Delayed Enhancement of Acetaminophen Hepatotoxicity by General Anesthesia Using Diethyl Ether or Halothane

Delayed Enhancement of Acetaminophen Hepatotoxicity by GeneralAnesthesia Using Diethyl Ether or Halothane. WELLS, P. G., RAMJI,P., AND KU, M. S. W. (1986). Fundam. App. Toxicol 6, 299–306.Acetaminophen (Tylenol) is a widely used analgesic/antipyreticdrug which is enzymatically bioactivated, or toxified, by thecytochromes P-450 to a hepatotoxic reactive intermediary metabolite.Brief general anesthesia with diethyl ether has been shown toinhibit both the toxifying cytochromes P-450 and enzymatic glucuronidation,the latter constituting up to 60% of acetaminophen eliminationvia a nontoxifying pathway. Thus ether potentially could producea temporally differentiated inhibition of bioactivating and"detoxifying" pathways, resulting in an enhancement of acetaminophenhepatotoxicity if the balance favored bioactivation. To evaluatethis possibility, separate groups of male NIH strain mice weretreated with acetaminophen at different times after 5 min ofanesthesia with ether. Ether produced a 40-fold enhancementin acetaminophen hepatotoxicity as determined by plasma glutamic-pyruvictransaminase (GPT) concentrations. This toxicologic enhancementwas observed only if acetaminophen administration was delayed,with a maximal enhancement when acetaminophen was given 6 hrafter ether, and no effect with a delay of 16 hr. Similar studiesin male CD-1 mice were carried out using halothane (Fluothane)as the general anesthetic given either over 5 min or over 1hr. While halothane given over 5 min had no effect, a 1 hr anestheticduration produced a 10-fold increase in acetaminophen hepatotoxicityas determined by peak GPT concentration, with no observed hepatotoxicityin the halothane controls. Toxicologic enhancement occurredonly with delayed administration of acetaminophen; however,the maximal enhancement observed with a 6-hr delay was stillevident with a 12-hr delay. Conversely, inhibition of acetaminophenhepatotoxicity was observed if acetaminophen was given either2 hr or 18 hr after halothane. These observations may have clinicalrelevance, and they indicate potential complications in theinterpretation of results obtained from animals subjected togeneral anesthesia.     

Studies on Lymphocytes. II. The Production of Lymphocytosis by Intravenous Heparin in Calves

1. Intravenous commercial heparin produces a lymphocytosis in the calf.The effect is not due to the preservative commonly present in heparin.

2. The lymphocytosis is mediated to a great extent by an increased inputof lymphocytes into the blood via the thoracic duct.

3. The necessity of considering, plus controlling the heparin effect onblood lymphocyte levels and on the output of thoracic duct lymphocytes inall studies on lymphocyte production, migration and behavior, is discussedand emphasized.

Submitted on March 29, 1962 Accepted on June 25, 1962     

AN OVERVIEW OF PROGNOSTIC MARKERS IN BREAST CANCER

For many years axillary lymph nodes metastasis was the most important prognostic factor to predict the overall and disease free survival and guided the oncologists for institution of chemotherapy in breast cancer cases. However this factor alone or in combination with other parameters like, age of the patient, tumour size, histological type and tumour grade failed to predict the prognosis accurately in number of these cases. In pursuit to achieve the perfection, many new parameters which are biological or molecular in nature have been discovered. It is claimed that these factors not only have the capability to predict the prognosis but are also able to identify ‘high risk’ group of patients. However analysing all these parameters in a given case is not only cost prohibitive but also not essential. In order to solve this problem few important biological parameters have been reviewed, which are considered to cover all the important facets of the breast cancer. The parameters reviewed are ER, PR, S phase fraction, DNA ploidy, MIB-1 antibody, p53, C-erb-2, nm23, Cathepsin, Topoisomerase II alpha.KEY WORDS: Biological parameters, Breast cancer, ER and PR     

ENDOTHELIAL CELL CULTURE AND SEEDING OF PROSTHETIC VASCULAR GRAFTS: AN EXPERIMENTAL STUDY

Current synthetic vascular prostheses do not acquire lining of vascular endothelium in humans or dogs. Endothelial seeding of vascular grafts has been proposed as a means of reducing the thrombogenicity of these grafts. We examined feasibility of cultivating endothelial cells (EC) by tissue culture technique and their subsequent seeding onto small diameter polytetra fluoroethylene (PTFE) grafts. Twenty adult dogs underwent common carotid artery interposition with 4 mm PTFE grafts. Ten dogs received seeded and the remaining ten received unseeded grafts. Grafts were removed at 4 and 12 weeks and their gross/morphological features compared. Cumulative patency rates for seeded grafts were 70% as compared to unseeded ones 30%. Seeded grafts were completely surfaced with a mono-layer of endothelium by 4 weeks. Small graft patency appears to be related to the establishment of an endothelial surface, the development of which is clearly facilitated by seeding with autogenous endothelium.KEY WORDS: Endothelial cell seeding, Vascular grafts     

SO2对雄性小鼠睾丸组织的氧化损伤作用

目的了解SO2对哺乳动物和人雄性生殖系统有无氧化损伤作用,探讨SO2污染对生殖的影响.方法SO2染毒剂量分别为(22±2)mg/m3,(64±3)mg/m3,(148±23)mg/m3,采用SO2动态吸入实验技术,使昆明小鼠吸入不同浓度的SO2,每天染毒6 h,共7 d,染毒后,测定小鼠睾丸组织氧化损伤和抗氧化状态的变化.结果SO2吸入能够引起小鼠睾丸中GSH-Px、SOD和CAT酶活性改变,GSH含量减少,脂质过氧化产物丙二醛含量显著增高,并且随着SO2熏气浓度的升高,氧化损伤程度愈加严重.结论SO2可对雄性小鼠生殖系统产生损伤作用.     

Restoration of MHC Class I Surface Expression and Endogenous Antigen Presentation by a Molecular Chaperone

Presentation of cytosolic peptides in the context of major histocompatibility complex (MHC) class I antigen is crucial for immune recognition of virus-infected and malignant cells. This process, which is often defective in cancer cells, involves a series of cellular events which may be facilitated by heat shock proteins (molecular chaperones). To address the influence of chaperone function on the presentation of cytosolic peptides, we have utilized B16 melanoma cells (H-2^b). These tumour cells are resistant to lysis by MHC class I-restricted cytotoxic T lymphocytes (CTL), due to a very low level of surface MHC expression. The authors found that stably transfected clones of B16 expressing a heterologous heat shock protein (Hsp65) exhibit significantly increased levels of MHC class I antigens on their surface, and are effectively lysed by alloreactive CTL. These MHC class I molecules can form functional MHC-peptide complexes which are recognized by virus-specific CTL. Moreover, mice immunized with Hsp65-expressing tumour cells, but not with control-transfected tumour cells, display a significantly increased resistance to a subsequent challenge with live, wild-type B16. Together, these results indicate that the suitable expression of a molecular chaperone can overcome a defect in MHC class I expression and antigen presentation, and suggest a novel approach to cancer immunotherapy.     

THE ROLE OF HAEMOLYSIS IN NEONATAL HYPERBILIRUBINAEMIA AS REFLECTED IN CARBOXYHAEMOGLOBIN LEVELS

Abstract. Carboxyhaemoglobin levels were measured in 250 consecutive, normal, term newborns and in a group of 75 severely jaundiced infants in an effort to assess the role of haemolysis in non-specific neonatal hyperbilirubinaemia—"Physiologic jaundice"—as well as in severe jaundice of various etiologies. In normal newborns a significant correlation ( r =0.3293, p <0.001) was found between third-day carboxyhaemoglobin and serum bilirubin levels. Significant correlations were also found between the cord and third day values for carboxyhaemoglobin (infants of non-smoking mothers) for reticulocyte count, and for serum bilirubin. Third day haemoglobin showed no correlation with any of the other parameters including cord haemoglobin. Of the infants with third day carboxyhaemoglobin up to 0.75%, 1.7% had third day serum bilirubin values above 16.0 mg/100 ml. The corresponding percentage for the infants with carboxyhaemoglobin above 0.75% was 6.1%. It is concluded that increased rates of haemolysis due to as yet unspecified causes play an important role in the non-specific hyperbilirubinaemia of normal term newborns. As expected, high levels of carboxyhaemoglobin were found in infants with severe jaundice due to Rhesus and ABO haemolytic disease and glucose-6-phosphate dehydrogenase deficiency but also in jaundiced prematures and in Greek infants with severe jaundice of unknown cause.     

Hormone Profiles at High Altitude in Man

Altitude induced alterations in circulatory levels of PRL, LH, FSH and testosterone were studied in seven eugonadal men at sea level (SL), during their stay at high altitude (HA, 3500 m) and a week after return to SL. The mean plasma PRL level at SL was 5.83 +/- 1.7 SE ng/ml. On day one and seven of arrival at HA, the PRL values of 7.81 +/- 1.81 and 9.21 +/- 1.64 ng/ml respectively were not significantly different (p greater than 0.05) than the initial SL values. However, on day 18 of stay at HA, PRL levels were significantly increased (p less than 0.01) to 17.68 +/- 1.82 ng/ml and returned to initial SL values within seven days of return to SL. A significant decrease (p less than 0.01) in LH and testosterone was observed on seventh day of stay at HA and the decreased levels were maintained till day 18 of observations. Plasma testosterone returned to the initial SL values within a week of return to SL, whereas LH levels remained significantly lower (p less than 0.01). The FSH levels did not show any significant change during their stay at HA or after return to SL. These observations suggest that exposure to altitude is associated with hyperprolactenemia and an impaired pituitary gonadal function. The decreased levels of LH and testosterone at HA could either be due to hypoxic stress per se or secondary to altitude induced hyperprolactenemia.