Intravenous acetaminophen for the treatment of intrapartum fever and resolution of fetal tachycardia: a novel use for an old medication.

This case series demonstrates a potential new role for the use of intravenous (IV) acetaminophen. The authors reviewed two cases, whereby patients that developed intrapartum fever leading to fetal tachycardia were effectively treated with IV acetaminophen, leading to rapid reduction of maternal temperature and resolution of fetal tachycardia. Both patients had an uncomplicated vaginal delivery of healthy neonates. Intravenous acetaminophen, with its increased bioavailability and more rapid onset of action, may have benefit in the intrapartum setting by reducing adverse neonatal and maternal outcomes associated with febrile morbidity.

Factors affecting drug concentrations and QT interval during thioridazine therapy.

The objective of this study was to investigate factors affecting steady-state plasma concentrations of thioridazine. A cross-sectional study of patients receiving chronic thioridazine was employed. Common allelic variants of CYP2D6 and CYP2C19, as well as thioridazine and metabolite concentrations and QTc intervals, were determined. In 97 patients, dose-corrected plasma concentrations (C/Ds) of thioridazine and metabolites were correlated with age but not sex or CYP2C19 genotype. Patients with no functional CYP2D6 alleles (n=9) had significantly higher C/D for thioridazine (P=0.017) and the ring sulfoxide metabolite and a significantly higher thioridazine/mesoridazine ratio compared with those with >/=1 functional CYP2D6 allele (n=82). Smokers had significantly lower C/D for thioridazine, mesoridazine, and sulforidazine and significantly lower thioridazine/ring sulfoxide ratios than non-smokers. QTc interval was not significantly affected by CYP2D6 or CYP2C19 genotypes. Plasma concentrations of thioridazine are influenced by age, smoking, and CYP2D6 genotype, but CYP2D6 genotype does not appear to influence on-treatment QTc interval.

Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells.

CD44 is a multifunctional protein involved in cell adhesion and signaling. The role of CD44 in prostate cancer (PCa) development and progression is controversial with studies showing both tumor-promoting and tumor-inhibiting effects. Most of these studies have used bulk-cultured PCa cells or PCa tissues to carry out correlative or overexpression experiments. The key experiment using prospectively purified cells has not been carried out. Here we use FACS to obtain homogeneous CD44(+) and CD44(-) tumor cell populations from multiple PCa cell cultures as well as four xenograft tumors to compare their in vitro and in vivo tumor-associated properties. Our results reveal that the CD44(+) PCa cells are more proliferative, clonogenic, tumorigenic, and metastatic than the isogenic CD44(-) PCa cells. Subsequent molecular studies demonstrate that the CD44(+) PCa cells possess certain intrinsic properties of progenitor cells. First, BrdU pulse-chase experiments reveal that CD44(+) cells colocalize with a population of intermediate label-retaining cells. Second, CD44(+) PCa cells express higher mRNA levels of several 'stemness' genes including Oct-3/4, Bmi, beta-catenin, and SMO. Third, CD44(+) PCa cells can generate CD44(-) cells in vitro and in vivo. Fourth, CD44(+) PCa cells, which are AR(-), can differentiate into AR(+) tumor cells. Finally, a very small percentage of CD44(+) PCa cells appear to undergo asymmetric cell division in clonal analyses. Altogether, our results suggest that the CD44(+) PCa cell population is enriched in tumorigenic and metastatic progenitor cells.

Thioridazine and sudden unexplained death in psychiatric in-patients.

BACKGROUND: Sudden death has been linked to antipsychotic therapy, but the relative risk associated with specific drugs is unknown. AIMS: To assess the risk of sudden unexplained death associated with antipsychotic drug therapy and its relation to drug dose and individual agents. METHOD: A case-control study of psychiatric in-patients dying suddenly in five hospitals in the north-east of England and surviving controls matched for age, gender and mental disorder. Logistic regression analysis was used to identify significant risk factors, and odds ratios were calculated. RESULTS: Sixty-nine case-control clusters were identified. Probable sudden unexplained death was significantly associated with hypertension, ischaemic heart disease and current treatment with thioridazine (adjusted odds ratio=5.3, 95% CI 1.7-16.2, P=0.004). There was no significant association with other individual antipsychotic drugs. CONCLUSIONS: Thioridazine alone was associated with sudden unexplained death, the likely mechanism being drug-induced arrhythmia.

Laparoscopic removal of a transabdominal cervical cerclage.

Cervical incompetence has been acknowledged as a significant entity predisposing patients to second-trimester miscarriage. Various surgical techniques and approaches have been used in an attempt to prolong pregnancy and improve perinatal outcome. These include transvaginal and transabdominal cervical cerclage. Some patients require the placement of a transabdominal cervicoisthmic cerclage. Should the cerclage fail or the patient have preterm premature rupture of membranes, removal of the cerclage may be necessary. As a result the application of laparoscopy for the management of cervicoisthmic cerclage removal has been advocated in an effort to limit surgical complications. We report a case of laparoscopic removal of a transabdominally placed cervical cerclage in a 32-year-old woman at 16 weeks' gestation with preterm premature rupture of membranes and inevitable miscarriage. Laparoscopy appeared to be a safe and effective means of managing the removal of this transabdominally placed cervicoisthmic cerclage.

QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients.

BACKGROUND: Sudden unexplained death in psychiatric patients may be due to drug-induced arrhythmia, of which lengthening of the rate-corrected QT interval (QTc) on the electrocardiogram is a predictive marker. We estimated the point prevalence of QTc lengthening in psychiatric patients and the effects of various psychotropic drugs. METHODS: Electrocardiograms were obtained from 101 healthy reference individuals and 495 psychiatric patients in various inpatient and community settings and were analysed with a previously validated digitiser technique. Patients with and without QTc lengthening, QTc dispersion, and T-wave abnormality were compared by logistic regression to calculate odds ratios for predictive variables. FINDINGS: Abnormal QTc was defined from the healthy reference group as more than 456 ms and was present in 8% (40 of 495) of patients. Age over 65 years (odds ratio 3.0 [95% CI 1.1-8.3]), use of tricyclic antidepressants (4.4 [1.6-12.1]), thioridazine (5.4 [2.0-13.7]), and droperidol (6.7 [1.8-24.8]) were robust predictors of QTc lengthening, as was antipsychotic dose (high dose 5.3 [1.2-24.4]; very high dose 8.2 [1.5-43.6]). Abnormal QT dispersion or T-wave abnormalities were not significantly associated with antipsychotic treatment, but were associated with lithium therapy. INTERPRETATION: Antipsychotic drugs cause QTc lengthening in a dose-related manner. Risks are substantially higher for thioridazine and droperidol. These drugs may therefore confer an increased risk of drug-induced arrhythmia.

Argon beam coagulation in the management of placenta accreta.

BACKGROUND: Placenta accreta has been estimated to complicate approximately one in 2500 deliveries, resulting in significant morbidity and mortality. Conservative treatment of placenta accreta has been done in certain clinical situations when preservation of the uterus and further childbearing are desired. The Argon beam coagulator is an electrosurgical device used for hemostasis during various operations. We report its use in a case complicated by placenta accreta. CASE: A 33-year-old woman, gravida 2 para 1, with placenta accreta was treated with the Argon beam coagulator, and hemostasis was achieved in the lower uterine segment. CONCLUSION: In selected cases, the Argon beam coagulator can assist conservative treatment of placenta accreta.

Rapid depletion of plasma tryptophan: a review of studies and experimental methodology.

Evidence that the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) plays a role in the pathophysiology of mood disorders has been accumulating over the past three decades. Recent studies on this neurotransmitter have extended across the spectrum of psychiatric disorder, suggesting a role for 5-HT in psychosis, aggression, eating disorders and addiction. However, much of the evidence has come from post-mortem examination of the brain or measures of peripheral rather than central 5-HT function. The technique of tryptophan depletion allows investigation of brain 5-HT function in living subjects by examining the behavioural responses to this pharmacological challenge. This review considers the current status of tryptophan depletion as an experimental technique and discusses the implications of findings both in affective disorders and in a range of other psychiatric syndromes. MEDLINE and PSYCHLIT searches were completed for the years 1966 to November 1996 using the key words 'serotonin', '5-hydroxytryptamine', 'tryptophan' and 'depletion'. In addition relevant journals were hand-searched for the period from 1980 to December 1996. Forty-four double-blind studies in humans and three clinical case reports were identified; these cover a range of psychiatric disorders including mood disorders and psychoses, anxiety and eating disorders and specific behaviours such as appetite, aggression and craving. The studies reviewed utilized a variety of differing methodologies reducing the extent to which results can be generalized. A series of studies in depressed patients (before and after treatment with antidepressants) and their first-degree relatives have shown the importance of an intact 5-HT system in the action of antidepressants and offer new insights into the biology of affective disorder. The mood change induced by tryptophan depletion may predict those patients likely to respond to 5-HT-specific drugs. Rapid tryptophan depletion has also been reported to exacerbate both panic and aggression in vulnerable individuals. Effects in other disorders are conflicting and further research is needed to clarify these findings.

Atrial natriuretic factor and arginine vasopressin production in tumor cell lines from patients with lung cancer and their relationship to serum sodium.

Patients with lung cancer (n = 263) were studied to determine the relationship among ectopic production of atrial natriuretic factors (ANF) and arginine vasopressin (AVP), serum sodium, and patient outcome. Of 133, 21 (16%) patients with small cell lung cancer (SCLC) had hyponatremia (serum sodium, < 130 mmol/liter), compared to none of 130 (0%) patients with non-small cell lung cancer (P < 0.0001). Patients with extensive-stage SCLC and hyponatremia had shorter survival than patients with extensive stage SCLC and normal serum sodium values (P = 0.012). Of the 11 hyponatremic patients with SCLC and tumor cell lines available for study, 9 produced ANF mRNA, 7 of 11 produced AVP mRNA, and 5 of 11 produced both ANF mRNA and AVP mRNA. All 11 cell lines produced either ANF mRNA and ANF peptide or AVP mRNA and AVP peptide, or both. The quantity of AVP peptide in the tumor cell lines was more closely associated with hyponatremia in the patients (P = 0.0026, r2 = 0.28) than was the production of ANF peptide (P = 0.066, r2 = 0.12), although neither association was strong. All tumor cell lines studied from SCLC patients with hyponatremia produce ANF and/or AVP mRNA and peptides.

The tumorigenicity of 5-azacytidine in the male Fischer rat.

5-Azacytidine was administered to young adult male Fischer rats. Tumors were found in 31 out of 70 rats that had received 5-azacytidine and survived 18 months from the start of the experiment. Several rats had multiple primary tumors. In the rats that were tested for complete carcinogenicity a variety of tumor types was found. These included acute leukemia and malignant reticuloendotheliosis, and tumors of the testis, skin, and bronchus. No hepatic tumors were found in the group that was tested for hepatic tumor initiation. Hepatocellular carcinomas were found only in the group that was examined for hepatic tumor promotion by receiving a prior initiating dose of diethylnitrosamine. No tumors were found in the age controls. Thus, in these initial experiments, 5-azacytidine appeared to be a complete carcinogen, inducing tumors in several organs, and a tumor promoter but not a complete carcinogen for the liver.

The effect of 5-azacytidine and cytidine analogs onDrosophila melanogaster cells in culture.

The effects of cytidine and cytidine analogs were studied inDrosophila embryonic cell cultures and two wild-type established cell lines, Oregon-R and Schneider line 2. Primary embryonic cultures have been shown to be an excellent system for the study of embryonic development; a number of cell types undergo normal differentiation in vitro. Treatment of these cultures with putative teratogens resulted in an inhibition of muscle and/or neuron differentiation in our study. Treatment of these cells with cytidine and seven other analogs had no effect on neuron and muscle differentiation. The compound 5-azacytidine, when added to primary cell cultures, inhibited normal differentiation at subtoxic doses while inducing the production of three proteins that comigrate with the heat-shock proteins, hsp 23, 22a and 22b. 5-Azacytidine did not stimulate differentiation in Oregon-R or SchneiderDrosophila cell lines. The in vitro blockage of differentiation by 5-azacytidine suggests that it may act as a teratogen.

DNA methylation in mouse cells in culture as measured by restriction enzymes.

Methylation of DNA in normal mouse cultured 3T3 cells and in their virally or chemically transformed derivatives was studied. DNA methylation was studied by restriction with HpaII, MspI, or HpaII plus MspI. DNA from the chemically transformed cells was cleaved about twice as often with HpaII than was the DNA of normal and virally transformed cells. Digests with MspI and HpaII plus MspI were identical in all cell lines studied. Densitometry of the restriction patterns allowed an estimate of total DNA methylation from the weight average lengths. The chemically transformed cell line showed 25% reduction in methylation compared to the other cell lines. Southern blot hybridization using satellite DNA showed that these sequences followed a pattern of modification similar to that of total DNA.

Methylation of mouse ribosomal RNA genes.

Ribosomal DNA (rDNA) methylation was studied in various strains of mice. We used restriction enzymes that are sensitive to methylation and a cloned probe containing the transcribed spacer and part of the 18S and 28S gene. Strains C3H/He3, C57/B6-3, and AKR/J were found to have less than 9% of the rDNA methylated. In sharp contrast, Balb/c mice showed 30-50% of the Hpa II and Hha I sites to be methylated. Further study of the Balb/c DNA showed that there are three groups of rDNA sequences. In the first group, all the Hpa II and Hha I sites are almost completely unmethylated; in the second group these sites are all methylated (greater than 30 sites for each enzyme); in the third group most sites are methylated, but there are discrete hypomethylation sites. These hypomethylation positions are at similar sites for both Hpa II and Hha I and show a tissue-specific pattern. Comparison of AKR/J with Balb/c copy level showed that AKR/J had about 60% fewer rDNA genes. The rDNA methylation level might thus be correlated directly with the number of rDNA genes. Finally, analysis of F1 mice from a cross between Balb/c and AKR/J showed both low copy number and low methylation levels.

Double-stranded RNA in Drosophila melanogaster cultured cells.

Various cultured cell lines of Drosophila melanogaster contain 10 to 13 discrete double-stranded RNAs ranging in length from 1 to 4 kilobases. These RNAs were characterized by nuclease susceptibility, density, solubility in LiCl, thermostability, electron microscopy and gel electrophoresis. These RNAs, which are similar to Reo virus RNA could not be detected in adult or embryonic tissues.