Cardiac pathology associated with high sustained +Gz: I. Subendocardial hemorrhage

Adult miniature swine were exposed to various levels and durations of +Gz. After exposure, all swine were euthanized and necropsied. Gross, histologic, and electronmicroscopic observations were made on the heart tissue. Subendocaridal hemorrhage (SEH) was commonly found in the left ventricle, rarely in the right ventricle, and its severity was directly related to : a) level and duration of G exposure, b) heart rate, and c) catecholamine activity. SEH was made more severe with i.v. atropine 4 mg, and prevented with i.v. propranolol 20 mg. Heart hemorrhage was usually limited to the immediate subendocardial region and frequently surrounded Purkinje's fibers. In severe cases, however, hemorrhages penetrated several millimeters into the heart muscle and sometimes penetrated Purkinje's fibers. Restraint of unanesthetized swine in the centrifuge couch, low G-levels, and/or i.v. injections of atropine or epinephrine produced minimal SEH lesions.     

A fatal drug interaction between clozapine and fluoxetine

A case is presented of a fatal drug interaction caused by ingestion of clozapine (Clozaril) and fluoxetine (Prozac). Clozapine is a tricyclic dibenzodiazepine derivative used as an "atypical antipsychotic" in the treatment of severe paranoid schizophrenia. Fluoxetine is a selective serotonin reuptake inhibitor used for the treatment of major depression. Clinical studies have proven that concomitant administration of fluoxetine and clozapine produces increased plasma concentrations of clozapine and enhances clozapine's pharmacological effects due to suspected inhibition of clozapine metabolism by fluoxetine. Blood, gastric, and urine specimens were analyzed for fluoxetine by gas chromatography/mass spectrometry (GC/MS) and for clozapine by gas-liquid chromatography (GLC). Clozapine concentrations were: plasma, 4.9 micrograms/mL; gastric contents, 265 mg; and urine, 51.5 micrograms/mL. Fluoxetine concentrations were: blood, 0.7 microgram/mL; gastric contents, 3.7 mg; and urine 1.6 micrograms/mL. Norfluoxetine concentrations were: blood, 0.6 microgram/mL, and none detected in the gastric contents or urine. Analysis of the biological specimens for other drugs revealed the presence of ethanol (blood, 35 mg/dL; vitreous, 56 mg/dL; and urine 153 mg/dL) and caffeine (present in all specimens). The combination of these drugs produced lethal concentrations of clozapine and high therapeutic to toxic concentrations of fluoxetine. The deceased had pulmonary edema, visceral vascular congestion, paralytic ileus, gastroenteritis and eosinophilia. These conditions are associated with clozapine toxicity. The combined central nervous system, respiratory and cardiovascular depression of these drugs was sufficient to cause death. The death was determined to be a clozapine overdose due to a fatal drug interaction.     

Intron "sliding" and the diversity of intron positions

Alignments of homologous genes typically reveal a great diversity of intron locations, far more than could fit comfortably in a single gene. Thus, a minority of these intron positions could be inherited from a single ancestral gene, but the larger share must be attributed to subsequent events of intron gain or intron "sliding" (movement from one position to another within a gene). Intron sliding has been argued from cases of discordant introns and from putative spatial clustering of intron positions. A list of 32 cases of discordant introns is presented here. Most of these cases are found to be artefactual. The spatial and phylogenetic distributions of intron positions from five published compilations of gene data, comprising 205 intron positions, have been examined systematically for evidence of intron sliding. The results suggest that sliding, if it occurs at all, has contributed little to the diversity of intron positions.     

Chromosomal instability and its relationship to other end points of genomic instability

Chromosomal destabilization is one end point of the more general phenomenon of genomic instability. We previously established that chromosomal instability can manifest in clones derived from single progenitor cells several generations after X-irradiation. To understand the potential relationship between chromosomal destabilization and the other end points of genomic instability, we generated a series of chromosomally stable and unstable clones by exposure to X-rays. All clones were derived from the human-hamster hybrid line GM10115, which contains a single copy of human chromosome 4 in a background of 20-24 hamster chromosomes. These clones were then subjected to a series of assays to determine whether chromosomal instability is associated with a general "mutator phenotype" and whether it modulates other end points of genomic instability. Thus, we analyzed clones for sister chromatid exchange, delayed reproductive cell death, delayed mutation, mismatch repair, and delayed gene amplification. Statistical analyses performed on each group of chromosomally stable and unstable clones indicated that, although individual clones within each group were significantly different from unirradiated clones for many of the end points, there was no significant correlation between chromosomal instability and sister chromatid exchange, delayed mutation, and mismatch repair. Delayed gene amplification was found to be marginally correlated to chromosomal instability (P < 0.1), and delayed reproductive cell death (the persistent reduction in plating efficiency after irradiation) was found to be significantly correlated (P < 0.05). These correlations may be explained by chromosomal destabilization, which can mediate gene amplification and can result in cellular lethality. These data implicate multiple molecular and genetic pathways leading to different manifestations of genomic instability in GM10115 cells surviving exposure to DNA-damaging agents.     

Serendipity in diagnostic imaging: magnetic resonance imaging of the breast

BACKGROUND: Magnetic resonance imaging (MRI) of the breast has been proposed as a noninvasive diagnostic test for evaluation of suspicious ("index") lesions noted on mammography and/or clinical breast examination (CBE). However, women may have incidental ("serendipitous") lesions detected by MRI that are not found on mammography or CBE. To understand better whether or not biopsy procedures should be performed to evaluate serendipitous lesions, we estimated the breast cancer risk for women with this type of lesion. METHODS: A decision analysis model was used to estimate the positive predictive value (i.e., the chance that a woman with a serendipitous lesion has cancer) of MRI for serendipitous lesions in women who had an abnormal mammogram and/or CBE suspicious for cancer (where a biopsy procedure is recommended). We restricted the analysis to data from women whose index lesions were noncancerous and used meta-analysis of published medical literature to determine the likelihood ratios (measures of how test results change the probability of having cancer) for MRI and the combination of CBE and mammography. The positive predictive value of MRI was calculated using the U.S. population prevalence of cancer (derived from registry data) and the likelihood ratios of the diagnostic tests. RESULTS: Under a wide variety of assumptions, the positive predictive value of MRI was extremely low for serendipitous lesions. For instance, assuming sensitivity and specificity values for MRI of 95.6% and 68.6%, respectively, approximately four of 1000 55- to 59-year-old women with serendipitous lesions would be expected to have cancer (positive predictive value = 0.44%, 95% confidence interval = 0.24%-0.67%). CONCLUSION: In women with a suspicious lesion discovered by mammography and/or CBE that is found to be benign, serendipitous breast lesions detected by MRI are extremely unlikely to represent invasive breast cancer. Immediate biopsy of such serendipitous lesions may, therefore, not be required.     

Pulse-to-pulse polarization-switching method for high-repetition-rate lasers

We report a method that enables dynamic switching of the pulse-to-pulse linear polarization orientation of a high-pulse-rate laser. The implications for laser micromachining, where polarization direction can be important, are also discussed.