Five-year changes in ovarian function restoration in premenopausal patients with breast cancer taking tamoxifen after chemotherapy: An ASTRRA study report.

BACKGROUND: Adding ovarian function suppression (OFS) after chemotherapy improves survival in young women with moderate- and high-risk breast cancer. Assessment of ovarian function restoration after chemotherapy becomes critical for subsequent endocrine treatment and addressing fertility issues. PATIENTS AND METHODS: In the adding OFS after chemotherapy trial, patients who resumed ovarian function up to 2 years after chemotherapy were randomised to receive either 5 years of tamoxifen or adding 2 years of OFS with tamoxifen. Ovarian function was evaluated from enrolment to randomisation, and patients who did not randomise because of amenorrhoea for 2 years received tamoxifen and were followed up for 5 years. Prospectively collected consecutive hormone levels (proportion of patients with premenopausal follicle-stimulating hormone [FSH] levels <30 mIU/mL and oestradiol [E2] levels ≥40 pg/mL) and history of menstruation were available for 1067 patients with breast cancer. RESULTS: Over 5 years of tamoxifen treatment, 69% of patients resumed menstruation and 98% and 74% of patients satisfied predefined ovarian function restoration as per serum FSH and E2 levels, respectively. Menstruation was restored in 91% of patients younger than 35 years at baseline, but in only 33% of 45-year-old patients over 5 years. Among these patients, 41% experienced menstruation restoration within 2 years after chemotherapy and 28% slowly restored menstruation after 2-5 years. Younger age (<35 years) at baseline, anthracycline without taxanes and ≤90 days of chemotherapy were predictors of menstruation restoration. CONCLUSIONS: During 5 years of tamoxifen treatment after chemotherapy, two-thirds of the patients experienced menstruation restoration, especially patients younger than 35 years. Young age, Adriamycin without taxanes and short duration of chemotherapy appeared to have a positive effect on ovarian reserves in the long term. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00912548.

The transcription factor Sp1 is responsible for aging-dependent altered nucleocytoplasmic trafficking.

Hyporesponsiveness to external signals, such as growth factors and apoptotic stimuli, is a cardinal feature of cellular senescence. We previously reported that an aging-dependent marked reduction in nucleocytoplasmic trafficking (NCT)-related genes could be responsible for this phenomenon. In searching for the mechanism, we identified the transcription factor, Sp1, as a common regulator of NCT genes, including various nucleoporins, importins, exportins, and Ran GTPase cycle-related genes. Sp1 knockdown led to a reduction of those genes in young human diploid fibroblast cells (HDF); Sp1 overexpression induced those genes in senescent cells. In addition, epidermal growth factor stimulation-induced p-ERK1/2 nuclear translocation and Elk-1 phosphorylation were severely impaired by Sp1 depletion in young HDFs; Sp1 overexpression restored the nuclear translocation of p-ERK1/2 in senescent HDFs. Furthermore, we observed that Sp1 protein levels were decreased in senescent cells, and H(2) O(2) treatment decreased Sp1 levels in a proteasome-dependent manner. In addition, O-GlcNAcylation of Sp1 was decreased in senescent cells as well as in H(2) O(2) -treated cells. Taken together, these results suggest that Sp1 could be a key regulator in the control of NCT genes and that reactive oxygen species-mediated alteration in Sp1 stability may be responsible for the generalized repression of those genes, leading to formation of the senescence-dependent functional nuclear barrier, resulting in subsequent hyporesponsiveness to external signals.

Prediction of high-grade squamous intraepithelial lesions using the modified Reid index.

BACKGROUND: Colposcopic grading provides an objective and meaningful guide to histologic severity and neoplastic progression of squamous intraepithelial lesions of the cervix. The objective of this study was to develop a more efficient and convenient method to overcome procedural complexities involved with the traditional Reid index in prediction of high-grade squamous intraepithelial lesion (HSIL). METHODS: The Reid index uses four colposcopic signs (margin, color, vessel, and iodine staining). The proposed modified Reid index system specifically incorporates the location of the lesion within the transformation zone in place of iodine staining. Three hundred women with suspected or abnormal cytologies or abnormal cervicographic findings were evaluated by colposcopy, directed biopsy, and HPV testing by the Hybrid Capture II method, which detects high-risk HPV DNA types. RESULTS: The sensitivity of high-risk HPV testing for detecting HSIL was 94.4%, the specificity was 65.0%, the positive predictive value was 75.5%, and the negative predictive value was 91.0%. The results of the colposcopic impression using the modified Reid index were superior to HPV testing. The sensitivity, specificity, positive predictive value, and negative predictive value of the colposcopic impression for detecting HSIL were 91.3, 92.9, 93.6, and 90.3% respectively. CONCLUSION: These results strongly indicate that the modified Reid index can accurately predict the histologic grade of squamous intraepithelial lesions of the cervix and can be applied easily and objectively in clinical practice without affecting the diagnostic accuracy of the traditional Reid index.

Alteration in metabolism and toxicity of acetaminophen upon repeated administration in rats.

Our previous studies showed that administration of a subtoxic dose of acetaminophen (APAP) to female rats increased generation of carbon monoxide from dichloromethane, a metabolic reaction catalyzed mainly by cytochrome P450 (CYP) 2E1. In this study we examined the changes in metabolism and toxicity of APAP upon repeated administration. An intraperitoneal dose of APAP (500 mg/kg) alone did not increase aspartate aminotransferase, alanine aminotransferase, or sorbitol dehydrogenase activity in serum, but was significantly hepatotoxic when the rats had been pretreated with an identical dose of APAP 18 h earlier. The concentrations and disappearance of APAP and its metabolites in plasma were monitored for 8 h after the treatment. APAP pretreatment reduced the elevation of APAP-sulfate, but increased APAP-cysteine concentrations in plasma. APAP or APAP-glucuronide concentrations were not altered. Administration of a single dose of APAP 18 h before sacrifice increased microsomal CYP activities measured with p-nitrophenol, p-nitroanisole, and aminopyrine as probes. Expression of CYP2E1, CYP3A, and CYP1A proteins in the liver was also elevated significantly. The results suggest that administration of APAP at a subtoxic dose may result in an induction of hepatic CYP enzymes, thereby altering metabolism and toxicological consequences of various chemical substances that are substrates for the same enzyme system.

Ipriflavone pharmacokinetics in mutant Nagase analbuminemic rats.

Ipriflavone, a derivative of naturally occurring isoflavones, was primarily metabolized in rats via hepatic CYP1A1/2 and 2C11. Protein and mRNA expression of CYP1A2 in the liver, reported to be increased in mutant Nagase analbuminemic rats (NARs), should influence the pharmacokinetic parameters of ipriflavone. In this study, the contribution of hepatic CYP2C11 and intestinal CYP1A protein to the metabolism and the pharmacokinetic parameters of ipriflavone were examined after intravenous (20 mg/kg) and oral (200 mg/kg) administration to male Sprague-Dawley (control) rats and NARs. There was no change in the protein expression of hepatic CYP2C11. By contrast, CYP1A protein of the intestine increased by almost 100%. After the intravenous administration of ipriflavone to NARs, the Cl(nr) and AUC were unchanged, suggesting that the contribution of the increase in protein expression and mRNA level of hepatic CYP1A2 to hepatic metabolism of the drug in NARs seemed to be almost negligible. However, after the oral administration of ipriflavone to NARs, the AUC was significantly lower than that in the control rats (53.0% decrease), possibly due to the increased intestinal CYP1A that resulted in increased intestinal metabolism and decreased gastrointestinal absorption of ipriflavone in NARs.

Faster clearance of omeprazole in mutant Nagase analbuminemic rats: possible roles of increased protein expression of hepatic CYP1A2 and lower plasma protein binding.

It is well known that there are various changes in the expression of hepatic and intestinal CYPs in mutant Nagase analbuminemic rats (NARs). It has been reported that the protein expression of hepatic CYP1A2 was increased, whereas that of hepatic CYP3A1 was not altered, and it was also found that the protein expression of the intestinal CYP1A subfamily significantly increased in NARs from our other study. In addition, in this study additional information about CYP changes in NARs was obtained; the protein expression of the hepatic CYP2D subfamily was not altered, but that of the intestinal CYP3A subfamily increased in NARs. Because omeprazole is metabolized via hepatic CYP1A1/2, 2D1, 3A1/2 in rats, it could be expected that the pharmacokinetics of omeprazole would be altered in NARs. After intravenous administration of omeprazole to NARs, the Cl(nr) was significantly faster than in the controls (110 versus 46.6 ml/min/kg), and this could be due to an increase in hepatic metabolism caused by a greater hepatic CYP1A2 level in addition to greater free fractions of the drug in NARs. After oral administration of omeprazole to NARs, the AUC was also significantly smaller (80.1% decrease) and F was decreased in NARs. This could be primarily due to increased hepatic and intestinal metabolism caused by greater hepatic CYP1A2 and intestinal CYP1A and 3A levels. In particular, the smaller F could mainly result from greater hepatic and intestinal first-pass effect in NARs than in the controls.

Abducens nerve palsy in pre-eclampsia after delivery: An unusual case report.

The common neurological manifestations of pre-eclampsia include headache, confusion, and visual disturbance; while isolated abducens nerve palsy in pre-eclampsia is very rare. We report one case of a severe pre-eclampsia with abducens nerve palsy at 39 weeks' gestation. There was no specific pathology, except hypertension, and the palsy resolved spontaneously.

Hepatic injury induces contrasting response in liver and kidney to chemicals that are metabolically activated: role of male sex hormone.

Injury to liver, resulting in loss of its normal physiological/biochemical functions, may adversely affect a secondary organ. We examined the response of the liver and kidney to chemical substances that require metabolic activation for their toxicities in mice with a preceding liver injury. Carbon tetrachloride treatment 24 h prior to a challenging dose of carbon tetrachloride or acetaminophen decreased the resulting hepatotoxicity both in male and female mice as determined by histopathological examination and increases in serum enzyme activities. In contrast, the renal toxicity of the challenging toxicants was elevated markedly in male, but not in female mice. Partial hepatectomy also induced similar changes in the hepatotoxicity and nephrotoxicity of a challenging toxicant, suggesting that the contrasting response of male liver and kidney was associated with the reduction of the hepatic metabolizing capacity. Carbon tetrachloride pretreatment or partial hepatectomy decreased the hepatic xenobiotic-metabolizing enzyme activities in both sexes but elevated the renal p-nitrophenol hydroxylase, p-nitroanisole O-demethylase and aminopyrine N-demethylase activities significantly only in male mice. Increases in Cyp2e1 and Cyp2b expression were also evident in male kidney. Castration of males or testosterone administration to females diminished the sex-related differences in the renal response to an acute liver injury. The results indicate that reduction of the hepatic metabolizing capacity induced by liver injury may render secondary target organs susceptible to chemical substances activated in these organs. This effect may be sex-specific. It is also suggested that an integrated approach should be taken for proper assessment of chemical hazards.

Contrasting changes in phase I and phase II metabolism of acetaminophen in male mice pretreated with carbon tetrachloride.

Effect of carbon tetrachloride (CCl(4)) pretreatment on the biotransformation and elimination of acetaminophen were examined in male mice. A 24 hr initial dose of CCl(4) (0.05 ml/kg, intraperitioneally) reduced the induction of hepatotoxicity resulting from acetaminophen treatment (350 mg/kg, intraperitoneally) as determined by changes in serum alanine and aspartate aminotransferase, and sorbitol dehydrogenase activities. Acetaminophen and the major metabolites in plasma were monitored for 12 hr following acetaminophen treatment. CCl(4) pretreatment decreased the plasma concentrations of acetaminophen-cysteine and acetaminophen-mercapturate, but acetaminophen-glucuronide and acetaminophen-sulfate were increased significantly. The elimination of the parent drug from plasma was not affected by CCl(4). In urine collected for 24 hr, the concentrations of acetaminophen-sulfate and acetaminophen-glucuronide were increased by 84% and 33%, respectively, whilst acetaminophen-cysteine and acetaminophen-mercapturate were reduced to approximately one third of control. Expression of cytochrome P450 (CYP) isozymes was determined using antibodies of 2E1 and 1A2 as probes. CYP2E1 and 1A2 expressions were decreased significantly by CCl(4). Likewise, CCl(4) treatment reduced the microsomal p-nitrophenol hydroxylase and p-nitroanisole O-demethylase activities to less than one third of control. The results indicate that, although CCl(4) reduces the generation of thioether conjugates of acetaminophen by decreasing the CYP activities, inhibition of the oxidative metabolism of acetaminophen is counterbalanced by the enhancement of conjugate formation via the glucuronide and sulfate pathways, resulting in elimination of the drug at a rate equivalent to that in normal mice. It is suggested that liver injury in patients may not warrant a mandatory reduction of drug doses extensively inactivated via phase II reactions.

A normative study of the CERAD neuropsychological assessment battery in the Korean elderly.

This study aimed to explore the effects of age, education and gender on the performance of eight tests in the Korean version of the CERAD neuropsychological assessment battery and to provide normative information on the tests in the Korean elderly. The battery was administered to 618 healthy volunteers aged from 60 to 90. People with serious neurological, medical and psychiatric disorders, including dementia, were excluded. Multiple linear regression analyses were performed to assess the relative contribution of the demographic factors on the score of each cognitive test. Age, education, and gender were found to have significant effects on the performance of many tests in the battery. Based on these results, 4 overlapping age normative tables (60 to 74, 65 to 79, 70 to 84, and 75 to 90 years of age) with 3 educational strata (0 to 3 years, 4 to 6 years, and 7 years and more) for both genders are presented. The normative information will be useful for a clinical interpretation of the CERAD neuropsychological battery in Korean elderly as well as for comparing the performance of the battery across countries.

Effect of age increase on metabolism and toxicity of ethanol in female rats.

Age-dependent change in the effects of acute ethanol administration on female rat liver was investigated. Female Sprague-Dawley rats, each aged 4, 12, or 50 weeks, received ethanol (2 g/kg) via a catheter inserted into a jugular vein. Ethanol elimination rate (EER), most rapid in the 4 weeks old rats, was decreased as the age advanced. Hepatic alcohol dehydrogenase activity was not altered by age, but microsomal p-nitrophenol hydroxylase activity was significantly greater in the 4 weeks old rats. Relative liver weight decreased with age increase in proportion to reduction of EER. Hepatic triglyceride and malondialdehyde concentrations increased spontaneously in the 50 weeks old nai;ve rats. Ethanol administration (3 g/kg, ip) elevated malondialdehyde and triglyceride contents only in the 4 and the 12 weeks old rats. Hepatic glutathione concentration was increasingly reduced by ethanol with age increase. Ethanol decreased cysteine concentration in the 4 weeks old rats, but elevated it significantly in the older rats. Inhibition of gamma-glutamylcysteine synthetase activity by ethanol was greater with age increase, which appeared to be responsible for the increase in hepatic cysteine. The results indicate that age does not affect the ethanol metabolizing capacity of female rat liver, but the overall ethanol metabolism is decreased in accordance with the reduction of relative liver size. Accordingly induction of acute alcoholic fatty liver is less significant in the old rats. However, progressively greater depletion of glutathione by ethanol in older rats suggests that susceptibility of liver to oxidative damage would be increased as animals grow old.

Development of the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease Assessment Packet (CERAD-K): clinical and neuropsychological assessment batteries.

A Korean version of the Consortium to Establish a Registry for Alzheimer's Disease Assessment Packet (CERAD-K) was created. The English-American version of CERAD clinical and neuropsychological assessment batteries was translated into Korean, and the psychometrical properties of the cognitive tests in the CERAD-K were established. In the translation, including back-translation, the basic structures of all measures in the original CERAD batteries were maintained. The CERAD-K was administered in a standardized manner to 106 dementia patients (aged 70.4 +/- 8.1 years), including 78 Alzheimer's disease (AD) patients, and 186 controls (aged 68.4 +/- 4.6 years) who were recruited from 3 university hospitals and 2 elderly welfare centers. The cognitive tests in the CERAD-K successfully differentiated controls from the dementia patients and from the AD patients. They also showed substantial interrater reliability and 1-month test-retest reliability. The CERAD-K is an equally reliable and valid equivalent for the English version of the CERAD clinical and neuropsychological assessment batteries.