Biomedical subjects
Publications and source records attributed to M G O'Sullivan.
Intramedullary capillary haemangioma is extremely rare and only four cases have been previously reported. We describe a further case, outlining the clinical, radiological, surgical and pathological features.
Patients in poor grade (WFNS IV and V) after aneurysmal subarachnoid hemorrhage (SAH) often have a bad outcome. To evaluate early GDC embolisation on such patients a prospective observational study, with comparison to a historical cohort was performed. From January 1996 to December 1998 113 patients were admitted to the Department of Clinical Neurosciences in poor grade after SAH (45 WFNS IV and 68 WFNS V). Eighty-one patients were managed actively with endovascular occlusion of the aneurysm (n = 42) where possible and delayed clipping (n = 16) where not. On an intention to treat basis, 46% had a favourable outcome (Glasgow Outcome Score IV or V) and 48% had died by 3 months. Compared to an historical cohort managed in the same unit between 1992 and 1995 (n = 62, 52% favourable outcome) these results suggest that early GDC aneurysmal occlusion has had a minimal impact on overall outcome.
The objective of the investigation was to report on the health-related quality of life (HRQoL) of patients diagnosed with skull base tumours using the Short Form Health Survey questionnaire (SF-36). Those patients suffering with vestibular schwannoma were examined to determine the effect facial nerve function had on their quality of life. It took place at the tertiary referral centre at the Department of Clinical Neurosciences, Western General Hospital, Edinburgh. A prospective study of 70 consecutive patients was taken, who harboured the following tumours: 54 vestibular schwannomas, 13 meningiomas, two haemangioblastomas and one hypoglossal schwannoma. Patients were interviewed using the short form 36 (SF-36) questionnaire. Facial nerve function was assessed in those patients who had vestibular schwannomas. The entire cohort of live skull base patients were assessed after a median follow-up time of 38.4 months. Patients with vestibular schwannoma treated conservatively with interval MRI had a quality of life similar to t he normal population. Those who underwent surgery had a significant difference in two of the SF-36 domains. No statistically significant correlation was found at final assessment between the degree of facial nerve functioning and any of the domains of SF-36. Patients with non-vestibular tumours had an impaired HRQoL in seven of the eight domains. Patients with skull base tumours have a significant impairment of their HRQoL. A conservative policy of follow up with interval MRI for patients with small vestibular schwannomas may therefore be more appropriate to preserve their HRQoL. Facial nerve outcome has little influence on quality of life in vestibular schwannoma patients.
Solid haemangioblastomas can be difficult to treat surgically because of their hypervascularity and requirement for circumferential dissection. We report two cases of large solid cerebellopontine angle haemangioblastomas that were safely resected utilizing wide transtemporal posterolateral skull-base exposures. In both cases, good tumour exposure was achieved with trans-cochlear approaches and division of the sigmoid sinus. These were large tumours and we felt that the added complexity of the approach was justified by providing panoramic exposure to allow safe resection.
We hypothesized that the atheroinhibitory and cardioprotective effects of estrogen may be mediated in part through increased prostacyclin formation by the artery wall. Atherosclerotic abdominal aorta was collected at necropsy from ovariectomized female monkeys fed an atherogenic diet alone or with added Premarin. Basal and arachidonate-stimulated prostacyclin and thromboxane synthesis by artery segments was measured by radioimmunoassay. In contrast to no observed differences in basal release of prostacyclin by the control and estrogen-treated arteries, there was a marked increase (approximately 165%) in arachidonate-stimulated formation of prostacyclin by estrogen-treated arteries, and prostacyclin synthesis was inversely correlated with plaque size. No differences were observed in basal or arachidonate-stimulated thromboxane synthesis by the control and estrogen-treated arteries. In light of known antiatherogenic and vasodilatory effects of estrogen, increased prostacyclin synthesis by estrogen-treated arteries may, in part, explain estrogen's beneficial effects on the artery wall.
The only molecular similarity in sex determination found so far among phyla is between the Drosophila doublesex (dsx) and Caenorhabditis elegans mab-3 genes. dsx and mab-3 contain a zinc finger-like DNA-binding motif called the DM domain, perform several related regulatory functions, and are at least partially interchangeable in vivo. A DM domain gene called Dmrt1 has been implicated in male gonad development in a variety of vertebrates, on the basis of embryonic expression and chromosomal location. Such evidence is highly suggestive of a conserved role(s) for Dmrt1 in vertebrate sexual development, but there has been no functional analysis of this gene in any species. Here we show that murine Dmrt1 is essential for postnatal testis differentiation, with mutant phenotypes similar to those caused by human chromosome 9p deletions that remove the gene. As in the case of 9p deletions, Dmrt1 is dispensable for ovary development in the mouse. Thus, as in invertebrates, a DM domain gene regulates vertebrate male development.
We have previously reported the identification of a novel simian parvovirus in cynomolgus monkeys, which causes severe anemia in immunosuppressed cynomolgus monkeys and is currently being studied as an animal model for human B19 infection. We now report two similar outbreaks of anemia in rhesus and pig-tailed macaques associated with two distinct but similar simian parvoviruses (pig-tailed macaque and rhesus parvovirus). Both viruses have been cloned and over 5000 nucleotides sequenced from each virus. The viruses show marked similarities to other members of the Erythrovirus genus in the Parvoviridae family.
Research conducted by this laboratory over the past decade has demonstrated the high susceptibility of the fetus to lung tumor formation following in utero exposure of the resistant C57BL/6 and DBA/2N strains of mice to 3-methylcholanthrene (MC). In this review, we describe our more recent studies on the effects of MC and cotreatment with the lung tumor promoter, butylated hydroxytoluene (BHT), on lung tumor formation in the intermediately susceptible BALB/c strain of mice, and the determination of the potential carcinogenicity of the heterocyclic amine, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in resistant mouse strains. BALB/c mice showed a similar incidence of lung tumors, both in terms of percentage of mice with tumors and number of tumors per mouse, as found in the resistant [D2 x B6D2F1]F2 mice. Ki-ras point mutations were found in 56% (20/36) of BALB/c lung lesions compared with an incidence of 79% in [D2 x B6D2F1]F2 mice. BALB/c lung lesions demonstrated a similar association of Ki-ras mutations with tumor stage. Interestingly, a strain-dependent difference was observed in the mutational spectrum, where 62% and 38% of the lesions in BALB/c mice exhibited G-->C and G-->T transversions, respectively, in contrast with the 16% and 84% incidences observed in [D2 x B6D2F1]F2 mice. BHT had no statistically significant effect on tumor incidence, multiplicity, or Ki-ras mutational spectrum in BALB/c mice treated in utero with MC, although a trend toward increased tumor multiplicity was observed. Finally, experiments initiated to assess the transplacental carcinogenicity of IQ in D2B6F1 mice demonstrated that 1 year after birth, no macroscopically or microscopically visible liver, lung, or colon tumors were found in the transplacentally treated offspring, nor was induction of Cyp1a1, Cyp1b1, or glutathione S-transferases (GSTs) in fetal lung and liver tissues observed. This implies that at least under these experimental conditions, IQ may not be an important transplacental carcinogen. Overall, these data demonstrate that mutagenic damage to Ki-ras is a critical early event mediating murine lung tumorigenesis in both sensitive and resistant strains. Strain-dependent differences in the Ki-ras mutational spectrum may be associated with their differential susceptibility to lung tumor initiation.
Accumulating evidence from human and experimental animal studies indicates that consumption of heterocyclic amines (HA), derived from cooked meat and fish, may be associated with an increased incidence of cancer. Experiments were initiated to assess the role of one of these compounds, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), as a potential transplacental carcinogen, as well as to evaluate whether in utero exposure to IQ results in the induction of fetal cytochrome P4501A1 (Cyp1a1), P4501B1 (Cyp1b1), and/or glutathione S-transferase (GST). Inducible, or responsive, backcrossed fetuses resulting from a cross between congenic C57BL/6 (Ah(d)Ah(d)) nonresponsive female mice and C57BL/6 (Ah(b)Ah(b)) responsive male mice were transplacentally exposed to olive oil or 6.25, 12.5, or 25 mg/kg of IQ on day 17 of gestation. No macroscopically or microscopically visible liver, lung, or colon tumors were found in the transplacentally treated offspring by one year after birth. Ethoxyresorufin O-deethylase (EROD) and 1-chloro-2,4-dinitrobenzene assays were performed to evaluate whether transplacental exposure to IQ results in the induction of fetal Cyp1a1 and GST, respectively, in lung and liver tissues. Results showed levels of EROD and GST activity in tissues of IQ-treated mice to be very close, if not identical, to those of mice treated with olive oil. Similarly, ribonuclease protection assay data showed that the levels of Cyp1a1 and Cyp1b1 RNA in tissues of IQ-treated mice were not significantly different from those of oil-treated controls. Previous studies have shown that the developing organism expresses very low levels of Cyp1a2. Thus, in utero exposure to IQ does not lead to induction of Cyp1a1, Cyp1a2, or Cyp1b1 in the fetal compartment, thereby maintaining the low levels of these activating enzymes in the developing organism. Taken together, these data imply that, at least under the conditions employed for these experiments, IQ may not play an important role in transplacentally induced tumorigenesis.
The carcinogenic effects of in utero exposure to 3-methylcholanthrene (MC) have been demonstrated in the tumor-resistant C57BL/6 (B6) and DBA (D2) strains of mice. In this study, we determined the effects of in utero exposure to MC in BALB/c mice, a strain which demonstrates greater susceptibility to lung tumor induction, and compared our findings with those previously found in [D2xB6D2F(1)]F(2) mice. In addition, we assessed the molecular pathogenesis of the chemically induced tumors and examined the effects of the putative lung tumor promoter butylated hydroxytoluene (BHT) in BALB/c mice. BALB/c mice were treated on day 17 of gestation with 5, 15 or 45 mg/kg MC and 6 weeks after birth with BHT for 6 consecutive weeks. Mice were killed at 6 months of age. Ki-ras, p16Ink4a and p19ARF gene loci were amplified from paraffin-embedded lung tumor tissue and screened for the presence of point mutations via allele-specific oligonucleotide hybridization and single strand conformation polymorphism (SSCP) analyses. Ki-ras point mutations were found in 56% (20/36) of BALB/c lung tumors, with 33% (2/6) of the hyperplasias, 58% (10/19) of the adenomas and 73% (8/11) of the carcinomas exhibiting point mutations at this gene locus. Similar incidences of Ki-ras mutations were previously found following transplacental exposure of [D2xB6D2F(1)]F(2) mice to MC and treatment of adult A/J mice with urethane. Interestingly, a strain-dependent difference was observed in the mutational spectrum. Sixty-two and 38% of the lung lesions in BALB/c mice exhibited G-->C and G-->T transversions, respectively, in contrast to the 13 and 84% incidences previously observed in [D2xB6D2F(1)]F(2) mice. SSCP analysis of the tumor suppressor gene p16Ink4a showed a 6% incidence of point mutations, consistent with that found in [D2xB6D2F(1)]F(2) mice. No mutations were found in exon 1beta of the p19ARF gene of either strain. BHT, a lung tumor promoter in adult mice, had no statistically significant effects on either tumor incidence, tumor multiplicity or the mutational spectrum produced in the Ki-ras gene by in utero MC treatment. However, though not significant, there was an observable trend in increased tumor multiplicity in mice co-treated with BHT. These data demonstrate the transplacental carcinogenic effect of MC in BALB/c mice and show that mutagenic damage to Ki-ras is a critical early event mediating murine lung tumorigenesis in both the tumor-sensitive and tumor-resistant strains. Unlike what occurs when adult BALB/c mice are treated with MC, BHT does not appear to significantly promote the formation of lung tumors following transplacental exposure to MC, possibly due to the rapid growth and cell proliferation in the developing organism. Strain-dependent differences in the Ki-ras mutational spectrum may be associated with their differential susceptibility to lung tumor initiation.
Two genes encode proteins with prostaglandin G/H synthase (PGHS) activity. PGHS-1 is primarily a constitutively expressed gene, whereas inflammatory agents such as bacterial lipopolysaccharide (LPS) endotoxin rapidly induce the PGHS-2 gene in leukocytes. Both PGHS-1 and PGHS-2 are rate-limiting enzymes for the production of prostaglandins and thromboxane following release of arachidonic acid by phospholipases. We previously reported that LPS perfusion into the circulation of isolated perfused rabbit lung (IPL) results in thromboxane-dependent pulmonary hypertension and lung edema when the LPS-primed lung is subsequently stimulated with platelet activating factor (PAF) (J. Clin. Invest. 1990;85:1135). In this study, we showed that the mechanism by which LPS primes IPL for enhanced production of thromboxane and pulmonary hypertension in response to PAF depends on specific upregulation of the PGHS-2 gene in the rabbit lung. LPS perfusion of IPL induced PGHS-2 gene expression, which correlated with the conversion of free arachidonic acid to thromboxane-B2 (TXB2) and the onset of pulmonary hypertension. LPS-induced PGHS-2 expression, TXB2 release, and pulmonary hypertension were inhibited by actinomycin D (an inhibitor of transcription) and cycloheximide (an inhibitor of protein synthesis). The constitutively expressed PGHS-1 remained unchanged with LPS perfusion, and did not convert free arachidonic acid to TXB2, suggesting that PGHS-1 does not contribute to the induction of pulmonary hypertension by LPS. These studies reveal a pathogenic role for induction of PGHS-2 in lung injury.
Most human cancers involve multiple genetic changes, including activation of oncogenes such as Ki-ras-2 (Kras2) and inactivation of any one of a number of tumor suppressor genes such as p53 and members of the retinoblastoma (Rb) regulatory axis. As part of an ongoing project to determine how in utero exposure to chemical carcinogens affects the molecular pathogenesis of murine lung tumors, the p53 and p16Cdkn2a genes were analyzed by using paraffin-embedded lung tissues from mice treated transplacentally with 3-methylcholanthrene. Single-strand conformation polymorphism analysis of exons 5-8 of the p53 gene, as well as their flanking introns, demonstrated an absence of mutations at this gene locus. However, a genetic polymorphism was identified at nt 708 in intron 4 of the DBA/2 strain of mice 5 bp downstream of a 3' branching-point splice signal. Analysis of exons 1 and 2 of the Cdkn2a gene by single-strand conformation polymorphism and sequence analyses revealed mutations in exon 2 in 7% of the tumors examined. Tumor 23-1 exhibited a CAC-->TAC transition at nt 301 (His74-->Tyr74), and tumor 36-1 exhibited a GGG-->GAG transition at nucleotide 350 (Gly90-->Glu90). Northern blot analysis of 14 of the larger tumors showed a marked decrease in the levels of Rb RNA expression. Immunohistochemical analysis revealed a spectrum of pRb expression, with the smaller adenomas showing moderate numbers of nuclei with heterogeneous staining for pRb in contrast with a highly reduced or near-complete absence of expression in the nuclei of larger tumors with features of adenocarcinomas. The low incidence of mutations at tumor suppressor loci suggested that inactivation of tumor suppressor genes was a late event in murine lung tumor pathogenesis. The identification of both mutations at the Cdkn2a gene locus and reduced levels of Rb expression combined with previous studies demonstrating a high incidence of mutated Kras2 alleles in these tumors implies that alterations of the Rb regulatory axis, in combination with mutation of Kras2, may be the preferred pathway for the pathogenesis of pulmonary tumors in transplacentally exposed mice.
Simian parvovirus is a recently discovered parvovirus that was first isolated from cynomolgus monkeys. It is similar to human B19 parvovirus in terms of virus genome, tropism for erythroid cells, and characteristic pathology in natural infections. Cynomolgus monkeys were infected with simian parvovirus to investigate their potential usefulness as an animal model of human B19 parvovirus. Six adult female cynomolgus monkeys were inoculated with purified simian parvovirus by the intravenous or intranasal route and monitored for evidence of clinical abnormalities; this included the preparation of complete hematological profiles. Viremia and simian parvovirus-specific antibody were determined in infected monkeys by dot blot and Western blot assays, respectively. Bone marrow was examined at necropsy 6, 10, or 15 days postinfection. All of the monkeys developed a smoldering, low-grade viremia that peaked approximately 10 to 12 days after inoculation. Peak viremia coincided with the appearance of specific antibody and was followed by sudden clearance of the virus and complete, but transient, absence of reticulocytes from the peripheral blood. Clinical signs were mild and involved mainly anorexia and slight weight loss. Infection was associated with a mild decrease in hemoglobin, hematocrit, and erythrocyte numbers. Bone marrow showed marked destruction of erythroid cells coincident with peak viremia. Our findings indicate that infection of healthy monkeys by simian parvovirus is self-limited and mild, with transient cessation of erythropoiesis. Our study has reproduced Koch's postulates and further shown that simian parvovirus infection of monkeys is almost identical to human B19 parvovirus infection of humans. Accordingly, this animal model may prove valuable in the study of the pathogenesis of B19 virus infection.
Two adult female cynomolgus monkeys (Macaca fascicularis) that had been housed together for 4 months died within 2 weeks of each other after brief illnesses. Monkey No. 1 presented with collapse, watery stool, and hypothermia and died overnight. Monkey No. 2 presented with dyspnea, nasal discharge, leukopenia, and hypoproteinemia and was euthanized after 2 days. Both animals had peritoneal effusions, massive necrosis of pharyngeal, esophageal, and gastric mucosa, and multifocal hepatic and pancreatic necrosis. Monkey No. 2 also had lingual ulcers and locally extensive necrosis of spleen, adrenal glands, and lymph nodes. Large numbers of eosinophilic intranuclear inclusion bodies were present in epithelial and syncytial cells adjoining the necrotic foci in Monkey No. 2 but were absent in Monkey No. 1. Monkey No. 1 seroconverted to cercopithecine herpesvirus 1 (CHV-1, commonly known as herpes B) in the month before death. CHV-1 was isolated from a sample of stomach from Monkey No. 2, and electron microscopy of liver from this animal demonstrated herpesvirus particles within hepatocytes. Both animals were seropositive for simian type D retrovirus, and the virus was cultured from the liver of Monkey No. 2. A diagnosis of disseminated CHV-1 infection was made, possibly occurring secondary to immunosuppression due to infection with simian type D retrovirus. Although a high percentage of cynomolgus monkeys are apparently infected with CHV-1, disseminated disease is rare. Because infection with CHV-1 in humans is associated with a high fatality rate, familiarity with the lesions of disseminated infection with this virus is important.
OBJECTIVE: The optimal management for patients with cavernous sinus meningiomas remains controversial. We attempt to contribute to the ongoing debate of appropriate surgical indications. METHODS: In this retrospective review, 39 patients, including 27 women and 12 men ranging in age from 24 to 73 years (median, 48 yr), underwent surgical treatment for this condition. Completeness of tumor resection, cranial nerve morbidity, general morbidity, and long-term outcome were studied. The cavernous internal carotid artery was partially encased in 15 patients, totally encased in 11 patients, and narrowed by tumor in 13 patients. RESULTS: Of eight patients who underwent complete tumor resection, seven had partial encasement of the internal carotid artery. Of 31 patients who underwent subtotal resection, 11 underwent postoperative radiotherapy. There were no deaths in the series. Morbidity was 17.9% for cranial nerves controlling extraocular motor function. Trigeminal nerve function did not improve after surgical treatment. The median follow-up period was 2 years (range, 6 mo-5.3 yr). Symptomatic and radiographic recurrence occurred in two patients who underwent complete tumor resection and in two patients who underwent subtotal resection. CONCLUSION: Based on our findings and a review of the literature, we conclude the following: 1) the resectability of meningiomas of the cavernous sinus depends on the degree of internal carotid artery involvement; 2) total excision of cavernous sinus meningiomas is possible but rarely achieved in holocavernous meningiomas; 3) cranial nerve morbidity is significant; and 4) subtotal excision with or without postoperative radiotherapy is an effective short-term oncological strategy.
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The prognosis for patients in poor neurological grade (WFNS grades IV and V) after subarachnoid haemorrhage (SAH) is grave. Previous reports of such patients have analysed outcome without defining either the cause or the course of the depressed level of consciousness. We report a retrospective study of the outcome of 62 consecutive patients in poor grade after SAH analysed with respect to their clinical course and the predominant computed tomographic feature. Neuroradiological findings were (1) intracranial haematoma, (2) hydrocephalus with or without intraventricular haemorrhage (IVH) and (3) SAH alone. Sixteen patients (25.8%) had a Glasgow Coma Score (GCS) < or = 12 on admission to hospital and subsequently deteriorated. The predominant computed tomographic feature of these patients was hydrocephalus/IVH. Twelve patients (19.4%) had a GCS < or = 12 on admission and subsequently improved without intervention; all had SAH on computed tomography (CT) on admission. Thirty-four patients (54.8%) had a GCS < or = 12 on admission and did not improve or improved only after emergency surgical intervention. Haematoma (44%) and hydrocephalus/IVH (47%) were the predominant CT features in this group. The overall mortality in the 62 patients was 44%. Fifty-two per cent of patients achieved a good outcome or were moderately disabled. Patients harbouring an intracerebral haematoma had a significantly poorer prognosis when compared with the other groups. Patients in poor neurological grade after SAH are a heterogenous group both clinically and neuroradiologically. Management approaches must consider the cause of clinical deterioration and the related CT findings.
Five cases of gastric infarction were observed in adolescent or adult cynomolgus monkeys (Macaca fascicularis) over a 20-month period. Gastric infarcts were encountered as striking and unexpected findings at necropsy. Gross and microscopic findings included gastric necrosis, hemorrhage, and edema that involved large areas of the fundus and pylorus. A consistent finding was the presence of thrombi in the gastric microvasculature, particularly in the venous system. All animals had acute clinical episodes with substantial tissue damage resulting from a variety of causes, including trauma, pancreatitis, necrotizing cystitis, and intestinal intussusception. In addition, three animals had microvascular thrombosis in nongastric tissues. Our findings suggest that cynomolgus monkeys may be predisposed to developing gastric infarction under conditions of severe systemic insult that predispose to disseminated intravascular coagulation.