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Biomedical subjects

T J O'Brien

Publications and source records attributed to T J O'Brien.

At least 19 recordsLinked to original sources

Anti-epileptic medication and bone health.

BACKGROUND: Epilepsy is a common chronic neurological disorder, usually requiring long-term treatment with anti-epileptic drugs (AED). Many studies have reported that AED therapy is associated with metabolic bone disease and is a major iatrogenic risk factor for fractures. There remains uncertainty about the type(s) of bone disease due to AED treatment, and the pathogenesis of AED-associated fractures. RATIONALE: Deficits in bone mineral density (BMD) are widely reported in AED-treated patient populations. However, much of the research conducted to date has been limited by factors such as small sample size, potentially biased subject selection, a lack of selection of appropriate control data, and failure to take account of important confounding influences. The pathogenesis of AED-associated fractures is likely to be multifactorial, due to factors including reduced BMD, impaired bone quality (due to osteoporosis and/or osteomalacia), increased propensity to fall, and fractures associated with seizures or loss of consciousness. RECOMMENDATIONS: Patients receiving long-term AED should be monitored for indices of bone health, including BMD and vitamin D status. Lifestyle factors should be optimized, vitamin D status maintained, and fall prevention strategies introduced as appropriate. Good seizure control is important. The use of additional, specific osteoporosis therapy is not evidence-based in this setting, but would appear reasonable in patients with clinically significant decreases in BMD, applying current treatment guidelines for osteoporosis. CONCLUSION: There is a pressing need for improved understanding of the pathogenesis of AED-associated bone disease, for better definition of the risk associated with specific AED regimens, and for the development of evidence-based preventive and treatment approaches in this common but neglected disorder.

Adult↗

An asymmetric shock wave in the 2006 outburst of the recurrent nova RS Ophiuchi.

Nova outbursts take place in binary star systems comprising a white dwarf and either a low-mass Sun-like star or, as in the case of the recurrent nova RS Ophiuchi, a red giant. Although the cause of these outbursts is known to be thermonuclear explosion of matter transferred from the companion onto the surface of the white dwarf, models of the previous (1985) outburst of RS Ophiuchi failed to adequately fit the X-ray evolution and there was controversy over a single-epoch high-resolution radio image, which suggested that the remnant was bipolar rather than spherical as modelled. Here we report the detection of spatially resolved structure in RS Ophiuchi from two weeks after its 12 February 2006 outburst. We track an expanding shock wave as it sweeps through the red giant wind, producing a remnant similar to that of a type II supernova but evolving over months rather than millennia. As in supernova remnants, the radio emission is non-thermal (synchrotron emission), but asymmetries and multiple emission components clearly demonstrate that contrary to the assumptions of spherical symmetry in models of the 1985 explosion, the ejection is jet-like, collimated by the central binary whose orientation on the sky can be determined from these observations.

Journal Article↗

Foetal malformations and seizure control: 52 months data of the Australian Pregnancy Registry.

The Australian Pregnancy Registry, affiliated European Register of Antiepileptic drugs in Pregnancy (EURAP), recruits informed consenting women with epilepsy on treatment with antiepileptic drugs (AEDs), those untreated, and women on AEDs for other indications. Enrolment is considered prospective if it has occurred before presence or absence of major foetal malformations (FMs) are known, or retrospective, if they had occurred after the birth of infant or detection of major FM. Telephone Interviews are conducted to ascertain pregnancy outcome and collect data about seizures. To date 630 women have been enrolled, with 565 known pregnancy outcomes. Valproate (VPA) above 1100 mg/day was associated with a significantly higher incidence of FMs than other AEDs (P < 0.05). This was independent of other AED use or potentially confounding factors on multivariate analysis (OR = 7.3, P < 0.0001). Lamotrigine (LTG) monotherapy (n = 65), has so far been free of malformations. Although seizure control was not a primary outcome, we noted that more patients on LTG than on VPA required dose adjustments to control seizures. Data indicate an increased risk of FM in women taking VPA in doses >1100 mg/day compared with other AEDs. The choice of AED for pregnant women with epilepsy requires assessment of balance of risks between teratogenicity and seizure control.

Abnormalities, Drug-Induced↗

Effect of antiepileptic medication on bone mineral measures.

OBJECTIVE: Long-term antiepileptic drug (AED) use has been associated with bone disease, but many previous studies have been limited by inadequate control subjects. We used a cotwin affected sib-pair model to investigate this issue. METHODS: The authors studied 31 female twin (15 monozygous and 16 dizygous) and four sibling pairs (< 3 years age difference) aged 21 to 75 years, in which one member had > 12 months of AED treatment. Areal bone mineral density (ABMD, g/cm2) was measured at the lumbar spine (LS), total hip (TH), femoral neck (FN), and total forearm (FA). Three primary a priori defined subgroups were analyzed: a) use for > 2 years, b) use of enzyme-inducing AEDs, or c) age older than 40 years. RESULTS: For all pairs (n = 35), there were no significant within-pair differences in any ABMD measure. However, in Subgroup a (n = 27), there was a within-pair difference at the FA (0.513 vs 0.534, -3.9%, p = 0.016). In Subgroup b (n = 29), there was also a within-pair difference at the FA for AED user vs nonuser (0.508 vs 0.529, -3.8%, p = 0.010). In Subgroup c (n = 15), there were within-pair differences at the FA (0.492 vs 0.524, -6.1%, p = 0.017) and the LS (0.884 vs 0.980, -9.8%, p = 0.036). CONCLUSIONS: Patients using AEDs for > 2 years, in particular those taking enzyme-inducing AEDs and those older than 40 years, have significantly lower bone mineral density at clinically relevant fracture risk sites.

Adult↗

Transmembrane serine protease TADG-15 (ST14/Matriptase/MT-SP1): expression and prognostic value in ovarian cancer.

Tumour-associated differentially expressed gene-15 (TADG-15/ST14/matriptase/MT-SP1) is a novel member of the transmembrane serine proteases. Previous studies indicated that TADG-15 is overexpressed in ovarian tumours; however, relationships between expression of TADG-15 and clinical characteristics of ovarian cancer remain unclear. The purpose of this study was to examine TADG-15 expression in ovarian cancers and determine any associations with clinicopathological characteristics or patient survival. Immunohistochemical study revealed that TADG-15 was expressed in 50 (56.2%) of 89 ovarian carcinomas, whereas it was not detected in normal ovaries. TADG-15 expression was significantly more common in patients with early stage disease compared with patients with advanced stage diseases (namely, stage I, 24 out of 33: 72.7%; stage II/III/IV, 26 out of 56: 46.4%; P=0.0157). Kaplan-Meier survival curves demonstrated that patients with TADG-15-positive tumours have had substantially longer survival (P=0.0480). The mean value of relative TADG-15 mRNA expression ratio was significantly higher in stage I tumours than in stage II/III/IV tumours (P=0.0053). Increased expression of TADG-15 is frequently detected in early stage cancers, with expression level downregulated during progression of disease. TADG-15 is associated with early stage ovarian cancer and longer patient survival; therefore, it may be a favourable prognostic marker for this malignancy.

Adult↗

MRI-negative PET-positive temporal lobe epilepsy: a distinct surgically remediable syndrome.

Most patients with non-lesional temporal lobe epilepsy (NLTLE) will have the findings of hippocampal sclerosis (HS) on a high resolution MRI. However, a significant minority of patients with NLTLE and electroclinically well-lateralized temporal lobe seizures have no evidence of HS on MRI. Many of these patients have concordant hypometabolism on fluorodeoxyglucose-PET ([18F]FDG-PET). The pathophysiological basis of this latter group remains uncertain. We aimed to determine whether NLTLE without HS on MRI represents a variant of or a different clinicopathological syndrome from that of NLTLE with HS on MRI. The clinical, EEG, [18F]FDG-PET, histopathological and surgical outcomes of 30 consecutive NLTLE patients with well-lateralized EEG but without HS on MRI (HS-ve TLE) were compared with 30 consecutive age- and sex-matched NLTLE patients with well-lateralized EEG with HS on MRI (HS+ve TLE). Both the HS+ve TLE group and the HS-ve TLE patients had a high degree of [18F]FDG-PET concordant lateralization (26 out of 30 HS-ve TLE versus 27 out of 27 HS+ve TLE). HS-ve TLE patients had more widespread hypometabolism on [18F]FDG-PET by blinded visual analysis [odds ratio (OR = + infinity (2.51, -), P = 0.001]. The HS-ve TLE group less frequently had a history of febrile convulsions [OR = 0.077 (0.002-0.512), P = 0.002], more commonly had a delta rhythm at ictal onset [OR = 3.67 (0.97-20.47), P = 0.057], and less frequently had histopathological evidence of HS [OR = 0 (0-0.85), P = 0.031]. There was no significant difference in surgical outcome despite half of those without HS having a hippocampal-sparing procedure. Based on the findings outlined, HS-ve PET-positive TLE may be a surgically remediable syndrome distinct from HS+ve TLE, with a pathophysiological basis that primarily involves lateral temporal neocortical rather than mesial temporal structures.

Adult↗

Discrimination between uterine serous papillary carcinomas and ovarian serous papillary tumours by gene expression profiling.

High-grade ovarian serous papillary cancer (OSPC) and uterine serous papillary carcinoma (USPC) represent two histologically similar malignancies characterised by markedly different biological behavior and response to chemotherapy. Understanding the molecular basis of these differences may significantly refine differential diagnosis and management, and may lead to the development of novel, more specific and more effective treatment modalities for OSPC and USPC. We used an oligonucleotide microarray with probe sets complementary to >10 000 human genes to determine whether patterns of gene expression may differentiate OSPC from USPC. Hierarchical cluster analysis of gene expression in OSPC and USPC identified 116 genes that exhibited >two-fold differences (P<0.05) and that readily distinguished OSPC from USPC. Plasminogen activator inhibitor (PAI-2) was the most highly overexpressed gene in OSPC when compared to USPC, while c-erbB2 was the most strikingly overexpressed gene in USPC when compared to OSPC. Overexpression of the c-erbB2 gene and its expression product (i.e., HER-2/neu receptor) was validated by quantitative RT-PCR as well as by flow cytometry on primary USPC and OSPC, respectively. Immunohistochemical staining of serous tumour samples from which primary OSPC and USPC cultures were derived as well as from an independent set of 20 clinical tissue samples (i.e., 10 OSPC and 10 USPC) further confirmed HER-2/neu as a novel molecular diagnostic and therapeutic marker for USPC. Gene expression fingerprints have the potential to predict the anatomical site of tumour origin and readily identify the biologically more aggressive USPC from OSPC. A therapeutic strategy targeting HER-2/neu may be beneficial in patients harbouring chemotherapy-resistant USPC.

Adult↗

Insertion of depth electrodes with or without subdural grids using frameless stereotactic guidance systems--technique and outcome.

Over recent years frameless stereotactic systems have begun replacing framed systems for many neurosurgical procedures. However, little has been published regarding the use of these systems to guide intracranial electrode implantation for epilepsy surgery patients. Here we report our experience utilising such a system to insert depth electrodes and subdural grid electrodes. The SteathStation Image-Guided System (SSIGS) (Sofamor Danek, Memphis TN.) was used to insert bilateral depth electrodes in 13 patients, of whom 5 also underwent the insertion of subdural grids or strip electrodes. Initially, a surgical plan based on an entry and target point on axial and sagittal images was performed for the insertion of electrodes. Navigational views, using three-planar images, were then performed to determine which structures the electrodes would pass through to be correctly placed in the amygdala and hippocampus. The correct site of electrode implantation was confirmed post-operatively by spiral CT scans in 4 patients (which were then co-registered to the pre-implantation MRI using a surface matching technique) and the other 9 patients by post-implantation MRI. The SSIGS was found to have a mean registration error of 2.0 mm (range 1.8-2.5) in 10 cases; in the 3 cases where the error was greater than 2.5 mm a surfacemerge technique was used with a mean error 0.9 (0.8-1.00). The post-implantation MRI or CT-MRI co-registration confirmed an accurate electrode placement in the mesial temporal region in all cases. Seizure onset lateralisation was achieved in 11 patients, all of whom went onto formal resections based on these results. The only long-term complication was a case of osteomyelitis which required removal of the bone flap. 73% of patients had an excellent seizure outcome. Frameless stereotactic systems can be safely used to intracranial electrodes, avoid the disadvantages of the framed system and have the added advantage of the surgeon being able to visualise the trajectory and to adjust this to avoid vital structures. As well they eliminate surgical obstruction to the insertion of subdural grids at the same operation, which may be caused by a framed system.

Adult↗

Novel immunotherapeutic strategies in gynecologic oncology. Dendritic cell-based immunotherapy for ovarian cancer.

The recognition of tumor antigen loaded dendritic cells as one of the most promising approaches to induce a tumor specific immune response in vivo has recently generated widespread interest in the use of these natural adjuvants for the therapy of human malignancies refractory to standard treatment modalities. However, many cancer patients may not benefit from current strategies of cancer vaccination because an effective tumor antigen associated with their cancer has not yet been identified or because sufficient amounts of tumor tissue cannot be obtained for antigen preparation. The recent identification and cloning of a group of preferentially expressed serine proteases as novel ovarian tumor-associated antigens may offer the opportunity to test in a large group of patients the potential of DC-based immunotherapy. In this review, we describe these ovarian tumor antigens and assess the potential for therapeutic DC vaccination for the treatment of chemotherapy-resistant ovarian cancer.

Adult↗

Prospective study of local cutaneous reactions in patients receiving IV phenytoin.

The authors prospectively examined the occurrence of subacute local cutaneous reactions (LCR) in patients receiving IV phenytoin over a 12-month period at a general hospital. LCR were detected in 29 of 115 patients (25.2%; 22 mild and seven moderate). All resolved within 3 weeks. Patients with LCR were older (median 68 versus 54.5 years, p = 0.004), were more likely to be in a general ward (86% versus 66%, p = 0.04), and had larger catheters (median 16 G versus 18 G, p = 0.05). The authors conclude that LCR are common in routine hospital practice, but are generally mild and benign.

Adult↗

Advances in neuroimaging: non-substrate-directed partial epilepsy.

Contemporary neuroimaging studies using structural and functional techniques are critical in the evaluation of patients with localization-related epilepsy. Imaging procedures may be used to localize the epileptic brain tissue or determine the likely pathologic findings underlying the epileptogenic zone, or both. The diagnostic yield of magnetic resonance imaging (MRI) has been demonstrated in patients with partial epilepsy. The identification of an MRI epileptogenic lesion is almost invariably a reliable indicator of the site of seizure onset. Peri-ictal single photon emission computed tomography (SPECT) may be of particular benefit in patients with normal MRI studies. The use of neuroimaging in the care and management of patients with partial epilepsy is discussed here.

Epilepsies, Partial↗

Multimodality image-guided epilepsy surgery.

Co-registration of imaging modalities in the diagnosis of epilepsy is now commonly used in major epilepsy centres. However, the incorporation of these registrations into an image-guided system has only recently been developed. Using techniques of segmentation, surface matching and/or voxel-based matching, we have been able to co-register FLAIR MRI, SPECT, PET, and subdural grids into the 3-D space of the volumetric MRI and use these images on the StealthStation Image-Guided System to resect these foci. This greatly aids the surgeon in performing a more precise tailoring of the cortical resection so as to maximize the excision of the epileptogenic zone while minimizing the impact on eloquent cortex and epileptogenic foci.

Adult↗

Underexpression of cyclin-dependent kinase inhibitor p27 is associated with poor prognosis in serous ovarian carcinomas.

Reduced expression of a cyclin-dependent kinase inhibitor, p27, has been reported to be associated with poor prognosis in several human cancers. The aim of this study was to investigate the potential role of p27 in ovarian cancer development and progression. Immunohistochemical expression of p27 was determined using 117 epithelial ovarian tumor tissues and 8 normal ovaries. p27 mRNA expression was examined by semi-quantitative PCR amplification using 26 ovarian cancer samples. Nuclear staining of p27 was commonly observed in the normal ovarian surface epithelium and the epithelial cells of germinal inclusion cysts. Positive p27 staining rates were significantly higher in serous adenomas (p=0.006) and in serous LMP tumors (p=0.013) than that in serous carcinomas (Fisher's exact test). In serous ovarian cancers, positive p27 staining rate was significantly higher in early stage (stage1/2) than that in advanced stage (stage 3/4) diseases (p=0.030, Fisher's exact test). Log-rank testing showed that negative p27 expression significantly correlates with poor survival in serous ovarian cancer patients (p=0.041). Considerable levels of p27 mRNA were detected in all ovarian cancer samples examined. These results suggest that the underexpression of p27 caused by post-translational mechanism may contribute to the development and progression and result in poor prognosis of serous ovarian cancers.

Cell Cycle Proteins↗

The utility of a 3-dimensional, large-field-of-view, sodium iodide crystal--based PET scanner in the presurgical evaluation of partial epilepsy.

UNLABELLED: (18)F-FDG PET is an accurate and reliable technique for localizing medically refractory temporal lobe epilepsy, but widespread use has been hindered by limited reimbursement in many countries because of the high cost of traditional PET equipment and radioisotopes. Additionally, the place of FDG PET as a cost-effective tool for presurgical evaluation of epilepsy has been questioned because of limited data showing that FDG PET provides localization information incremental to that provided by more established techniques, particularly MRI and ictal electroencephalography (EEG). Three-dimensional (3D), large-field-of-view, sodium iodide crystal-based scanners have lower equipment and running costs and better multiplanar resolution than traditional 2-dimensional bismuth germinate (BGO) systems but have not yet been validated for evaluation of epilepsy. Our purpose was to investigate the localization rate, accuracy, and prognostic value of FDG PET images acquired on a 3D, large-field-of-view, sodium iodide crystal-based PET scanner in the presurgical evaluation of intractable partial epilepsy. We also wanted to establish the incremental value of FDG PET over established MRI and ictal EEG techniques. METHODS: Fifty-five patients who were surgical candidates because of medically refractory partial epilepsy were examined. For most of these patients, the lesions had not been clearly localized on conventional assessment. The FDG PET scans were reviewed independently by 2 reviewers who were unaware of the patients' clinical details, ictal EEG findings, and volumetric MRI results, and the FDG PET results were correlated with those of MRI and EEG and with postsurgical outcome. RESULTS: Forty-two patients (76%) had localizing FDG PET images (37 temporal, 5 extratemporal). The ictal EEG recordings were localizing in 66%, and the MRI findings were localizing in 27% (which increased to 35% after the MRI findings were reviewed again after PET). Concordance between the site of the PET localizations and the site of the MRI or EEG localizations was 100%. The PET images were localizing in 63% and 69% of patients with nonlocalizing ictal EEG and MRI findings, respectively. Twenty-one of 24 patients who subsequently underwent epilepsy surgery had localizing FDG PET images; of these 21 patients, 18 (86%) had a class I outcome. Multiple regression analysis showed the FDG PET results to be predictive of postsurgical outcome independently of the MRI findings. CONCLUSION: For intractable partial epilepsy, FDG PET using a 3D, large-field-of-view, sodium iodide crystal-based scanner provided clinically useful localizing information that was at least as accurate as the results reported for traditional BGO-based scanners. The PET images provided prognostically significant localization information incremental to that provided by volumetric MRI and ictal EEG, particularly if 1 of these studies was nonlocalizing.

Adolescent↗

Mechanism of apoptosis and determination of cellular fate in chromium(VI)-exposed populations of telomerase-immortalized human fibroblasts.

The cellular responses to carcinogen exposure influence cellular fate, which in turn modulates the neoplastic response. Certain hexavalent chromium [Cr(VI)] compounds are implicated as occupational respiratory carcinogens at doses that are both genotoxic and cytotoxic. We examined the mechanism of Cr(VI)-induced apoptosis in normal human fibroblasts (BJ) immortalized by human telomerase gene transfection (BJ-hTERT), and we assessed the spectrum of cumulative cellular fates [(a) regaining of replicative potential; (b) terminal growth arrest; or (c) apoptosis] for a narrow range of increasingly genotoxic doses of Cr(VI). Exposure of BJ-hTERT cells to Cr(VI) resulted in a dose-dependent increase in apoptosis that involved mitochondrial disruption as evidenced by mitochondrial membrane depolarization and cytochrome c release. The initial response to Cr(VI) exposure was inhibition of cell cycle progression. At the lowest dose tested (1 microM; 32% clonogenic survival), the cell cycle inhibition led to terminal growth arrest but no apoptosis. The fraction of terminally growth arrested cells increased as the dose was increased to 3 microM but then decreased at 4, 5, and 6 microM as apoptosis became the predominant cell fate. Our results suggest that cell populations exposed to Cr(VI) have a different spectrum of responses, depending on the extent of DNA damage, and that the regaining of replicative potential after relatively higher genotoxic exposures may be attributable to either escape from, or resistance to, terminal growth arrest or apoptosis.

Apoptosis↗

Subtraction peri-ictal SPECT is predictive of extratemporal epilepsy surgery outcome.

OBJECTIVES: To determine whether localization of extratemporal epilepsy with subtraction ictal SPECT coregistered with MRI (SISCOM) is predictive of outcome after resective epilepsy surgery, whether SISCOM images provide prognostically important information compared with standard tests, and whether blood flow change on SISCOM images is useful in determining site and extent of excision required. BACKGROUND: The value of SISCOM in predicting surgical outcome for extratemporal epilepsy is unknown, especially if MRI findings are nonlocalizing. METHODS: SISCOM images in 36 consecutive patients were classified by blinded reviewers as "localizing and concordant with site of surgery," "localizing but nonconcordant with site of surgery," or "nonlocalizing." SISCOM images were coregistered with postoperative MRI, and reviewers visually determined whether cerebral cortex underlying the SISCOM focus had been completely resected, partially resected, or not resected. RESULTS: Twenty-four patients (66.7%) had localizing SISCOM, including 13 (76.5%) of those without a focal MRI lesion. Eleven of 19 patients (57.9%) with localizing SISCOM concordant with the surgical site, compared with 3 of 17 (17.6%) with nonlocalizing or nonconcordant SISCOM, had an excellent outcome (p < 0.05). With logistic regression analysis, SISCOM findings were predictive of postsurgical outcome, independently of MRI or scalp ictal EEG findings (p < 0.05). The extent of resection of the cortical region of the SISCOM focus was significantly associated with the rate of excellent outcome (100% with complete resection, 60% with partial resection, and 20% with nonresection, p < 0.05). CONCLUSION: SISCOM images may be useful in guiding the location and extent of resection in extratemporal epilepsy surgery.

Adolescent↗

Ovarian tumor cells express a novel multi-domain cell surface serine protease.

Serine proteases serve many functions in normal biological processes. These functions are often usurped by cancer cells to allow progression of tumors by increasing the growth and metastatic potential of the neoplasia. Here, we have used a polymerase chain reaction (PCR)-based strategy to clone Tumor Associated Differentially-expressed Gene-12 (TADG-12), a new serine protease from ovarian carcinoma. This technique also revealed a variant splicing form of TADG-12 that could lead to a truncated protein product. Semi-quantitative PCR showed that TADG-12 is overexpressed in 41 of 55 ovarian cancer specimens relative to normal expression, and the variant form, TADG-12V is found at increased levels in 8 of 22 carcinomas examined. Northern blot revealed three transcripts, the largest of which is approximately 2.4 kb. An ovarian tumor cDNA library was screened, and the entire cDNA of TADG-12 has been identified. This sequence encodes a putative protein of 454 amino acids which includes a potential transmembrane domain, an LDL receptor-like domain, a scavenger receptor cysteine-rich domain, and a serine protease domain. These features imply that TADG-12 will be at the cell surface, and it may be useful as a molecular target for therapy or a diagnostic marker.

Amino Acid Sequence↗

Evaluation of SPECT in the assessment and treatment of intractable childhood epilepsy.

The authors retrospectively examined the role of SPECT in 65 children undergoing video-EEG telemetry. SPECT was concordant in most children whose lesions were already localized by MRI and epilepsy syndrome and provided localizing data in more than half not localized by these modalities. Ictal SPECT provided no additional prognostic benefit in patients undergoing epilepsy surgery (n = 23) who have a localized MRI lesion. In patients without lesions, however, ictal SPECT provides useful additional localization that may be used as a guide to intracranial implantation.

Brain↗