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Biomedical subjects

P M Thompson

Publications and source records attributed to P M Thompson.

At least 55 records · Page 3Linked to original sources
PubMed2000

Mathematical/computational challenges in creating deformable and probabilistic atlases of the human brain.

Striking variations in brain structure, especially in the gyral patterns of the human cortex, present fundamental challenges in human brain mapping. Probabilistic brain atlases, which encode information on structural and functional variability in large human populations, are powerful research tools with broad applications. Knowledge-based imaging algorithms can also leverage atlased information on anatomic variation. Applications include automated image labeling, pathology detection in individuals or groups, and investigating how regional anatomy is altered in disease, and with age, gender, handedness and other clinical or genetic factors. In this report, we illustrate some of the mathematical challenges involved in constructing population-based brain atlases. A disease-specific atlas is constructed to represent the human brain in Alzheimer's disease (AD). Specialized strategies are developed for population-based averaging of anatomy. Sets of high-dimensional elastic mappings, based on the principles of continuum mechanics, reconfigure the anatomy of a large number of subjects in an anatomic image database. These mappings generate a local encoding of anatomic variability and are used to create a crisp anatomical image template with highly resolved structures in their mean spatial location. Specialized approaches are also developed to average cortical topography. Since cortical patterns are altered in a variety of diseases, gyral pattern matching is used to encode the magnitude and principal directions of local cortical variation. In the resulting cortical templates, subtle features emerge. Regional asymmetries appear that are not apparent in individual anatomies. Population-based maps of cortical variation reveal a mosaic of variability patterns that segregate sharply according to functional specialization and cytoarchitectonic boundaries.

Aged↗
PubMed2000

Identification of a 1-megabase consensus region of deletion at 1p36.3 in primary neuroblastomas.

BACKGROUND: Deletion of the distal short arm of chromosome 1 occurs frequently in neuroblastoma. In addition, neuroblastoma has been described in children with constitutional deletions within 1p36, supporting the existence of one or more neuroblastoma suppressor genes within this region. PROCEDURE: We have pursued a 1p36 tumor suppressor gene identification strategy that has included deletion mapping of 566 primary neuroblastomas and 46 neuroblastoma-derived cell lines, and have determined the parental origin of the deleted 1p homologue in 44 cases to determine whether there is evidence for genomic imprinting within this region. RESULTS AND CONCLUSIONS: We have identified a 1-Mb consensus region of deletion within 1p36.3 defined by primary tumor deletions, constructed a physical map of the region that is being sequenced to completion, and have identified and prioritized candidate genes within this region for further analyses.

Alleles↗
PubMed2000

BIN1 inhibits colony formation and induces apoptosis in neuroblastoma cell lines with MYCN amplification.

BACKGROUND: MYCN amplification and overexpression occurs in 25% of neuroblastomas and independently predicts for poor prognosis disease, an effect thought to be mediated by its role as a transcriptional activator of growth promoting genes. However, in many mammalian cells, deregulated expression of MYC family genes (including MYCN) induces apoptosis. We hypothesized that BIN1, a MYC interacting protein capable of inducing apoptosis, may be an important regulator of MYCN in neuroblastoma. RESULTS: BIN1 expression was found to be reduced in MYCN-amplified cell lines. Further, forced expression of BIN1 markedly reduced colony formation in MYCN-amplified, but not single-copy, cell lines. This effect appeared to be caused by an increase in apoptosis, and was augmented by serum deprivation and concurrent cytotoxic drug therapy in cell culture CONCLUSION: BIN1 inactivation may be necessary for MYCN overexpression to lead to cellular proliferation rather than programmed cell death in neuroblastomas with MYCN amplification.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Evaluating the parent-of-origin effect in bipolar affective disorder. Is a more penetrant subtype transmitted paternally?

BACKGROUND: Numerous genetic mechanisms and modes of transmission underlying bipolar affective disorder (BPAD) have been postulated. Recently, the discovery of genomic imprinting and mitochondrial transmission of illness in humans has stimulated study of parent-of-origin effects in the transmission of BPAD. METHODS: We examined a large sample of families from an associated linkage study to search for a possible parent-of-origin effect. Selecting for unilineal families with at least one offspring and/or parent diagnosed with BPAD after structured interview, we conducted three analyses: (1) the rates of illness among mothers and fathers of offspring affected with BPAD; (2) the observed frequency of transmission and rates of illness among maternal and paternal lineages; and (3) the rates of affective illness among offspring of parents affected with BPAD. RESULTS: Our results indicate no significant differences in the rates of illness among mothers and fathers of offspring affected with BPAD. Also, the frequency of transmission and rates of illness among maternal and paternal lineages did not differ significantly. However, the rate of BPAD among the offspring of fathers affected with BPAD was significantly higher than for mothers with the illness. LIMITATIONS: Substantially more women than men, and maternal than paternal relatives were studied - introducing possible gender biases. CONCLUSIONS: These results suggest a possible paternal parent-of-origin effect.

Bipolar Disorder↗
PubMed2000

Mapping morphology of the corpus callosum in schizophrenia.

The nature and extent of callosal morphological alterations in schizophrenia remain unresolved. A parametric surface modeling approach using magnetic resonance (MR) images was employed. This provided spatially accurate representations of midsagittal callosal surfaces in schizophrenic patients (n = 25; 15 males) and normal controls (n = 28; 15 males). Areas of functionally relevant callosal channels and measures reflecting callosal shape were visualized and compared across groups. To register neuroanatomical landmarks surrounding the corpus callosum, each three-dimensional MR volume was scaled according to Talairach AC-PC distance, and raw distances included as covariates in multivariate analyses. Results revealed: (i) a marked vertical displacement of the corpus callosum in patients (P < 0.01); (ii) increases in curvature of superior and inferior callosal surfaces (P < 0.001); and (iii) significant increases in maximum widths in anterior and posterior regions in male patients compared to male controls; as well as (iv) increased patterns of callosal variability in female patients but no effects of diagnosis between female groups. These findings demonstrate a clear index of structural neuropathology in male schizophrenic patients. Displacement and curvature increases were highly correlated with structural differences in surrounding neuroanatomical regions, including increased volume of the lateral ventricles (P < 0.01).

Adult↗
PubMed2000

Brain abnormalities in early-onset schizophrenia spectrum disorder observed with statistical parametric mapping of structural magnetic resonance images.

OBJECTIVE: The purpose of this study was to assess neuroanatomic abnormalities in children and adolescents with childhood-onset schizophrenia by using whole-brain voxel-based morphometric analyses. Previous volumetric studies of brain abnormalities in childhood-onset schizophrenia have revealed anomalies similar to those in subjects with adult-onset schizophrenia. Specifically, low cerebral volume, high ventricular volume, and thalamic, basal ganglia, callosal, and temporal lobe abnormalities have been observed in childhood-onset schizophrenia. Relatively few anatomical structures have been delineated and measured in this rare population, partly because of the labor involved in the slice-by-slice region definition required of conventional volumetric image analyses. METHOD: The subjects were 10 normal children and adolescents and nine children and adolescents with early-onset schizophrenia (mean age at diagnosis, 11.0 years; range, 7-16 years). The authors conducted voxel-by-voxel and volumetric statistical analyses of high-resolution structural magnetic resonance images. RESULTS: Statistical parametric maps of gray matter, white matter, and CSF differences between the groups revealed that the subjects with early-onset schizophrenia had larger ventricles, predominantly in the posterior horns of the lateral ventricles, and midcallosal, posterior cingulate, caudate, and thalamic abnormalities. Volumetric analyses of the lateral ventricles in native image data space confirmed significantly higher volume in posterior, but not anterior, regions. Randomization tests confirmed the overall statistical significance of the group differences and validity of the parametric maps. CONCLUSIONS: These findings are generally consistent with the findings of other research groups, but localization of enlarged ventricles specific to the posterior region may be a new finding in the literature on childhood-onset schizophrenia.

Adolescent↗
PubMed2000

Loss of heterozygosity at 1p36 independently predicts for disease progression but not decreased overall survival probability in neuroblastoma patients: a Children's Cancer Group study.

PURPOSE: To determine the independent prognostic significance of 1p36 loss of heterozygosity (LOH) in a representative group of neuroblastoma patients. PATIENTS AND METHODS: Diagnostic tumor specimens from 238 patients registered onto the most recent Children's Cancer Group phase III clinical trials were assayed for LOH with 13 microsatellite polymorphic markers spanning chromosome band 1p36. Allelic status at 1p36 was correlated with other prognostic variables and disease outcome. RESULTS: LOH at 1p36 was detected in 83 (35%) of 238 neuroblastomas. There was a correlation of 1p36 LOH with age at diagnosis greater than 1 year (P = .026), metastatic disease (P<.001), elevated serum ferritin level (P<.001), unfavorable histopathology (P<.001), and MYCN oncogene amplification (P<.001). LOH at 1p36 was associated with decreased event-free survival (EFS) and overall survival (OS) probabilities (P<.0001). For the 180 cases with single-copy MYCN, 1p36 LOH status was highly correlated with decreased EFS (P = .0002) but not OS (P = .1212). Entering 1p36 LOH into a multivariate regression model suggested a trend toward an independent association with decreased EFS (P = .0558) but not with decreased OS (P = .3687). Furthermore, allelic status at 1p36 was the only prognostic variable that was significantly associated with decreased EFS in low-risk neuroblastoma patients (P = .0148). CONCLUSION: LOH at 1p36 is independently associated with decreased EFS, but not OS, in neuroblastoma patients. Determination of 1p36 allelic status may be useful for predicting which neuroblastoma patients with otherwise favorable clinical and biologic features are more likely to have disease progression.

Child↗
PubMed1999

Mapping biochemistry to metabolism: FDG-PET and amyloid burden in Alzheimer's disease.

We evaluated the relationship between amyloid-beta protein (A beta) concentration and the metabolic abnormality in an Alzheimer's disease (AD) patient as measured by [18F]fluorodeoxyglucose positron emission tomography (FDG-PET). Across most regions there were significant inverse correlations among FDG-PET intensity values and both insoluble. The temporal lobe samples showed no significant correlation between FDG-PET values and A beta deposition. Findings support A beta as contributing to the hypometabolism in regions of the AD brain that are still relatively viable metabolically; those regions with chronic pathologic damage, such as temporal cortex, may have other factors that contribute to metabolic deficits.

Aged↗
PubMed1999

Allelic deletion at 11q23 is common in MYCN single copy neuroblastomas.

Deletions of the long arm of chromosome 11 (11q) have been noted in primary neuroblastomas, but a comprehensive analysis has not been performed. Therefore, we analysed 331 neuroblastomas (295 sporadic, 15 familial and 21 tumor-derived cell lines) to determine the prevalence of 11q allelic deletions, to map the location of a putative tumor suppressor gene and to perform clinical correlative studies. Assays for loss of heterozygosity (LOH) were performed at 24 microsatellite loci spanning 11q. LOH was observed at multiple 11q loci in 129/295 (44%) sporadic neuroblastomas, 5/15 (33%) familial neuroblastomas, and 5/21 (24%) neuroblastoma cell lines. A single region of 2.1 cM within 11q23.3, flanked by markers D11S1340 and D11S1299, was deleted in all specimens with 11q LOH. Allelic loss at 11q23 was inversely related to MYCN amplification (P<0.001). Within the subset of cases with a single copy of MYCN, 11q LOH was associated with advanced stage disease (P=0.008), unfavorable histopathology (P=0.042), and decreased overall survival probability (P=0.008). However, 11q LOH was not independently prognostic in multivariate analyses. These data support the hypothesis that a tumor suppressor gene mapping within 11q23.3 is commonly inactivated during the malignant evolution of a large subset of neuroblastomas, especially those with unamplified MYCN.

Alleles↗
PubMed1999

Epidermal diseases in bottlenose dolphins: impacts of natural and anthropogenic factors.

Experimental studies have highlighted the potential influence of contaminants on marine mammal immune function and anthropogenic contaminants are commonly believed to influence the development of diseases observed in the wild. However, estimates of the impact of contaminants on wild populations are constrained by uncertainty over natural variation in disease patterns under different environmental conditions. We used photographic techniques to compare levels of epidermal disease in ten coastal populations of bottlenose dolphins (Tursiops truncatus) exposed to a wide range of natural and anthropogenic conditions. Epidermal lesions were common in all populations (affecting > 60% of individuals), but both the prevalence and severity of 15 lesion categories varied between populations. No relationships were found between epidermal disease and contaminant levels across the four populations for which toxicological data were available. In contrast, there were highly significant linear relationships with oceanographic variables. In particular, populations from areas of low water temperature and low salinity exhibited higher lesion prevalence and severity. Such conditions may impact on epidermal integrity or produce more general physiological stress, potentially making animals more vulnerable to natural infections or anthropogenic factors. These results show that variations in natural environmental factors must be accounted for when investigating the importance of anthropogenic impacts on disease in wild marine mammals.

Animals↗
PubMed1999

Localizing age-related changes in brain structure between childhood and adolescence using statistical parametric mapping.

Volumetric studies have consistently shown reductions in cerebral gray matter volume between childhood and adolescence, with the most dramatic changes occurring in the more dorsal cortices of the frontal and parietal lobes. The purpose of this study was to examine the spatial location of these changes employing methods typical of functional imaging studies. T1-weighted structural MRI data (1.2 mm) were analyzed for nine normally developing children and nine normal adolescents. Validity and reliability of the tissue segmentation protocol were assessed as part of several preprocessing analyses prior to statistical parametric mapping (SPM). Using SPM96, a simple contrast of average gray matter differences between the two age groups revealed 57 significant clusters (SPM[Z] height threshold, P<0.001, extent threshold 50, uncorrected). The pattern and distribution of differences were consistent with earlier findings from the volumetric assessment of the same subjects. Specifically, more differences were observed in dorsal frontal and parietal regions with relatively few differences observed in cortices of the temporal and occipital lobes. Permutation tests were conducted to assess the overall significance of the gray matter differences and validity of the parametric maps. Twenty SPMs were created with subjects randomly assigned to groups. None of the random SPMs approached the number of significant clusters observed in the age difference SPM (mean number of significant clusters = 5.8). The age effects observed appear to result from regions that consistently segment as gray matter in the younger group and consistently segment as white matter in the older group. The utility of these methods for localizing relatively subtle structural changes that occur between childhood and adolescence has not previously been examined.

Adolescent↗
PubMed1999

CSF SNAP-25 in schizophrenia and bipolar illness. A pilot study.

Research efforts to identify and understand the pathophysiology of schizophrenia and bipolar illness are limited by the inability to study neuronal tissue of living patients. An alternative to sampling brain tissue from living patients is to measure neuronal proteins found in cerebral spinal fluid. One such candidate protein is synaptosomal-associated protein 25kDa. Our hypothesis is that the level of this protein in cerebral spinal fluid may be a marker of neuronal pathology. Cerebral spinal fluid from headache, schizophrenic, bipolar, and control subjects was used to measure the SNAP-25 level by quantitative dot blotting. Schizophrenic subjects had significantly elevated levels of SNAP-25 as compared to headache and control subjects. However, there was no significant difference between the bipolar group and schizophrenic or control groups. This study reports on a potentially useful clinical marker in schizophrenia, and the presence of elevated cerebral spinal fluid SNAP-25 may indicate alterations in neuronal functioning.

Adolescent↗
PubMed1999

Modeling the pharmacoeconomic cost of three selective serotonin reuptake inhibitors.

The authors present a method for modeling cost data on three selective serotonin reuptake inhibitors (SSRIs)-fluoxetine, paroxetine, and sertraline-from a large clinical outcomes study in a university-affiliated mental health center. Using data from 2,779 patients, average drug cost per day was calculated based on the percentage of patients on each daily dose of each medication. Given no overall significant difference between the SSRIs in effectiveness, the actual average cost per day determined by dose distribution was $1.79 for fluoxetine, $1.41 for paroxetine, and $1.21 for sertraline (using halved 100 mg tablets). The results suggest that cost can serve as one measure to help guide choice of medications.

Dose-Response Relationship, Drug↗
PubMed1999

Antidepressant medication change in a clinical treatment setting: a comparison of the effectiveness of selective serotonin reuptake inhibitors.

BACKGROUND: This investigation focuses on the 3 most frequently used selective serotonin reuptake inhibitors (SSRIs) (paroxetine, fluoxetine, sertraline) and examines the rate of medication switches as a measure of effectiveness. We answer 2 questions: (1) What is the likelihood that a patient starting treatment with an SSRI will complete treatment with the same agent? and (2) Depending on the initial SSRI agent used, do patients switch at different frequencies? METHOD: A retrospective chart review was performed on 2779 patients treated in a university outpatient clinic from March 1995 to January 1997. Of these, 263 patients given antidepressants were randomly selected: 214 were prescribed SSRIs; 24, novel antidepressants; and 25, tricyclic antidepressants. RESULTS: There was no significant difference in rate of switching between the different classes of antidepressant (p = .1) nor between drugs within the SSRI class (p = .513). When medication change was the independent factor, significant differences between the groups were total time in treatment and number of visits (p < .001 and p = .011, respectively). Age, education, and Clinical Global Impressions-Severity of Illness scale scores (admission, discharge, and change) were not significantly different between the groups. CONCLUSION: Approximately 25% of patients started with an SSRI will switch to another antidepressant in the course of their treatment. The SSRIs appear to be equivalent in effectiveness. They are not interchangeable, because patients who discontinue one SSRI for lack of tolerability or response can generally be treated effectively with another.

Adolescent↗
PubMed1999

Intravesical chemotherapy with epirubicin: a dose response study.

PURPOSE: We determined the difference in response to high and standard doses of intravesical epirubicin for treatment of superficial bladder cancer. MATERIALS AND METHODS: A total of 122 patients were entered into a randomized trial to compare the response of a marker tumor at 3 months, time to first recurrence and recurrence rates for 2 years after intravesical chemotherapy for superficial (pTa/pT1) bladder cancer. Patients were randomized to receive treatment for 1 hour with 1 (standard dose) or 2 mg./ml. (high dose) epirubicin (50 or 100 mg./50 ml. solution). RESULTS: There was no difference in the marker tumor response rate in 24 of 52 patients treated with the standard dose compared with 21 of 50 treated with the higher dose of epirubicin (p = 0.67). Similarly, the higher dose was not superior in regard to time to first recurrence, with a hazard ratio of 1.46 (p = 0.14, 95% confidence intervals 0.88 to 2.42). Considering the upper end of the confidence interval, we can reliably exclude an absolute difference of greater than 4% at 1 year for time to first recurrence in favor of higher dose chemotherapy. CONCLUSIONS: Epirubicin at double the standard dose for intravesical chemotherapy of superficial bladder cancer is not superior in regard to marker tumor response, time to first recurrence or recurrence rate.

Administration, Intravesical↗