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Biomedical subjects

C E Thomas

Publications and source records attributed to C E Thomas.

At least 19 recordsLinked to original sources
PubMed2006

Undiagnosed phaeochromocytoma mimicking severe preeclampsia in a pregnant woman at term.

We report an unusual case of phaeochromocytoma in pregnancy. The patient presented with severe hypertension, visual disturbances, proteinuria, glycosuria and pulmonary oedema at 38 weeks' gestation. The initial diagnosis was severe preeclampsia, but rapid deterioration of the fetus necessitated an emergency caesarean section under general anaesthesia, following which the maternal condition deteriorated rapidly. Differential diagnoses included pulmonary embolus, cardiomyopathy, amniotic fluid embolus and ischaemic/embolic cerebrovascular accident. Despite aggressive maximal treatment, mother and baby died 36 h later. Post mortem examination of the mother revealed a 5.5-cm tumour of the right adrenal gland confirmed histologically as a phaeochromocytoma. We examine the diagnostic dilemmas of this case and consider the treatment and management options when faced with a critically ill mother and the need to deliver her fetus by emergency caesarean section. We also question the clinical priorities during management of a sudden deterioration in both maternal and fetal health.

Adrenal Gland Neoplasms↗
PubMed2004

DNA immunization of mice with a plasmid encoding Neisseria gonorrhea PorB protein by intramuscular injection and epidermal particle bombardment.

Immunogenicity of a DNA vaccine encoding PorB from Neisseria gonorrhoeae strain FA1090 was analyzed in BALB/C mice immunized by intramuscular needle injection or epidermal gene gun bombardment. Both delivery routes generated measurable specific antibodies although the gene gun response was slower. Antibody isotypes were indicative of Th2 activation following gene gun immunization and of Th1 activation following intramuscular injection. In both immunization protocols, boosting with either renatured recombinant (rr) PorB protein or PorB expressed from Venezuelan equine encephalitis virus replicon particles (VRPs) significantly increased anti-PorB antibody levels. Boosting with rrPorB protein had little effect on antibody isotypes, while boosting with VRPs expressing PorB-enhanced a Th1 type response. Whole cell binding experiments showed that a portion of the antibodies recognized the surface of the homologous N. gonorrhoeae strain. Serum from groups with high antibody levels showed some opsonization of the homologous strain using human neutrophils. These results showed the potential of DNA vaccination for the purpose of priming an antibody response against PorB of N. gonorrhoeae. When combined with a protein or VRP boost, DNA priming resulted in high-titer and long-lasting responses. Based on different prime-boost protocols, we could polarize immune responses to predominantly Th1 or Th2, which should enable future studies of the types of immune responses that are protective in mouse models of gonorrhea.

Adjuvants, Immunologic↗
PubMed2004

Fluoxetine-induced change in rat brain expression of brain-derived neurotrophic factor varies depending on length of treatment.

Recent studies indicate that brain-derived neurotrophic factor (BDNF) may be implicated in the clinical action of antidepressant drugs. Repeated (2-3 weeks) administration of antidepressant drugs increases BDNF gene expression. The onset of this response as well as concomitant effects on the corresponding BDNF protein is however, unclear. The present study investigated the effects of acute and chronic administration of the selective serotonin reuptake inhibitor, fluoxetine (10mg/kg p.o.), upon regional rat brain levels of BDNF mRNA and protein expression. To improve the clinical significance of the study, fluoxetine was administered orally and mRNA and protein levels were determined ex vivo using the techniques of in situ hybridisation histochemistry and immunocytochemistry respectively. Direct measurement of BDNF protein was also carried out using enzyme-linked immunosorbent assay (ELISA). Four days of once daily oral administration of fluoxetine induced decreases in BDNF mRNA (hippocampus, medial habenular and paraventricular thalamic nuclei). Whilst 7 days of treatment showed a non-significant increase in BDNF mRNA, there were marked and region-specific increases following 14 days of treatment. BDNF protein levels remained unaltered until 21 days of fluoxetine treatment, when the numbers of BDNF immunoreactive cells were increased, reaching significance in the pyramidal cell layer of CA1 and CA3 regions of Ammon's horn (CA1 and CA3) but not in the other sub-regions of the hippocampus. Indicative of the highly regional change within the hippocampus, the ELISA method failed to demonstrate significant up-regulation at 21 days, measuring levels of BDNF protein in the whole hippocampus. In contrast to the detected time dependent and biphasic response of the BDNF gene, activity-regulated, cytoskeletal-associated protein (Arc) mRNA showed a gradual increase during the 14-day course of treatment. The results presented here show that BDNF is expressed differentially depending on length of fluoxetine administration, which could contribute in explaining the slow onset of antidepressant activity observed with selective serotonin reuptake inhibitors.

Animals↗
PubMed2001

Preexisting antiadenoviral immunity is not a barrier to efficient and stable transduction of the brain, mediated by novel high-capacity adenovirus vectors.

The utility of first-generation adenovirus vectors for long-term gene transfer in humans is limited by preexisting antiadenoviral immunity. We demonstrate here that new-generation high-capacity adenovirus vectors (HC-Ads) can efficiently transduce the brain and mediate stable transgene expression for at least 2 months, even in the presence of a preexisting antiadenoviral immune response. First-generation vector-mediated transduction was almost completely abolished in preimmunized animals within 60 days of the vector injection. Levels of HC-Ad-mediated transduction by 3 days postinjection were not significantly affected by preimmunization, were reduced within 14 days to 56% of those levels seen in nonimmunized animals, and remained stable until day 60 postinjection. Acute brain inflammation elicited by the HC-Ad vector injection was more transient, and was reduced in intensity compared with brain inflammation elicited by the first-generation vector injection in immunized animals. Inflammation was significantly higher in all immunized animals than in nonimmunized animals. Our results show that preexisting antiadenoviral immunity does not significantly reduce initial HC-Ad-mediated infection of the brain and is not a barrier to stable HC-Ad vector-mediated transduction of the CNS. Although input HC-Ad capsid proteins injected into the brain may contain transient targets for a brain-infiltrating cellular adenovirus-specific immune response, this fails to eliminate transgene expression. Thus HC-Ads show promise for gene therapy of chronic brain disease.

Adenoviridae↗
PubMed2001

Acute direct adenoviral vector cytotoxicity and chronic, but not acute, inflammatory responses correlate with decreased vector-mediated transgene expression in the brain.

The potential utility of adenoviruses for the treatment of chronic neurological disease is controversial due to reports of vector-associated toxicity, inflammation, and transient transgene expression. To focus upon the mechanism by which transgene expression is lost, we injected increasing doses [1 x 10(6) to 1 x 10(9) infectious units (iu)] of a first-generation adenovirus vector expressing beta-galactosidase into the brains of immune-competent adult rats. Transgene expression was evaluated simultaneously with acute neuronal and glial cell cytotoxicity, and acute and chronic inflammation using immunohistochemistry, at 3 and 30 days post-vector administration. Our results show a clear threshold effect of viral dose upon the amount of transgene expression persisting by 30 days after vector administration. Below 10(8) iu, transgene expression remained stable over the 30-day period. Following infection of more than 10(8) iu, the extent of transgene expression at 30 days was inversely correlated with increasing viral dose. The severity of acute inflammation increased proportionally with increasing vector dose from 10(6) to 10(9) infectious units. In contrast, acute vector-mediated cytotoxicity and chronic inflammation were observed only above the threshold level of vector dose. Above 10(8) iu both the extent of the acute toxicity and the severity of the chronic inflammation were inversely correlated with transgene expression at 30 days. Thus, our data suggest that both an acute loss of cells through direct vector-mediated toxicity and the elicitation of chronic inflammation (but not acute inflammation) may account for the decline in transduction persistence at high vector doses.

Adenoviridae↗
PubMed2001

Neurologic complications of the Novacor left ventricular assist device.

BACKGROUND: The left ventricular assist device (LVAD) is a bridging mechanism for patients with severe heart failure to remain viable until heart transplantation. The rate of cerebral embolism has been reported as high as 47% in some studies but the rate of other neurologic complications in patients with LVADs is not known. METHODS: Retrospective chart review of all patients who had LVADs implanted at our hospital from September 1993 until September 1997. Complications from the time of implantation until heart transplantation or death and functional outcome were assessed. RESULTS: Twenty-three patients had LVADs placed in the four-year period. Of 23 patients, 9 had neurologic complications after placement of the LVAD. These included four strokes, three seizures, and two cases of delirium. The 3 patients with seizures all died from multiorgan failure. All of the patients with strokes received a transplant. One patient with delirium died from multiorgan failure and another received a transplant. The most devastating medical complication was renal failure, which occurred in 7 patients and was associated with 100% mortality. All surviving patients with neurologic complications went on to transplant and good functional outcome. CONCLUSIONS: Neurologic complications are common in patients with LVADs, occurring in 9 out of 23 patients in our series. Seizures are a poor prognostic indicator and were associated with 100% mortality. Strokes did not have a negative impact on outcome. Patients with delirium had a mixed outcome, which reflects the multifactorial nature of delirium. Further study needs to be done to limit the neurologic complications associated with LVADs and further improve outcomes.

Adolescent↗
PubMed2001

Cloning, overexpression, purification, and immunobiology of an 85-kilodalton outer membrane protein from Haemophilus ducreyi.

We have identified an 85-kDa outer membrane protein that is expressed by all tested strains of Haemophilus ducreyi. Studies of related proteins from other pathogenic bacteria, including Haemophilus influenzae, Pasteurella multocida, Neisseria gonorrhoeae, Neisseria meningitidis, and Shigella dysenteriae, suggested a role for these proteins in pathogenesis and immunity. In keeping with the first such described protein from Haemophilus influenzae type B, we termed the H. ducreyi protein D15. The gene encoding the H. ducreyi D15 protein was cloned and sequenced, and the deduced amino acid sequence was found to be most similar to sequences of the D15-related proteins from other Pasteurella spp. The arrangement of the flanking genes was similar to that of H. influenzae Rd and suggested that D15 was part of a multigene operon. Attempts to make a null mutation of the D15 gene were unsuccessful, paralleling results in other D15 gene studies. Overexpression of H. ducreyi D15 in Escherichia coli resulted in a source of recombinant D15 (rD15) from which it was readily purified. rD15 was immunogenic, and it was found that immunization of rabbits with an rD15 vaccine preparation conferred partial protection against a virulent challenge infection. Antisera to an N-terminal peptide recognized all tested strains of H. ducreyi.

Amino Acid Sequence↗
PubMed2000

NMDA-sensitive neurons profoundly influence delayed staurosporine-induced apoptosis in rat mixed cortical neuronal cultures.

We have investigated cell killing in cultured rat embryonic cortical neurons exposed to the protein kinase inhibitor staurosporine, the excitatory amino acid N-methyl-D-aspartate (NMDA), or a combination thereof. Our data indicate that there are several populations of neurons that differ in their response to these agents. Cultures exposed to NMDA undergo cell death typified by lactate dehydrogenase (LDH) leakage which is likely primarily necrotic in that little caspase-3 activation or oligonucleosome formation is observed even when followed for 48 h. Cells exposed to staurosporine (STS) exhibit rapid, extensive activation of caspase-3 with coincident LDH leakage, oligonucleosome formation and TUNEL staining. Both LDH leakage and oligonucleosome content were significantly more elevated at 48 h than at 20 h with STS treatment while caspase-3 activity peaked early (8-20 h) and declined markedly by 48 h. Deletion of NMDA-responsive neurons by pre-treatment of the cultures with NMDA for 4 days prevented the late phase (20-48 h) increases in LDH leakage and oligonucleosomes in the remaining neuronal population. Caspase-3 activity was also completely abolished by NMDA pre-treatment. These results indicate that cells susceptible to acute NMDA-induced toxicity can be killed by non-apoptotic means when exposed to NMDA; however, they undergo a delayed, apoptotic death when exposed to STS. Interestingly, removal of NMDA-responsive cells prevents the processing of procaspase-3; thus, STS-induced apoptosis in cells resistant to NMDA-mediated killing proceeds independent of caspase-3 activation. The data indicate that nearly all neurons in these mixed cultures can undergo apoptosis in response to appropriate stimuli such as STS but that the temporal nature, and the pathways activated in response to STS, vary amongst the subpopulations of neurons. These findings may help to explain the simultaneous appearance of features of both apoptosis and necrosis observed in vivo following cerebral ischemia.

Animals↗
PubMed2000

Peripheral infection with adenovirus causes unexpected long-term brain inflammation in animals injected intracranially with first-generation, but not with high-capacity, adenovirus vectors: toward realistic long-term neurological gene therapy for chronic diseases.

Although adenoviral vectors provide prolonged gene expression in the brain by comparison to peripheral organs, expression is eliminated by a severe inflammatory infiltration (i.e., activated macrophages/microglia and T-lymphocytes) after peripheral infection with adenovirus. Here, we demonstrate that high-capacity adenoviral (HC-Ad) vectors succeed in maintaining long-term transgene expression in the brain, even in the presence of an active peripheral immunization with adenovirus that completely eliminates expression from first-generation vectors within 60 days. Importantly, even 60 days after the peripheral infection, brains injected with first-generation vectors exhibited evidence of a chronic infiltration of CD8(+) cells, macrophage/microglial activation, and up-regulation of brain MHC-I expression. No inflammation was observed in the brains injected with the HC-Ad vector. Thus, these results demonstrate that HC-Ad vectors will allow safe, stable, and long-term transgene expression in the brain, even in the presence of peripheral infection with adenovirus. This markedly improves the prospects for the use of adenoviral vectors for long-term gene therapy of neurological disorders.

Adenoviridae Infections↗
PubMed2000

Embolic stroke secondary to an aortic arch tumor--a case report.

An acute stroke from an aortic arch tumor is reported. These tumors are rare and have to be differentiated from atheromas. Aortic atheromas commonly present with embolic phenomena and occasionally as masses. Aortic tumors are more likely to produce obstructive phenomena, presenting as a coarctation or dissection. Magnetic resonance imaging with gadolinium can facilitate the diagnosis. A literature review of aortic masses and their diagnosis and treatment are presented.

Aorta, Thoracic↗
PubMed1999

The caudal infrasylvian surface in dyslexia: novel magnetic resonance imaging-based findings.

OBJECTIVE: To detect anatomic abnormalities of auditory association cortex in dyslexia by measuring the area of the perisylvian region known as the caudal infrasylvian surface(s) (cIS) in dyslexic and control subjects. BACKGROUND: Several quantitative morphometric investigations of cortical areas in dyslexia have focused on the cIS, which encompasses the supratemporal plane and the inferior bank of the posterior ascending ramus of the sylvian fissure. Inconsistencies in the results of these studies may be attributable in part to the use of measurement methods that do not account fully for surface undulations of the cIS. METHODS: The authors used an MRI-based surface reconstruction technique that models the curvature of the cerebral cortex in three dimensions to obtain whole-hemisphere and regional surface area estimates. Measurements were obtained in both hemispheres of eight right-handed male dyslexic subjects and eight right-handed male control subjects. RESULTS: The cIS area of dyslexic subjects was significantly larger than that of control subjects, and this result was not attributable to a difference in whole-hemisphere surface area. Neither the dyslexic nor control subjects showed a left or right asymmetry in this region, although there was a trend toward less variance of the asymmetry scores in dyslexic subjects. CONCLUSIONS: The gross anatomic organization of this region is different in dyslexic subjects, and elucidation of the precise nature of these differences may be aided by surface modeling techniques.

Adult↗
PubMed1999

Inhibition of iron-dependent and ischemia-induced brain damage by the alpha-tocopherol analogue MDL 74,722.

Free radical-induced lipid peroxidation is an important factor in the pathogenesis of ischemic brain damage. We studied the effects of the alpha-tocopherol analogue MDL 74,722 on iron-dependent lipid peroxidation and infarct volume after transient focal cerebral ischemia. The effects of MDL 74,722 on iron-induced lipid peroxidation were tested in cerebellar granule cell cultures by means of a thiobarbituric acid reactive substances (TBARS) assay. The absorbance resulting from mitochondrial reduction of 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) was taken as a measure of cell viability. Besides, in male Wistar rats the left middle cerebral artery (MCA) was occluded for 3 h by means of an intraluminal filament. Rats were treated with vehicle (n = 19) or MDL 74,722 (n = 17), administered intravenously for 3 h in a dose of 2 mg/(kg.h), starting 105 min after MCA occlusion. Infarct volume was measured in coronal brain sections stained with hematoxylin and eosin. In cerebellar granule cell cultures, MDL 74,722 resulted in a dose-dependent inhibition of TBARS formation and prevention of cell toxicity. The compound reduced infarct volume after transient occlusion of the MCA in rats by 49%. It is concluded that MDL 74,722 is a potent inhibitor of lipid peroxidation and reduces infarct volume by about one half, even when treatment is delayed. This contributes to its potential clinical usefulness.

Animals↗
PubMed1999

Novel free radical spin traps protect against malonate and MPTP neurotoxicity.

Both malonate and 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine (MPTP) are neurotoxins which cause energy depletion, secondary excitotoxicity, and free radical generation. Malonate is a reversible inhibitor of succinate dehydrogenase, while MPTP is metabolized to 1-methyl-4-phenylpyridinium, an inhibitor of mitochondrial complex I. We examined the effects of pretreatment with the cyclic nitrone free radical spin trap MDL 101,002 on malonate and MPTP neurotoxicity. MDL 101,002 produced dose-dependent neuroprotection against malonate-induced striatal lesions. MDL 101, 002 produced significant protection against MPTP induced depletions of dopamine and its metabolites. MDL 101,002 also significantly attenuated MPTP-induced increases in striatal 3-nitrotyrosine concentrations. The free radical spin trap tempol also produced significant protection against MPTP neurotoxicity. These findings provide further evidence that free radical spin traps produce neuroprotective effects in vivo and suggest that they may be useful in the treatment of neurodegenerative diseases.

Animals↗
PubMed1999

What are the reciprocal influences of randomized clinical trials and the patient-psychiatrist relationship?

The goal of this prospective investigation was to study the course and the quality of patient-psychiatrist relationships during phase II / phase III clinical trials of antidepressant medication prescribed for depressive disorders. All patients who participated in the clinical trials (and subsequently in this survey) signed written informed consent statements and were subject to random double blind treatment assignment. Retrospective analysis of 118 investigations was carried out, and the patients involved were questioned concerning their experiences and impressions during and after the study. Data show that the outcome of clinical trials of antidepressant drugs are not a function of pre-existing good patient-psychiatrist relationships. On the other hand, no effects on the patient-psychiatrist relationship were found as a result of the experimental procedure, and it can be concluded that no detrimental effects on future patient-psychiatrist relationships were incurred.

Adult↗
PubMed1998

MDL 101,002, a free radical spin trap, is efficacious in permanent and transient focal ischemia models.

The present work describes the neuroprotective effects of the free radical spin trap, MDL 101,002, in models of permanent and transient focal ischemia. Permanent focal ischemia was carried out by occlusion of the distal segment of the middle cerebral artery (MCA) and CCA's in Spontaneously Hypertensive (SH) and Wistar rats. Transient focal ischemia was undertaken by occluding the origin of the MCA for 180 min by the intraluminar monofilament method in Wistar rats. With permanent distal MCA occlusion in SH rats, 100 mg/kg i.v. at 30 min post-ischemia resulted in a significant 40% reduction in infarct volume. Similarly, a 75 mg/kg bolus + 45 mg/kg-h dose of MDL 101,002 given i.v. at 5 min post-ischemia resulted in a 90% or 60% decrease in infarct volume in the mixed permanent/transient distal MCA model with Wistar rats using 120 or 180 min of CCA occlusion, respectively. When full reperfusion was established, after 180 min of occlusion in the proximal MCA model, a dose of 40 mg/kg + infusion and 75 mg/kg + infusion resulted in a significant 50% and 70% decrease in ischemic damage, respectively. MDL 101,002 is clearly an effective neuroprotective agent in all models examined. This work would suggest that this novel cyclic nitrone spin trap affords effective neuroprotection and is useful for the treatment of ischemic stroke.

Animals↗