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Biomedical subjects

M J O'Connor

Publications and source records attributed to M J O'Connor.

At least 19 recordsLinked to original sources
PubMed2006

Duplication 8q22.1-q24.1 associated with bipolar disorder and speech delay.

OBJECTIVE: To report a case of a child with bipolar disorder found to have an unbalanced translocation involving the long arm of chromosome 8, a region that has been previously implicated in genome-wide linkage scans. CASE REPORT: A 7-year-old boy with a complex psychiatric symptom presentation including attention deficits, distractibility, impulsivity, pressured speech, sleep disturbance, aggressive behavior, and hypersexuality diagnosed with bipolar disorder. He also showed evidence of borderline intellectual and adaptive functioning and had mild dysmorphic features with a duplication of distal 8q that arose as an unbalanced chromosomal translocation due to a maternal 15p;8q insertion. CONCLUSION: This finding of an unbalanced translocation provides further evidence to support previous linkage studies of a potential causative gene on 8q for bipolar disorder.

Aggression↗
PubMed2004

Association between variation in the human KCNJ10 potassium ion channel gene and seizure susceptibility.

PURPOSE: Our research program uses genetic linkage and association analysis to identify human seizure sensitivity and resistance alleles. Quantitative trait loci mapping in mice led to identification of genetic variation in the potassium ion channel gene Kcnj10, implicating it as a putative seizure susceptibility gene. The purpose of this work was to translate these animal model data to a human genetic association study. METHODS: We used single stranded conformation polymorphism (SSCP) electrophoresis, DNA sequencing and database searching (NCBI) to identify variation in the human KCNJ10 gene. Restriction fragment length polymorphism (RFLP) analysis, SSCP and Pyrosequencing were used to genotype a single nucleotide polymorphism (SNP, dbSNP rs#1130183) in KCNJ10 in epilepsy patients (n = 407) and unrelated controls (n = 284). The epilepsy group was comprised of patients with refractory mesial temporal lobe epilepsy (n = 153), childhood absence (n = 84), juvenile myoclonic (n = 111) and idiopathic generalized epilepsy not otherwise specified (IGE-NOS, n = 59) and all were of European ancestry. RESULTS: SNP rs#1130183 (C > T) alters amino acid 271 (of 379) from an arginine to a cysteine (R271C). The C allele (Arg) is common with conversion to the T allele (Cys) occurring twice as often in controls compared to epilepsy patients. Contingency analysis documented a statistically significant association between seizure resistance and allele frequency, Mantel-Haenszel chi square = 5.65, d.f. = 1, P = 0.017, odds ratio 0.52, 95% CI 0.33-0.82. CONCLUSION: The T allele of SNP rs#1130183 is associated with seizure resistance when common forms of focal and generalized epilepsy are analyzed as a group. These data suggest that this missense variation in KCNJ10 (or a nearby variation) is related to general seizure susceptibility in humans.

Chi-Square Distribution↗
PubMed2003

Mania following temporal lobectomy.

OBJECTIVE: To determine clinical and diagnostic variables that predict the development of mania after temporal lobectomy for treatment of refractory epilepsy. METHODS: From a large surgical database, 16 patients with new-onset mania after temporal lobectomy were identified. Mania patients were frequency matched for age, gender, and laterality of surgery to 16 temporal lobectomy patients with no postoperative mood disorder. These groups were compared on pre- and postoperative clinical and diagnostic data with each other and with 30 patients with depression after temporal lobectomy. Posthoc analyses compared mania and depression groups with the general surgical database matched for gender and laterality of surgery. RESULTS: Preoperative evaluations in postoperative mania patients, in particular EEG, were more likely to yield findings of brain dysfunction localizing to the hemisphere contralateral to temporal lobectomy. Right temporal lobectomy was more common in the postoperative mania group. Duration of manic episodes was usually transient, and all but one case remitted within 1 year after onset. In comparison with the control group, mania and depression groups had a higher likelihood for preoperative generalized tonic-clonic seizures and lack of seizure freedom following surgery. CONCLUSIONS: A limitation of this study was the relatively small number of patients. Despite this, clinical features that distinguish patients at risk for postoperative mania from those with depression and those with no psychiatric illness include bihemispheric abnormalities, in particular bitemporal EEG activity, and right temporal lobectomy.

Adult↗
PubMed2001

An experimental and computational study of 1,2-hydrogen migrations in 2-hydroxycyclopentylidene and its conjugate base.

Thermal decomposition of alpha-hydroxydiazirine 2 gives primarily cyclopentanone and some allylic alcohol, in similar amounts as the known cyclohexyl analogue 1. Calculations (B3LYP/6-31+G) also show cyclopentanone to be the major product of this carbene rearrangement. Diazirine 2 and the lithium salt of the corresponding conjugate base 3 were decomposed by photolysis. The proportion of ketone formed increases with deprotonation, a trend also found computationally. In comparison, the base-induced isomerization of cyclopentene oxide, which proceeds via alpha-elimination to a carbenoid intermediate similar to that obtained from 3, yields primarily allylic alcohol rather than ketone; neither ring size nor charge thus accounts for the unusual product distribution observed. Interestingly, the calculations reveal that in the gas phase with no counterion, the singlet, oxyanionic carbene, and the alpha-deprotonated epoxide are the same, rather than discrete structures. This intramolecular complexation stablilizes the oxyanionic carbene by 20-25 kcal/mol.

Journal Article↗
PubMed2001

Neurosurgical treatment of medically intractable status epilepticus.

Medically intractable status epilepticus can be defined as status epilepticus (SE) that persists or recurs despite medical treatment with intravenous agents that suppress cortical activity. We describe the successful neurosurgical treatment of three patients with medically intractable status epilepticus who responded either to focal resection, multiple subpial transection, or callosal section. The duration of medically intractable status epilepticus before surgery ranged between 23 and 42 days, and multiple medical complications occurred during the failed medical therapy. We suggest that patients with medically intractable status epilepticus who fail to respond to three courses of cerebral suppressant therapy for approximately 2 weeks be considered for surgical treatment in the absence of any known remitting etiology. Focal resection and/or subpial transection is preferred for intractable partial SE with focal electrographic changes or a focal lesion demonstrated by structural or functional neuroimaging. Corpus callosotomy may be used for patients with generalized or non-localizable intractable status epilepticus.

Adult↗
PubMed2001

Association of fear auras with mood and anxiety disorders after temporal lobectomy.

PURPOSE: Epilepsy has been associated with increased occurrence of behavioral disorders. Auras reflect abnormal stimulation of brain areas in close proximity to regions from which clinical seizures originate. The purpose of our study was to investigate whether fear auras are associated with a higher rate of mood and anxiety disorders before and 1 year after temporal lobectomy. METHODS: Twenty-two patients with fear auras were compared with matched groups with other auras and no auras. Neurologic and neuropsychological evaluations before, 1-2 months after, and 1 year after temporal lobectomy were reviewed for mood and anxiety disorders and psychotropic medication treatment. A logistic regression model examined effects of patient group and psychiatric status on postoperative psychiatric status. RESULTS: The majority of patients in the three groups experienced mood and anxiety disorders before surgery. Mood and anxiety disorders declined in the control, but not in the fear aura group after surgery. Presence of auras at 1 year after surgery was not related to psychiatric outcome. Postoperative mood and anxiety disorders were more common in patients with persistence of seizures and in those in the fear group who were seizure free. The minority of patients in all groups underwent psychotropic treatment before surgery, but the majority with fear auras underwent treatment after surgery. CONCLUSIONS: Postoperative mood and anxiety disorders were more common in fear aura patients after temporal lobectomy, in particular, if seizure free. Possible mechanisms include the role of the amygdala in fear conditioning, the concepts of forced normalization, and kindling.

Adult↗
PubMed2001

Lack of association between an interleukin 1 beta (IL-1beta) gene variation and refractory temporal lobe epilepsy.

PURPOSE: We attempted to confirm recent findings of Kanemoto et al. that demonstrated a positive association (p < 0.017) between a polymorphism in the promoter region of the interleukin 1-beta (IL-1beta) gene and the clinical phenotype of temporal lobe epilepsy with hippocampal sclerosis (TLE+HS). METHODS: We determined the frequency of this polymorphism in a group of 61 TLE+HS patients of European ancestry and compared it with that found in 119 ethnically matched control subjects. RESULTS: Analysis of genotype and allele frequencies showed no statistically significant difference in the distribution of the polymorphism between the two groups (p = 0.10). CONCLUSIONS: These data suggest that this IL-1beta promoter polymorphism does not act as a strong susceptibility factor for TLE+HS in a population of individuals of European ancestry.

Epilepsy, Temporal Lobe↗
PubMed2001

RASTA: a distributed temporal abstraction system to facilitate knowledge-driven monitoring of clinical databases.

The time dimension is very important for applications that reason with clinical data. Unfortunately, this task is inherently computationally expensive. As clinical decision support systems tackle increasingly varied problems, they will increase the demands on the temporal reasoning component, which may lead to slow response times. This paper addresses this problem. It describes a temporal reasoning system called RASTA that uses a distributed algorithm that enables it to deal with large data sets. The algorithm also supports a variety of configuration options, enabling RASTA to deal with a range of application requirements.

Algorithms↗
PubMed2000

Temporal lobectomy outcome in older versus younger adults.

A total of 340 patients age 50 years and older were compared with 30 patients younger than 50 years, all of whom had anterior temporal lobectomy for refractory epilepsy. Seizure outcome, neuropsychological test scores, and change in driving status were analyzed. Age and duration of epilepsy were related independently to outcome, but laterality of interictal sharp waves (an early epilepsy risk factor) and presence of tumor were not. Sixteen patients (52%) in the older group and 257 patients (75.6%) in the younger group (p < 0.008) were seizure free. Postoperative neuropsychological outcome and driving status were similar in older and younger patients.

Adolescent↗
PubMed2000

Lack of association between temporal lobe epilepsy and a novel polymorphism in the alpha 2 subunit gene (ATP1A2) of the sodium potassium transporting ATPase.

Genetic linkage studies in rodents and humans have identified specific chromosomal regions harboring seizure susceptibility genes. We have identified a novel polymorphism in the human alpha 2 subunit gene (ATP1A2) of the sodium potassium transporting ATPase (NaK-pump), a candidate gene for human temporal lobe epilepsy (TLE) based on its chromosomal location and function in ion homeostasis. The polymorphism consists of a four base pair insertion 12 base pairs upstream of the start of exon 2. We performed an association study between this polymorphism and TLE. Our study did not find a significant difference in the frequency of this polymorphism between TLE patients and controls, indicating that this variation is not a major susceptibility factor. However, since the number of patients studied so far is small and the functional consequence of the polymorphism is unknown, the variation may yet be found to play a minor role in increased risk for seizure susceptibility. In contrast to the findings in TLE patients and controls, we did find a significant difference in the frequency of the variation between African Americans and persons of European descent. This finding demonstrates the potential effect of population stratification on studies of this type and supports the growing use of parental and familial samples for controls in association studies. Further study of this polymorphism is warranted as it may be involved in other disease processes for which there are known ethnic-specific susceptibilities. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:79-83, 2000.

Base Sequence↗
PubMed2000

Relationships between the fatty acid composition of muscle and erythrocyte membrane phospholipid in young children and the effect of type of infant feeding.

Muscle membrane fatty acid (FA) composition is linked to insulin action. The aims of this study were to compare the FA composition of muscle and erythrocyte membrane phospholipid in young children; to investigate the effect of diet on these lipid compositions; and to investigate differential incorporation of FA into muscle, erythrocyte and adipose tissue membrane phospholipid, and adipose tissue triglyceride. Skeletal muscle biopsies and fasting blood samples were taken from 61 normally nourished children (45 males and 16 females), less than 2 yr old (means +/- SE, 0.80 +/- 0.06 yr), undergoing elective surgery. Adipose tissue samples were taken from 15 children. There were significant positive correlations between muscle and erythrocyte docosahexaenoic acid (DHA) (r = 0.44, P < 0.0001), total n-3 polyunsaturated fatty acids (PUFA) (r = 0.39, P = 0.002), and the n-6/n-3 PUFA ratio (r = 0.39, P = 0.002). Adipose tissue triglyceride had lower levels of long-chain PUFA, especially DHA, than muscle and erythrocytes (0.46 +/- 0.18% vs. 2.44 +/- 0.26% and 3.17 +/- 0.27%). Breast-fed infants had higher levels of DHA than an age-matched group of formula-fed infants in both muscle (3.91 +/- 0.21% vs. 1.94 +/- 0.18%) and erythrocytes (3.81 +/- 0.40% vs. 2.65 +/- 0.23%). The results of this study show that (i) erythrocyte FA composition is a reasonable index of muscle DHA, total n-3 PUFA, and the n-6/n-3 PUFA ratio; (ii) breast feeding has a potent effect on the FA composition of all these tissues; and (iii) there is a wide range in long-chain PUFA levels in muscle, erythrocytes, and adipose tissue.

Adipose Tissue↗
PubMed2000

Nuclear matrix attachment regions of human papillomavirus type 16 repress or activate the E6 promoter, depending on the physical state of the viral DNA.

Two nuclear matrix attachment regions (MARs) bracket a 550-bp segment of the long control region (LCR) containing the epithelial cell-specific enhancer and the E6 promoter of human papillomavirus type 16 (HPV-16). One of these MARs is located in the 5' third of the LCR (5'-LCR-MAR); the other lies within the E6 gene (E6-MAR). To study their function, we linked these MARs in various natural or artificial permutations to a chimeric gene consisting of the HPV-16 enhancer-promoter segment and a reporter gene. In transient transfections of HeLa cells, the presence of either of these two MARs strongly represses reporter gene expression. In contrast to this, but similar to the published behavior of cellular MARs, reporter gene expression is stimulated strongly by the E6-MAR and moderately by the 5'-LCR-MAR in stable transfectants of HeLa or C33A cells. To search for binding sites of soluble nuclear proteins which may be responsible for repression during transient transfections, we performed electrophoretic mobility shift assays (EMSAs) of overlapping oligonucleotides that represented all sequences of these two MARs. Both MARs contain multiple sites for two strongly binding proteins and weak binding sites for additional factors. The strongest complex, with at least five binding sites in each MAR, is generated by the CCAAT displacement factor (CDP)/Cut, as judged by biochemical purification, by EMSAs with competing oligonucleotides and with anti-CDP/Cut oligonucleotides, and by mutations. CDP/Cut, a repressor that is down-regulated during differentiation, apparently represses HPV-16 transcription in undifferentiated epithelials cells and in HeLa cells, which are rich in CDP/Cut. In analogy to poorly understood mechanisms acting on cellular MARs, activation after physical linkage to chromosomal DNA may result from competition between the nuclear matrix and CDP/Cut. Our observations show that cis-responsive elements that regulate the HPV-16 E6 promoter are tightly clustered over at least 1.3 kb and occur throughout the E6 gene. HPV-16 MARs are context dependent transcriptional enhancers, and activated expression of HPV-16 oncogenes dependent on chromosomal integration may positively select tumorigenic cells during the multistep etiology of cervical cancer.

Base Sequence↗
PubMed2000

Psychiatric aspects of temporal lobe epilepsy before and after anterior temporal lobectomy.

OBJECTIVES: Psychopathology has been reported to be prevalent both before and after surgical treatment for medically intractable temporal lobe epilepsy. Individual patients were evaluated prospectively to assess the effect of anterior temporal lobectomy (ATL) on prevalence and severity of psychiatric disease. METHODS: Psychiatric status was assessed in a consecutive series of epilepsy patients before and 6 months after ATL using a structured psychiatric interview, psychiatric rating scales, and self report mood measures. RESULTS: A DSM-III-R axis I diagnosis was present in 65% of patients before and after surgery. The most common diagnoses were depression, anxiety, and organic mood/personality disorders. There was a trend for major psychiatric diagnoses to be more common in patients with right compared to left temporal lobe seizure focus, both before and after surgery. The apparent stability in the overall rate of psychiatric dysfunction concealed onset of new psychiatric problems in 31% of patients in the months shortly after surgery, and resolution of psychiatric diagnoses in 15% of patients. In the group as a whole, the severity of psychiatric symptoms was lower at 6 months postsurgery than before temporal lobectomy. CONCLUSIONS: The overall prevalence of psychiatric dysfunction was comparably high before and after ATL, but individual changes in psychiatric status and changes in severity of symptoms occurred in many patients in the 6 months after surgery.

Adult↗
PubMed2000

The differentiation-specific factor CDP/Cut represses transcription and replication of human papillomaviruses through a conserved silencing element.

The life cycles of human papillomaviruses (HPVs) are intimately linked to the differentiation program of infected stratified epithelia, with both viral gene expression and replication being maintained at low levels in undifferentiated basal cells and increased upon host cell differentiation. We recently identified, in HPV-16, a negative regulatory element between the epithelial-cell-specific enhancer and the E6 promoter that is capable of silencing E6 promoter activity, and we termed this element a papillomavirus silencing motif (PSM) and the unknown cellular factor that bound to it PSM binding protein (PSM-BP). Here we show that the homologous genomic segments of six other distantly related genital HPV types contain a PSM that binds PSM-BP and is capable of repressing transcription. Conservation of the PSM suggests that it is indispensable for the HPV life cycle. Purification, electrophoretic mobility shift assay experiments, and the use of specific antibodies proved that the cellular factor PSM-BP is identical to a previously described transcriptional repressor, the CCAAT displacement protein (CDP), also referred to as the human Cut protein (Cut). CDP/Cut repression of HPV-16 may stem from the modification of specifically positioned nucleosomes, as suggested by transcriptional stimulation under the influence of the histone deacetylase inhibitor trichostatin A. CDP/Cut is an important developmental regulator in several different tissues. It was recently shown that CDP/Cut is expressed in basal epithelial cells but not in differentiated primary keratinocytes. This suggests the possibility that repression by PSM couples HPV transcription to the stratification of epithelia. In each of the studied HPV types, the two CDP/Cut binding sites of PSM overlap with the known or presumed binding sites of the replication initiator protein E1. Transfection of CDP/Cut expression vectors into cells that support HPV-16 or HPV-31 replication leads to the elimination of viral episomes. Similarly, two PSM-like motifs overlapping the E1 binding site of bovine papillomavirus type 1 bind CDP/Cut, and CDP/Cut overexpression reduces the copy number of episomally replicating BPV-1 genomes in mouse fibroblasts. CDP/Cut appears to be a master regulator of HPV transcription and replication during epithelial differentiation, and PSMs are important cis-responsive targets of this repressor.

Animals↗
PubMed2000

Characterization of cultured microglia that can be infected by HIV-1.

Parenchymal microglia are targets of HIV infection. We, as well as others, have used in vitro microglia culture systems to study the tropism and replication of HIV. Characterization of perivascular and parenchymal microglia surface markers in vivo, in vitro, and ex vivo, has led to the understanding that these cell populations are different, and data from both the HIV and SIV models support the hypothesis that they may play different roles in infection of the CNS. We determined that human adult parenchymal microglia cultured from temporal lobe tissue for use in HIV replication studies, were CD11c+, CD45+, CD68+, CD14- when cultured with standard serum/cytokine-supplemented media. To determine the influence of serum and cytokines on HIV replication in microglia, we designed a new protocol for culturing microglia, and compared the results obtained with this protocol with the standard approach previously described. Microglia cultured in the presence of a 'feeder' layer of glial cells and in the absence of serum and cytokines expressed the same surface markers as pure microglia (>95%) cultured in supplemented media. However, pure microglia cultured in the absence of both serum/cytokines supplements and other glial cells, did not have characteristic microglial morphology and did not support HIV replication to as high a level. Lastly, we determined that unlike monocytes, ex vivo parenchymal microglia were capable of supporting HIV replication.

Adult↗
PubMed2000

Prenatal alcohol exposure and depressive features in children.

BACKGROUND: This study examined the association between prenatal alcohol exposure and self-report of depressive symptoms in 5- to 6-year-old children. Higher levels of prenatal alcohol exposure were hypothesized to be associated with endorsement of a greater number of depressive symptoms in children. It was also hypothesized that maternal depression, although associated with drinking behavior, would contribute independently to outcome. Finally, the mother's behavior toward the child, as well as current drinking practices, were postulated to mediate the relationship between prenatal alcohol exposure and child depressive symptoms. METHODS: Participants were 41 mother-child dyads who had been followed longitudinally since the children were 1 year of age. Self-report questionnaires for maternal and child depression were used. RESULTS: Results revealed that prenatal alcohol exposure, maternal depression, and child gender seemed to be highly associated with child depressive symptoms. Girls who had higher levels of prenatal alcohol exposure and whose mothers acknowledged higher levels of depression endorsed the highest number of depressive symptoms. Neither the mother's behavior in interaction with the child nor her current level of alcohol consumption mediated the relationship. CONCLUSIONS: The importance of considering prenatal alcohol exposure as a risk variable in the prediction of childhood-onset depression and the possible neurological mechanisms underlying depression in children with alcohol exposure in utero are discussed.

Adult↗
PubMed2000

Representation of temporal indeterminacy in clinical databases.

Temporal indeterminancy is common in clinical medicine because the time of many clinical events is frequently not precisely known. Decision support systems that reason with clinical data may need to deal with this indeterminancy. This indeterminacy support must have a sound foundational model so that other system components may take advantage of it. In particular, it should operate in concert with temporal abstraction, a feature that is crucial in several clinical decision support systems that our group has developed. We have implemented a temporal query system called Tzolkin that provides extensive support for the temporal indeterminancies found in clinical medicine, and have integrated this support with our temporal abstraction mechanism. The resulting system provides a simple, yet powerful approach for dealing with temporal indeterminancy and temporal abstraction.

Databases as Topic↗