase activity was also induced about 2-fold compared with that of control rats at 500, 1,000, and 2,000 mg/kg dose levels of tetrachloroethylene. However, 7-ethoxycoumarin O-deethylase and 7-methoxyresorufin O-demethylase activities were increased significantly at only the 1,000 mg/kg dose level of tetrachloroethylene (1.4- and 1.5-fold). Although other cytochrome P450-mediated monooxygenase activities such as nitrosodimethylamine N-demethylase, aminopyrine N-demethylase and erythromycin N-demethylase were also induced by tetrachloroethylene, the relative induction to control activity was lower than those of 7-pentoxyresorufin O-depentylase and 7-benzyloxyresorufin O-debenzylase. Western immunoblotting showed that the levels of CYP2B1 and CYP2B2 proteins in liver microsomes were increased at doses of 1,000 and 2,000 mg/kg of tetrachloroethylene. In addition to cytochrome P450-mediated monooxygenases, there was significant induction of the Phase II drug-metabolizing enzymes, DT-diaphorase, glutathione S-transferase activities towards 1-chloro-2,4-dinitrobenzene and 1,2-dichloro-4-nitrobenzene, and UDP-glucuronyltransferase activities towards 4-nitrophenol and 7-hydroxycoumarin. The results indicate that tetrachloroethylene induces both Phase I (CYP2B-mediated monooxygenase) and Phase II drug-metabolizing enzymes (DT-diaphorase, glutathione S-transferase and UDP-glucuronyltransferase) in the rat liver.     

Are cerebrovascular factors involved in Alzheimer's disease?

Recent epidemiological studies have shown that vascular risk factors may be involved in Alzheimer's disease (AD) as well as dementia in general. To investigate the relation between a vascular disorder and AD pathology, current criteria are defective because most depend on exclusion of a cerebrovascular disorder. Epidemiological studies have indicated the possibilities that arteriosclerosis, abnormal blood pressure, diabetes mellitus and smoking may be related to the pathogenesis of AD. As for the mechanism that vascular disorders influence AD, it is presumed that amyloid deposition may be caused by a vascular disorder. Alternatively, a vascular event may cause progression of subclinical AD to a clinical stage. Insulin resistance and apolipoprotein E may also be involved in these mechanisms. Our studies show that ischemia-induced the Alzheimer-associated gene presenilin 1 (PS1) and endoplasmic reticulum-stress, generated from a vascular disorder, may unmask clinical AD symptoms caused by presenilin mutation, suggesting that a vascular factor might be involved in the onset of familial AD.     

Sperm morphological assessment based on strict criteria and in-vitro fertilization outcome.

One-hundred-and-twenty-three in-vitro fertilization (IVF) cycles were analysed in order to clarify the influence of strictly normal morphology (SNM) of spermatozoa on IVF outcome. SNM was defined using strict criteria according to Kruger with our modifications. The IVF cycles studied were divided into three groups: %SNM less than 12% (13 cycles), 12 less than 40% (68 cycles), greater than or equal to 40% (42 cycles). The cleavage rates per oocyte were higher in the groups with 12-40% and greater than or equal to 40% of %SNM than in the group with %SNM less than 12%. The embryo transfer rate per cycle increased with increasing %SNM. The overall pregnancy rate per cycle increased with increasing %SNM (7.7% in %SNM less than 12%, 22.1% in 12-40% of %SNM, and 40.5% in %SNM greater than or equal to 40%). The ongoing pregnancy rate per cycle also increased with increasing %SNM (7.7% in %SNM less than 12%, 14.7% in 12-40% of %SNM, and 31.0% in %SNM greater than or equal to 40%). The miscarriage rate was lower in %SNM greater than or equal to 40% (23.5%) than in 12-40% of %SNM (33.3%). It was suggested that %SNM is a good predictor of IVF outcome.     

Developmental switch from GABA to glycine release in single central synaptic terminals

Early in postnatal development, inhibitory inputs to rat lateral superior olive (LSO) neurons change from releasing predominantly GABA to releasing predominantly glycine into the synapse. Here we show that spontaneous miniature inhibitory postsynaptic currents (mIPSCs) also change from GABAergic to glycinergic over the first two postnatal weeks. Many 'mixed' mIPSCs, resulting from co-release of glycine and GABA from the same vesicles, are seen during this transition. Immunohistochemistry showed that a large number of terminals contained both GABA and glycine at postnatal day 8 (P8). By P14, both the content of GABA in these mixed terminals and the contribution of GABA to the mixed mIPSCs had decreased. The content of glycine in terminals increased over the same period. Our results indicate that switching from GABAergic to glycinergic inputs to the LSO may occur at the level of a single presynaptic terminal. This demonstrates a new form of developmental plasticity at the level of a single central synapse.     

A HhaI/BstUI polymorphism in a novel gene at human chromosome 11p15.5

We found a HhaI/BstUI polymorphism in the 3′ untranslated region of a novel gene which was localized to 11p15.5. This region is one of prominent imprinting domains and contains multiple imprinted genes, such as H19, IGF2 , KVLQT1, and p57 ^KIP2 , which suggests that regional factors might contribute to the imprinting. This polymorphism will be useful in the allelic analysis of expression and methylation of the novel gene. Received: July 24, 1998 / Accepted: July 29, 1998     

Molecular targeting for epidermal growth factor receptor expressed on breast cancer cells by human fusion protein

Recombinant human ribonuclease 1 (RNasel) was chemically linked to recombinant human epidermal growth factor (EGF). The cytotoxicity of this conjugate was assayed using MTT assay. The EGF-RNase conjugate showed dose-dependent cytotoxicity against breast and squamous cell carcinomas overexpressing the EGF receptor (EGFR). The cytotoxicity of the conjugate correlated positively with the level of EGFR expression by each cell line. These results suggest that the EGF-RNase conjugate is a more effective anticancer agent with less immunogenicity and toxicity than conventional chimeric breast cancer toxins.     

Inhibition of rat hepatic cytochrome P450 activities by biodegradation products of 4-tert-octylphenol ethoxylate.

1. The effects of some biodegradation products of 4-tert-octylphenol ethoxylate (OPEO), namely 4-tert-octylphenol (OP), 4-tert-octylphenol diethoxylate (OP2EO) and 4-tert-octylphenol monocarboxylate (OPIEC) on the kinetics of cytochrome P450 (P450) -dependent monooxygenases in rat liver microsomes have been studied. 2. Testosterone 16beta-hydroxylase (TS16BH), testosterone 2alpha-hydroxylase (TS2AH) and testosterone 6beta-hydroxylase (TS6BH) activities were extensively inhibited by OP at 100 microM (56.0-90.3%). Inhibition was competitive for all P450-dependent monooxygenases. Ki(s) of TS16BH, TS2AH and TS6BH from Lineweaver-Burk plots were 6.37, 3.38 and 34.8 microM respectively. 3. The activities of acetanilide 4-hydroxylase (AA4H), 7-ethoxycoumarin O-deethylase (ECOD) and bufuralol 1'-hydroxylase (BF1'H) were also effectively inhibited by OP at 100 microM (48.6-56.0%). The inhibition of these P450-dependent monooxygenases was non-competitive, and Ki(s) (50.1-63.90 microM) were higher than those of TS16BH, TS2AH and TS6BH. 4. OP2EO also inhibited AA4H, ECOD, TS16BH, TS2AH, BF1'H and TS6BH activities by 38.7-69.3% at 100 microM, although the inhibition rates were slightly lower than those for OP. K(i)s were 14.4-106 microM, and the inhibition was of mixed type (AA4H and ECOD), competitive (TS16BH, TS2AH and TS6BH) and non-competitive (BF1'H). 5. Testosterone 7alpha-hydroxylase (TS7AH), 4-nitrophenol 2-hydroxylase (4NP2H) and lauric acid omega-hydroxylase (LAOH) activities were only slightly affected by OP and OP2EO. 6. The ability of OP1EC to inhibit P450-dependent monooxygenase activities was generally weaker than that of OP and of OP2EO: Ki >200 microM. 7. These results suggest that OPEO biodegradation products interact with constitutive P450 isoforms, CYP1A2, CYP2A2, CYP2B2, CYP2C11 and CYP3A2 in rat liver in vitro (OP > OP2EO > OP1EC), and that the mechanism of this interaction differs depending on the compound and P450 isoform.