Mutations of ras protooncogenes and p53 tumor suppressor gene in cardiac hemangiosarcomas from B6C3F1 mice exposed to 1,3-butadiene for 2 years

1,3-Butadiene is a multisite carcinogen in rodents. Incidences of cardiac hemangiosarcomas were significantly increased in male and female B6C3F1 mice that inhaled 1,3-butadiene (BD) for 2 years. Eleven BD-induced cardiac hemangiosarcomas were examined for genetic alterations in ras protooncogenes and in the p53 tumor suppressor gene. Nine of 11 (82%) BD-induced hemangiosarcomas had K-ras mutations and 5 of 11 (46%) had H-ras mutations. All of the K-ras mutations were G-->C transversions (GGC-->CGC) at codon 13; this pattern is consistent with reported results in BD-induced lung neoplasms and lymphomas. Both K-ras codon 13 CGC mutations and H-ras codon 61 CGA mutations were detected in 5 of 9 (56%) hemangiosarcomas. The 11 hemangiosarcomas stained positive for p53 protein by immunohistochemistry and were analyzed for p53 mutations using cycle sequencing of polymerase chain reaction (PCR) amplified DNA isolated from paraffin-embedded sections. Mutations in exons 5 to 8 of the p53 gene were identified in 5 of 11 (46%) hemangiosarcomas, and all of these were from the 200- or 625-ppm exposure groups that also had K-ras codon 13 CGC mutations. Our data indicate that K-ras, H-ras, and p53 mutations in these hemangiosarcomas most likely occurred as a result of the genotoxic effects of BD and that these mutations may play a role in the pathogenesis of BD-induced cardiac hemangiosarcomas in the B6C3F1 mouse.     

Contribution of magnetic resonance microscopy in the 12-week neurotoxicity evaluation of carbonyl sulfide in Fischer 344 rats

In this carbonyl sulfide (COS) study, magnetic resonance microscopy (MRM) and detailed light microscopic evaluation effectively functioned in parallel to assure that the distribution and degree of pathology in the brain was accurately represented. MRM is a powerful imaging modality that allows for excellent identification of neuroanatomical structures coupled with the ability to acquire 200 or more cross-sectional images of the brain, and the ability to display them in multiple planes. F344 rats were exposed to 200-600 ppm COS for up to 12 weeks. Prior to MRM, rats were anesthetized and cardiac perfused with McDowell Trump's fixative containing a gadolinium MR contrast medium. Fixed specimens were scanned at the Duke Center for In Vivo Microscopy on a 9.4 Tesla magnetic resonance system adapted explicitly for microscopic imaging. An advantage of MRM in this study was the ability to identify lesions in rats that appeared clinically normal prior to sacrifice and the opportunity to identify lesions in areas of the brain which would not be included in conventional studies. Other advantages include the ability to examine the brain in multiple planes (transverse, dorsal, sagittal) and obtain and save the MRM images in a digital format that allows for postexperimental data processing and manipulation. MRM images were correlated with neuroanatomical and neuropathological findings. All suspected MRM images were compared to corresponding H&E slides. An important aspect of this study was that MRM was critical in defining our strategy for sectioning the brain, and for designing mechanistic studies (cytochrome oxidase evaluations) and functional assessments (electrophysiology studies) on specifically targeted anatomical sites following COS exposure.     

Mental Health of Mothers of Children with Juvenile Rheumatoid Arthritis: Appraisal as a Mediator

Examined direct and mediated relations between condition parametersand maternal mental health for 53 mothers of 2- to 11-year-oldchildren with juvenile rheumatoid arthritis (JRA). Multivariateanalyses revealed that when considered simultaneously, indicesof both biological severity and functional severity were associatedsignificantly with maternal mental health. Further, mother'sappraisals of the impact of the child's illness on the familypartially mediated the effects of medication type and child'sfunctional status on mother's mental health. Results providesupport for conceptual models that emphasize the cognitive mechanismsby which condition parameters such as biological and functionalseverity might affect maternal mental health. Explicating theprocesses by which a child's JRA might lead to psychologicaladjustment problems in the parent has implications for developingpreventive and treatment interventions.     

Acute fluoxetine treatment potentiates amphetamine hyperactivity and amphetamine-induced nucleus accumbens dopamine release: possible pharmacokinetic interaction

Amphetamine stimulates locomotor activity, in large part by activating central dopaminergic systems. Serotonin shares on overlapping distribution with dopamine and has been shown to modulate dopaminergic function and dopamine-mediated behaviors. The present study examined whether increasing serotonergic function, via the selective serotonin reuptake inhibitor fluoxetine, would alter the stimulatory effects of amphetamine on locomotor activity and dopamine overflow in the nucleus accumbens. In addition, the present study determined whether fluoxetine treatment would alter the metabolism of amphetamine. Results show that 5.0 mg/kg fluoxetine potentiated the locomotor activity induced by amphetamine (0.5–1.0 mg/ kg), and enhanced the increased dopamine overflow in the nucleus accumbens induced by amphetamine. Fluoxetine treatment also resulted in a higher concentration of amphetamine in the CNS. Together, these findings indicate that acute fluoxetine treatment potentiates the locomotor stimulating and dopamine activating effects of amphetamine. Further, the results indicate that fluoxetine potentiates the effects of amphetamine by decreasing the metabolism of amphetamine, probably through inhibition of cytochrome P450 isozymes. Received: 5 May 1998/Final version: 7 July 1998     

Plasma fibronectin levels in meningococcal disease

Fibronectin (a glycoprotein which modulates inflammation) may decrease mortality in systemic infection. Children with meningococcal disease (MCD) may have low fibronectin levels. We aimed to compare plasma fibronectin levels in children with MCD and controls, correlate fibronectin levels with interleukin-6 (IL-6), shock and death, and assess fibronectin as an aid to early diagnosis in MCD. Samples were taken on admission from 99 children with MCD and 49 controls. Plasma fibronectin was measured using a turbidimetric immunoassay. Plasma fibronectin was significantly lower in MCD compared to controls (57 μg/ml vs 105 μg/ml; P < 0.005). Children who died had significantly lower levels than survivors (29 μg/ml vs 62 μg/ml; P = 0.01). Fibronectin levels were negatively correlated with IL-6 levels. Fibronectin was a poor predictor of MCD. Conclusion Plasma fibronectin levels are decreased in children with MCD, especially in shock and death. This decrease is associated with high IL-6 levels. Fibronectin could be a novel therapy in severe MCD. Received: 6 June 1996 / Accepted: 16 October 1996     

Cranio-osteoarthropathy in sibs

Primary hypertrophic osteoarthropathy is a condition characterized by clubbing, arthropathy and periostosis of long tubular bones. Three variants of primary hypertrophic osteoarthropathy are distinguished: pachydermoperiostosis, which shows as additional symptom pachydermia; cranio-osteoarthropathy, which has a decreased neurocranium ossification as additional feature; and a secondary form. Primary hypertrophic osteoarthropathy is also genetically heterogeneous, with evidence for both autosomal dominant and autosomal recessive inheritance. We describe two sibs with cranio-osteoarthropathy and briefly review previously reported cases. The present cases demonstrate the phenotypic variability of the condition. The consanguinity in the present family and analysis of previously described cases support autosomal recessive inheritance for cranio-osteoarthropathy.     

Contrasting selected reproductive challenges of today with those of antiquity—the past is prologue

Viewing human history through a medical lens provides a renewed appreciation for today’s vexing reproductive challenges, as some modern dilemmas are actually continuations of similar challenges experienced long ago. Certainly there are many examples of assisted fertility therapy that were entirely theoretical only a generation ago, but have become commonplace in modern practice and society. In particular posthumous birth and infertility have, over time, been the focus of compelling social interest, occasionally even impacting national security and dynastic succession. While the concepts have remained static, the tools available to extend and improve reproductive success have changed radically. Appropriately regarded as confidential and private, an individual’s reproductive details are typically impervious to formal study. Yet, archival sources including ancient literature and formal court records can occasionally provide evidence of otherwise deeply personal concerns of a different era. Our assessment finds the issues, worries, and desires of patients of antiquity to align closely with contemporary reproductive challenges. Because children and family have always been central to the human experience, the consequences of reproduction (or the lack thereof) can make substantial imprints upon the cultural, economic, and political landscape—irrespective of civilization or century. In this article, selected motifs are described in a broad historical context to illustrate how challenges of human reproduction have remained essentially unchanged, despite a vast accumulation of knowledge made possible by gains in reproductive science and technology.Plus ça change, plus c’est la même chose.-Jean-Baptiste Alphonse Karr (1808–1890)