D K Pearl

Publications of D K Pearl

• Bayesian modelling of the dynamics of hepatotoxicity.

  Authors: Q Li, X Shen, D K Pearl

  Statistics in medicine. 09/2007; 26(19):3591-611.

  Hepatotoxicity (liver damage) is a common problem in drug treatment trials but is observed only indirectly through biomarkers measured in the blood. This creates the need to infer an individual'sHepatotoxicity (liver damage) is a common problem in drug treatment trials but is observed only indirectly through biomarkers measured in the blood. This creates the need to infer an individual's unobserved liver function dynamically using blood tests and other patient baseline characteristics. Major statistical challenges include high dimensionality, irregular time observation points over patients, presence of missing observations, and noise involved in measurement and biological processes. This article introduces a class of multivariate Bayesian dynamic stochastic models for detecting and forecasting changes in an individual's liver function in two situations: without and with drug. These models separate measurement error from variation inherent in a biological process, and describe the underlying process of liver detoxification, whereby, drug affects liver function which in turn induces changes in observed analytes. We apply the Bayesian methodology to make an inference. A clinical toxicity study is examined, together with simulated data. The results suggest that changes in observed analytes can be captured by the proposed models.

• Diagnostic and prognostic value of glycosyltransferase mRNA in glioblastoma multiforme patients.

  Authors: J L Oblinger, D K Pearl, C L Boardman, H Saqr, T W Prior, B W Scheithauer, R B Jenkins, P C Burger, A J Yates

  Neuropathology and applied neurobiology. 09/2006; 32(4):410-8.

  Glioblastoma multiforme (GBM) is the most common and aggressive primary human brain tumour in adults with an average survival of 11 months. The 2-year survival is less than 10%, and only a smallGlioblastoma multiforme (GBM) is the most common and aggressive primary human brain tumour in adults with an average survival of 11 months. The 2-year survival is less than 10%, and only a small proportion of patients are alive at 3 years. Despite improved treatment strategies and aggressive therapy, the prognosis of GBM has changed little in past decades. Thus, any test that can reliably and rapidly diagnose the tumour and predict patient survival could be a valuable tool. Herein we report the use of quantitative real-time polymerase chain reaction (PCR) to quantify five glycosyltransferase transcripts in gliomas. Our results indicate that measuring GM1 synthase (beta-1,3 galactosyltransferase) mRNA may provide a useful method for segregating GBMs from other types of gliomas. In these studies, 97% of gliomas (36/37 tumours) below a threshold value had a diagnosis of GBM compared with 49% (52/106 tumours) above the threshold. More importantly, the increased expression of GD3 synthase mRNA in combination with decreased GalNAcT message correlated with increased survival in 79 GBM patients (proportional hazards model controlling for age, P = 0.02). These data were further corroborated by a data analysis from one of our previous studies on gangliosides of 80 GBMs, in which increased amounts of GM3 and GD3 (which accumulate in the absence of GalNAcT) correlated with a longer survival (P < 0.01). Thus, measuring GalNAcT and GD3 transcripts may provide a rapid method to assess prognosis in GBM patients. In summary, the data indicate that measuring glycosyltransferase mRNA levels by real-time PCR may be clinically useful for determining both diagnosis and prognosis in GBM patients.

• Small cell architecture--a histological equivalent of EGFR amplification in glioblastoma multiforme?

  Authors: P C Burger, D K Pearl, K Aldape, A J Yates, B W Scheithauer, S M Passe, R B Jenkins, C D James

  Journal of neuropathology and experimental neurology. 12/2001; 60(11):1099-104.

  Although there is much written about the molecular definitions of "primary" glioblastomas (GBM), there is little known about the histological features of this predominant subtype. We hypothesizedAlthough there is much written about the molecular definitions of "primary" glioblastomas (GBM), there is little known about the histological features of this predominant subtype. We hypothesized that the "small cell architecture" would represent a histological feature of most primary GBMs. This was tested by comparing the presence of the small cell phenotype with the presence or absence of amplification of the epidermal growth factor receptor (EGFR), a common event in primary GBMs. After a pilot study that found a correlation between this small cell phenotype and EGFR amplification, we selected 9 pure small cell GBMs (SCGBM) and 12 non-SCGBMs to be studied for EGFR amplification by fluorescence in situ hybridization (FISH). In this set of 21 cases, 8 of 9 SCGBMs and 5 of 12 non-SCGBMs were amplified for EGFR. We then correlated the EGFR status of 79 GBMs unselected for their histological features from a set that had been previously characterized in regard to EGFR amplification. Fourteen of 21 (67%) exclusively small cell neoplasms, 8 of 25 (32%) GBMs with both small cell and non-small cell areas, and 3 of 33 (9%) non-small cell GBMs were amplified for EGFR (p = 0.0004 with an exact test). We conclude that EGFR amplification is associated with a small cell phenotype in GBMs and that SCGBMs are an important component of "primary" GBMs.

• Somatic INK4a-ARF locus mutations: a significant mechanism of gene inactivation in squamous cell carcinomas of the head and neck.

  Authors: M J Poi, T Yen, J Li, H Song, J C Lang, D E Schuller, D K Pearl, B C Casto, M D Tsai, C M Weghorst

  Molecular carcinogenesis. 02/2001; 30(1):26-36.

  The INK4a-ARF locus is located on human chromosome 9p21 and is known to encode two functionally distinct tumor-suppressor genes. The p16(INK4a) (p16) tumor-suppressor gene product is a negativeThe INK4a-ARF locus is located on human chromosome 9p21 and is known to encode two functionally distinct tumor-suppressor genes. The p16(INK4a) (p16) tumor-suppressor gene product is a negative regulator of cyclin-dependent kinases 4 and 6, which in turn positively regulate progression of mammalian cells through the cell cycle. The p14(ARF) tumor-suppressor gene product specifically interacts with human double minute 2, leading to the subsequent stabilization of p53 and G(1) arrest. Previous investigations analyzing the p16 gene in squamous cell carcinomas of the head and neck (SCCHNs) have suggested the predominate inactivating events to be homozygous gene deletions and hypermethylation of the p16 promoter. Somatic mutational inactivation of p16 has been reported to be low (0-10%, with a combined incidence of 25 of 279, or 9%) and to play only a minor role in the development of SCCHN. The present study examined whether this particular mechanism of INK4a/ARF inactivation, specifically somatic mutation, has been underestimated in SCCHN by determining the mutational status of the p16 and p14(ARF) genes in 100 primary SCCHNs with the use of polymerase chain reaction technology and a highly sensitive, nonradioactive modification of single-stranded conformational polymorphism (SSCP) analysis termed "cold" SSCP. Exons 1alpha, 1beta, and 2 of INK4a/ARF were amplified using intron-based primers or a combination of intron- and exon-based primers. A total of 27 SCCHNs (27%) exhibited sequence alterations in this locus, 22 (22%) of which were somatic sequence alterations and five (5%) of which were a single polymorphism in codon 148. Of the 22 somatic alterations, 20 (91%) directly or indirectly involved exon 2, and two (9%) were located within exon 1alpha. No mutations were found in exon 1beta. All 22 somatic mutations would be expected to yield altered p16 proteins, but only 15 of them should affect p14(ARF) proteins. Specific somatic alterations included microdeletions or insertions (nine of 22, 41%), a microrearrangement (one of 22, 5%), and single nucleotide substitutions (12 of 22, 56%). In addition, we analyzed the functional characteristics of seven unique mutant p16 proteins identified in this study by assessing their ability to inhibit cyclin-dependent kinase 4 activity. Six of the seven mutant proteins tested exhibited reduced function compared with wild-type p16, ranging from minor decreases of function (twofold to eightfold) in four samples to total loss of function (29- to 38-fold decrease) in two other samples. Overall, somatic mutation of the INK4a/ARF tumor suppressor locus, resulting in functionally deficient p16 and possibly p14(ARF) proteins, seems to be a prevalent event in the development of SCCHN. Mol. Carcinog. 30:26-36, 2001.

• Glycolipid markers of astrocytomas and oligodendrogliomas.

  Authors: A J Yates, T Comas, B W Scheithauer, P C Burger, D K Pearl

  Journal of neuropathology and experimental neurology. 12/1999; 58(12):1250-62.

  Neutral glycolipids and gangliosides were analyzed in 149 astrocytomas (A), 46 oligodendrogliomas (O), and 21 oligoastrocytomas (OA) to determine if specific glycolipids correlate with histologicNeutral glycolipids and gangliosides were analyzed in 149 astrocytomas (A), 46 oligodendrogliomas (O), and 21 oligoastrocytomas (OA) to determine if specific glycolipids correlate with histologic diagnosis and grade. Positivity for asialoGM1 (GA1) and negativity for paragloboside by immuno-TLC correlated with histological diagnosis of O and OA, whereas the reverse pattern correlated with A. High levels (over 5 microg hexose per mg dry weight) of CMH generally correlated with an O component, but the association was not as strong as for either GA1 presence or paragloboside absence. Pilocytic astrocytomas and pleomorphic xanthoastrocytomas had high proportions (> 15%) of globoside, low ratios (< 0.5) of GD1a: GD1b, and identifiable ceramide trihexoside (CTH). Three gangliosides of the 1b pathway were progressively lost with increasing grade of A, but a similar correlation with grade was not seen in O or OA. A high proportion of cases expressing sialosylparagloboside (3'LM1; 6'LM1) were grade 4 A. Glycolipids are synthesized by glycosyltransferases that add specific sugars to the nascent oligosaccharide. Correlation of specific glycolipids with histological diagnoses and grades indicate that these tumor types express specific patterns of glycosyltransferases, several of which have been cloned. It is possible that critical genes coding for these enzymes are deleted, overexpressed, or mutated in certain tumor types and grades, thus leading to the patterns of glycolipids that we found to be associated with these tumors.

• Immunohistochemical staining for ganglioside GD1b as a diagnostic and prognostic marker for primary human brain tumors.

  Authors: T C Comas, T Tai, D Kimmel, B W Scheithauer, P C Burger, D K Pearl, S D Jewell, A J Yates

  Neuro-oncology. 11/1999; 1(4):261-7.

  Immunohistochemical staining intensity for ganglioside GD1b was determined for 108 human neuroectodermal tumors. Most of the tissue elements that immunostained were tumor cells; only a few axons andImmunohistochemical staining intensity for ganglioside GD1b was determined for 108 human neuroectodermal tumors. Most of the tissue elements that immunostained were tumor cells; only a few axons and occasional neurons reacted in some specimens. All pilocytic astrocytomas stained very positively, whereas none of the ependymomas and only 11% of primitive neuroectodermal tumors, 20% of glioblastomas, and 28% of anaplastic astrocytomas showed more than faint staining. A similar association between grade and immunostaining was seen in tumors containing an oligodendrogliomatous component, but reactivity was not as strong as in astrocytic tumors or primitive neuroectodermal tumors. Results of Cox regression showed significant associations between immunostaining intensity and survival for all cases taken together (P = 0.007); for the group consisting of astrocytomas, oligoastrocytomas, and oligodendrogliomas (P = 0.002); and for astrocytomas alone (P = 0.04). Results were also significant using a proportional hazards model controlling for patient age (all cases P = 0.005; astrocytomas only P = 0.02), but not when controlling for tumor grade. Our results indicate that immunohistochemical staining for GD1b is correlated with tumor grade and that it may be of prognostic utility in some primary human brain tumors, especially astrocytomas.

• Gangliosides and neutral glycolipids in ependymal, neuronal and primitive neuroectodermal tumors.

  Authors: A J Yates, T K Franklin, P McKinney, R Collins, T Comas, C P Boesel, D K Pearl

  Journal of molecular neuroscience : MN. 05/1999; 12(2):111-21.

  Neutral glycolipid and ganglioside compositions were determined on 11 ependymal tumors, 12 medulloblastomas, 6 other neuronal tumors of the brain, 4 peripheral neuroblastomas, 1 cerebral primitiveNeutral glycolipid and ganglioside compositions were determined on 11 ependymal tumors, 12 medulloblastomas, 6 other neuronal tumors of the brain, 4 peripheral neuroblastomas, 1 cerebral primitive neuroectodermal tumor (PNET), and 1 PNET of the thoracic wall. Within the group of tumors that can demonstrate neuronal phenotypes, there was an association between the degree of neuronal differentiation usually demonstrated by these tumors and the proportions of both GD1a and 1b-pathway gangliosides. The amount of globoside also correlated with the amount of 1b pathway gangliosides. Patients with medulloblastomas whose 1b gangliosides made up over 15% of the total gangliosides survived longer that those with lower proportions of 1b gangliosides. The only gangliosides in the choroid plexus papilloma were GM3 and GD1a, but other ependymal tumors had significant amounts of GD1b and its metabolic precursors. Ependymoma and anaplastic ependymoma had similar neutral glycolipid compositions, which were different from subependymoma, which lacked ceramide monohexoside and ceramide dihexoside. These differences in glycolipid compositions suggest that there may be fundamental biological differences between these types of ependymal tumors.

• Sex- and age-related differences in ceramide dihexosides of primary human brain tumors.

  Authors: A J Yates, T K Franklin, B W Scheithauer, P C Burger, D K Pearl

  Lipids. 02/1999; 34(1):1-4.

  Neutral glycolipids (NGL) are promising diagnostic markers of human gliomas, but differences in NGL with age and sex have not been examined. Previous work demonstrated that ceramide dihexosides (CDH)Neutral glycolipids (NGL) are promising diagnostic markers of human gliomas, but differences in NGL with age and sex have not been examined. Previous work demonstrated that ceramide dihexosides (CDH) levels in mouse kidney are age- and sex-dependent, probably due to levels of sex hormones. We quantitated CDH in 181 human gliomas and found significant differences with sex and age, particularly menopause and male puberty. This emphasizes the importance of assessing results of studies on glycolipids in disease states with respect to age and sex in order to avoid erroneous conclusions concerning the relationship of glycolipid composition with diagnosis and pathogenesis.

• The I1307K polymorphism of the APC gene in colorectal cancer.

  Authors: T W Prior, R B Chadwick, A C Papp, A N Arcot, A M Isa, D K Pearl, G Stemmermann, A Percesepe, A Loukola, L A Aaltonen, A de la Chapelle

  Gastroenterology. 01/1999; 116(1):58-63.

  BACKGROUND & AIMS: Colorectal cancer is one of the most frequent cancers in humans. Recently, a germline missense mutation, I1307K, was identified in the adenomatous polyposis coli (APC) gene thatBACKGROUND & AIMS: Colorectal cancer is one of the most frequent cancers in humans. Recently, a germline missense mutation, I1307K, was identified in the adenomatous polyposis coli (APC) gene that was suggested to increase cancer predisposition in Ashkenazi Jews. However, a second study indicated that the I1307K mutation did not contribute greatly to the risk of colon cancer in Ashkenazi breast-ovarian cancer families, and a role of mismatch repair deficiency was suggested. This study investigated the frequency of the I1307K mutation in several non-Ashkenazi Jewish populations. We also compared the distribution and frequency of APC mutations from colon tumors that were positive and negative for the I1307K mutation. Finally, the association between the presence of mutations in the I1307K region and mismatch repair deficiency was studied. METHODS: We tested for I1307K in 345 patients who were not Ashkenazi Jews using a heteroduplex screen. We also performed an extensive mutational analysis in this region of the APC gene on DNA extracted from 240 Italian, Finnish, and Hawaiian-Japanese colon tumors and determined replication error status. RESULTS: The I1307K mutation was not found among 345 non-Ashkenazis. Somatic mutations occurred at a lower frequency and were more randomly distributed when the I1307K allele was not present. The most common characteristic somatic mutation occurring around codon 1307 in I1307K-positive patients did not occur in tumors negative for the I1307K mutation. An association between mutations in the region around APC codon 1307 and mismatch repair deficiency was not found. CONCLUSIONS: Our findings support the hypothesis that the I1307K mutation is unique to the Ashkenazi Jews, contributes to tumor predisposition in colorectal cancer, and is unrelated to mismatch repair deficiency.

• Mitosis identification in diffuse gliomas: implications for tumor grading.

  Authors: S W Coons, D K Pearl

  Cancer. 05/1998; 82(8):1550-5.

  BACKGROUND: The histologic differentiation of mitotic figures is a cornerstone of several highly predictive grading systems for gliomas. In some systems, the presence of even a single mitotic figureBACKGROUND: The histologic differentiation of mitotic figures is a cornerstone of several highly predictive grading systems for gliomas. In some systems, the presence of even a single mitotic figure is sufficient to classify an astrocytoma as high grade. However, the extent of microscopic examination necessary to exclude the presence of significant mitotic activity has not been determined. METHODS: Hematoxylin and eosin-stained slides from 410 astrocytomas and 107 oligodendrogliomas/oligoastrocytomas were reviewed until the first mitosis was identified or 100 400x fields had been reviewed without identification of a mitosis. The number of the field in which the first mitosis was found was correlated with diagnosis, grade, and survival. RESULTS: A review of 50 400x fields was necessary to achieve a >90% sensitivity in identifying a mitosis in a Grade 3 astrocytoma specimen, compared with 20 400x fields in anaplastic (Grade 3 and 4) oligodendroglioma specimens. For Grade 3 astrocytomas, there was a significant independent correlation between survival and the field in which the first mitosis was found (P = 0.02). For the oligodendroglial tumors, there was a strong correlation between the number of fields counted until the first mitosis was found and grade (P < 0.0001). CONCLUSIONS: The evaluation of mitotic activity offers more prognostic information than can be obtained by the simple approach of noting only their presence or absence. Data were acquired regarding the diligence of the microscopic examination necessary to evaluate the presence or absence of mitotic activity. A 1 cm x 0.1 cm needle biopsy contains adequate tissue to evaluate mitotic activity for the purpose of histologic grading; however, this adequacy is dependent on the sample's being representative and composed entirely of cellular tumor.

• The prognostic significance of Ki-67 labeling indices for oligodendrogliomas.

  Authors: S W Coons, P C Johnson, D K Pearl

  Neurosurgery. 10/1997; 41(4):878-84; discussion 884-5.

  OBJECTIVE: The prognostic significance of quantitative measurement of tumor proliferative activity was evaluated for oligodendroglial tumors. METHODS: Ki-67/MIB-1 immunochemistry was used to measureOBJECTIVE: The prognostic significance of quantitative measurement of tumor proliferative activity was evaluated for oligodendroglial tumors. METHODS: Ki-67/MIB-1 immunochemistry was used to measure proliferative activity in 81 oligodendrogliomas and oligoastrocytomas. The relationship among survival, proliferation, histological features, and clinical variables were evaluated using a Cox proportional hazards analysis. RESULTS: After stratifying by histological grade and adjusting for age at diagnosis, there was a significant association between the Ki-67/MIB-1 labeling index (LI) (percentage of positive cells) and survival (P = 0.04). This association was illustrated further by the significantly different survival of two groups based on LI ranges of less than or equal to 5 and greater than 5 (P < 0.0001). CONCLUSION: The poor correlation between mitotic figures and survival in oligodendrogliomas that has been reported previously emphasizes the need for an accurate method to measure proliferative activity. Our study demonstrated the usefulness of the Ki-67/MIB-1 LI and demonstrated that LI ranges can be defined for clinical application.

• Ganglioside GM1 enhances induction by nerve growth factor of a putative dimer of TrkA.

  Authors: T Farooqui, T Franklin, D K Pearl, A J Yates

  Journal of neurochemistry. 07/1997; 68(6):2348-55.

  GM1 enhances nerve growth factor (NGF)-stimulated neuritogenesis and prevents apoptotic death of PC12 cells; both may be due to enhancement of TrkA dimerization. In this study, we examined the effectGM1 enhances nerve growth factor (NGF)-stimulated neuritogenesis and prevents apoptotic death of PC12 cells; both may be due to enhancement of TrkA dimerization. In this study, we examined the effect of GM1 on NGF-induced TrkA dimerization in Trk-PC12 (6-24) cells. NGF increased tyrosine phosphorylation of the 140-kDa protein (TrkA monomer), and preincubation with GM1 potentiated this effect. Adding the protein cross-linker bis(sulfosuccinimidyl) suberate with NGF resulted in the appearance of two major bands (220 and 330 kDa) when probed with antibodies against TrkA or phosphotyrosine, and GM1 also enhanced this effect. We interpret the 330-kDa band as being a homodimer of TrkA. The identity of the 220-kDa band is still not certain but may consist of a posttranslationally modified form of TrkA. Our results suggest that GM1 is augmenting the effects of NGF on PC12 cells by enhancing the dimerization and activation of the TrkA receptor.

• Improving diagnostic accuracy and interobserver concordance in the classification and grading of primary gliomas.

  Authors: S W Coons, P C Johnson, B W Scheithauer, A J Yates, D K Pearl

  Cancer. 05/1997; 79(7):1381-93.

  BACKGROUND: Accurate histologic diagnosis of gliomas is fundamental to proper patient management and to the interpretation of basic and clinical investigations. Diagnostic accuracy andBACKGROUND: Accurate histologic diagnosis of gliomas is fundamental to proper patient management and to the interpretation of basic and clinical investigations. Diagnostic accuracy and reproducibility are compromised by the subjective histologic criteria currently used to classify and grade gliomas. METHODS: The histologic features of 4 sets of gliomas (a total of 244 cases) were reviewed independently by 4 neuropathologists to determine interobserver diagnostic concordance rates. Cases wherein diagnostic disagreements arose were reviewed jointly to identify and refine the histologic criteria that were adversely affecting diagnostic reproducibility. Using the criteria developed in the study, a set of 315 gliomas with known survival data was evaluated in order to validate the usefulness of the criteria. RESULTS: There was significant improvement in diagnostic concordance with each session (P = 0.02). For the first session, the concordance rates were as follows: all 4 reviewers, 52%; any 3 reviewers, 60%; 2 reviewers, 70%. For the fourth session, the respective rates were 69%, 75%, and 80%. Although features important in grading, particularly microvascular proliferation, were sometimes problematic, most disagreements related to the classification of tumors. Much of the improvement related to the refinement of criteria distinguishing diffuse astrocytomas from oligodendrogliomas/oligoastrocytomas and pilocytic astrocytomas. It was concluded that the presence of any typical oligodendroglioma was sufficient to remove a tumor from the astrocytoma category. CONCLUSIONS: The authors' data indicate that oligodendroglial tumors comprise up to 25% of gliomas, a significantly higher proportion than was previously recognized. The data also suggest that the wide range of survival times reported for patients with anaplastic astrocytoma may reflect "contamination" resulting from misdiagnosis, particularly of oligodendroglial tumors and pilocytic astrocytomas.

• Mutational spectrum in the neurofibromatosis type 2 gene in sporadic and familial schwannomas.

  Authors: D B Welling, M Guida, F Goll, D K Pearl, M E Glasscock, D G Pappas, F H Linthicum, D Rogers, T W Prior

  Human genetics. 09/1996; 98(2):189-93.

  Using a heteroduplex approach and direct sequencing, we have completed the screening of approximately 88% of the neurofibromatosis type 2 (NF2)-coding sequence of DNA extracted from 33 schwannomasUsing a heteroduplex approach and direct sequencing, we have completed the screening of approximately 88% of the neurofibromatosis type 2 (NF2)-coding sequence of DNA extracted from 33 schwannomas from NF2 patients and from 29 patients with sporadic schwannomas. The extensive screening has resulted in the identification of 33 unique mutations. Similarly to other human genes, we have shown that the CpG sites are more highly mutable in the NF2 gene. The frequency, distribution, and types of mutations were shown to differ between the sporadic and familial tumors. The majority of the mutations resulted in protein truncation and were consistent with more severe phenotype, however three missense mutations were identified during this study and were all associated with milder manifestations of the disease.

• Glycolipids and myelin proteins in human oligodendrogliomas.

  Authors: C C Sung, R Collins, J Li, D K Pearl, S W Coons, B W Scheithauer, P C Johnson, A J Yates

  Glycoconjugate journal. 07/1996; 13(3):433-43.

  We studied myelin proteins and glycolipids in 24 human oligodendrogliomas (16 pure, eight mixed), including two grade I, 13 grade II, five grade III, and four grade IV. Tumours with a 1b gangliosideWe studied myelin proteins and glycolipids in 24 human oligodendrogliomas (16 pure, eight mixed), including two grade I, 13 grade II, five grade III, and four grade IV. Tumours with a 1b ganglioside content (GD1b, GT1b and GQ1b) over 30% of total gangliosides occur more frequently in the WHO grade I and II (47%) and grade III (40%) than in the grade IV (25%) group; there was no difference in the amounts of total ganglioside or individual gangliosides between pure and mixed oligodendrogliomas. The presence of 6'-LM1 correlated with higher grades of tumours (chi 2 P approximately 0.02); however, 3'-LM1 and total neolacto-series gangliosides did not correlated with grade. Immunohistochemical studies of oligodendrocyte and myelin markers (GalCer, sulfatide, 2',3' -cyclic nucleotide phosphodiesterase, myelin basic protein and proteolipid protein) using specific antibodies showed only a very small proportion of tumour cells staining. These data do not support the hypothesis that tumours classified as oligodendrogliomas are derived from mature oligodendrocytes.

• The incidence of the gene for thermolabile methylene tetrahydrofolate reductase in African Americans.

  Authors: P E McAndrew, J T Brandt, D K Pearl, T W Prior

  Thrombosis research. 07/1996; 83(2):195-8.

  Increased levels of homocysteine have been linked to both arterial and venous thromboembolic problems (1,2). Homocystinuria is a relatively rare disorder caused by a deficiency of cystathioneIncreased levels of homocysteine have been linked to both arterial and venous thromboembolic problems (1,2). Homocystinuria is a relatively rare disorder caused by a deficiency of cystathione synthase and is characterized by markedly increased levels of homocysteine and premature vascular disease (3-5). Epidemiological studies have suggested that mild elevations of homocysteine are also associated with vascular disease (2). Recent evidence suggests that a polymorphism of the gene encoding for 5,10-methylene tetrahydrofolate reductase (MTHFR) gives rise to a thermolabile form of the enzyme that is associated with increased levels of homocysteine when inherited as a homozygous trait (6). This polymorphism is due to a C --> T substitution at nucleotide 677 which converts an alanine to valine in a conserved portion of the molecule (6). The allele frequency for the thermolabile form of the enzyme was quite high (0.38) in a population of French Canadians. This polymorphism thus appears to be a common risk factor for increased plasma levels of homocysteine and vascular diseases. As the incidence of such genetic polymorphisms often varies among ethnic populations, we were interested in comparing the incidence of this polymorphism in Caucasians and African Americans.

• Spectrum of small mutations in the dystrophin coding region.

  Authors: T W Prior, C Bartolo, D K Pearl, A C Papp, P J Snyder, M S Sedra, A H Burghes, J R Mendell

  American journal of human genetics. 08/1995; 57(1):22-33.

  Duchenne and Becker muscular dystrophies (DMD and BMD) are caused by defects in the dystrophin gene. About two-thirds of the affected patients have large deletions or duplications, which occur in theDuchenne and Becker muscular dystrophies (DMD and BMD) are caused by defects in the dystrophin gene. About two-thirds of the affected patients have large deletions or duplications, which occur in the 5' and central portion of the gene. The nondeletion/duplication cases are most likely the result of smaller mutations that cannot be identified by current diagnostic screening strategies. We screened approximately 80% of the dystrophin coding sequence for small mutations in 158 patients without deletions or duplications and identified 29 mutations. The study indicates that many of the DMD and the majority of the BMD small mutations lie in noncoding regions of the gene. All of the mutations identified were unique to single patients, and most of the mutations resulted in protein truncation. We did not find a clustering of small mutations similar to the deletion distribution but found > 40% of the small mutations 3' of exon 55. The extent of protein truncation caused by the 3' mutations did not determine the phenotype, since even the exon 76 nonsense mutation resulted in the severe DMD phenotype. Our study confirms that the dystrophin gene is subject to a high rate of mutation in CpG sequences. As a consequence of not finding any hotspots or prevalent small mutations, we conclude that it is presently not possible to perform direct carrier and prenatal diagnostics for many families without deletions or duplications.

• Correlation of ganglioside patterns of primary brain tumors with survival.

  Authors: C C Sung, D K Pearl, S W Coons, B W Scheithauer, P C Johnson, M Zheng, A J Yates

  Cancer. 03/1995; 75(3):851-9.

  BACKGROUND. Classification/grading schemes for brain tumors are based mainly on histologic examinations, but these have major limitations, which has led to a search for more objective prognosticBACKGROUND. Classification/grading schemes for brain tumors are based mainly on histologic examinations, but these have major limitations, which has led to a search for more objective prognostic markers. Gangliosides have several biologic effects relevant to tumors, and ganglioside compositions of primary brain tumors correlate with diagnosis. This led to the authors' hypothesis that ganglioside patterns of brain tumors might be useful as prognostic indicators. METHODS. Gangliosides in primary brain tumors of different histologic types from 84 patients were analyzed. Specific ganglioside patterns and several other relevant variables were examined for associations with survival using a Cox proportional hazards model. Kaplan-Meier survival curves were analyzed using the log-rank test. RESULTS. Patients in whom less than 30% of total tumor gangliosides consisted of 1b pathway gangliosides (GD1b, GT1b, and GQ1b) had significantly higher risk ratios than those with more than 30% 1b gangliosides (P approximately 0.03). The presence of 6'-LM1 (NeuAc alpha 2-->6Gal beta 1-->4Glc-NAc beta 1-->3Gal beta 1-->4Glc beta 1-->1Cer was also associated with a higher risk ratio (P approximately 0.007). Combinations of 1b gangliosides and 6'-LM1 identified three groups of patients regardless of histologic diagnosis. Group A, with less than 30% 1b and the presence of 6'-LM1, had a median survival time of 331 days. Group B, with less than 30% 1b but no 6'-LM1, had a median survival time of more than 698 days. Group C, with more than 30% 1b had a median survival time of more than 776 days. CONCLUSIONS. The correlation of ganglioside patterns with survival in this initial investigation suggests the potential of 1b gangliosides and 6'-LM1 to be used as prognostic indicators. Continuing research is being conducted to assess this possibility prospectively.

• Influence of academic stress and season on 24-hour mean concentrations of ACTH, cortisol, and beta-endorphin.

  Authors: W B Malarkey, D K Pearl, L M Demers, J K Kiecolt-Glaser, R Glaser

  Psychoneuroendocrinology. 01/1995; 20(5):499-508.

  We investigated the influence of a common stressful event, i.e., academic examinations, on the 24-h mean concentration of adrenocorticotropic hormone (ACTH), cortisol, and/or beta-endorphin. InWe investigated the influence of a common stressful event, i.e., academic examinations, on the 24-h mean concentration of adrenocorticotropic hormone (ACTH), cortisol, and/or beta-endorphin. In addition, we evaluated the effect of season on the endocrine response to this stressor. We studied medical students (n = 55), screened for a variety of health and life style factors, from three consecutive medical school classes 1 month before, during, and 2 weeks following examinations. Hourly blood samples were obtained from an indwelling catheter and two serum pools were made (0800-2200h = day and 2300-0700h = night). Examinations produced a significant (p < .001) increase in perceived stress scores. In addition, we found a significant (p < .001) effect of examination stress on the increase in mean daytime but not nocturnal ACTH levels during autumn, but not during the spring. In contrast, the examination stress did not significantly affect day or night mean cortisol levels from baseline to examination week. We further divided the students by whether their perceived stress scores increased during examination week and fell during recovery (Group 1) or whether their perceived stress scores did not follow the expected pattern (Group 2). We found that in the Group 1 students who perceived the most stress, cortisol levels significantly increased (p < .001) from baseline to examination. Therefore, the nature of the stressor and the state of the responder were of equal importance in the observed cortisol response during examinations among these students. Further, academic stress had no significant effect on beta-endorphin levels. Finally, we found that the mean day and night ACTH levels were higher (p < .001) in the spring than in the fall; a seasonal influence on cortisol and beta-endorphin concentrations, however, was not observed. In summary, we have demonstrated that stress associated with the taking of examinations produces a dissociation among mean 24-h levels of ACTH, cortisol, and beta-endorphin. In addition, daytime cortisol levels increased during examinations only in the group of students whose perceived stress scores increased. Further, a seasonal influence on ACTH secretion was suggested by these results with higher levels observed in the spring than in the fall.

• GM1 ganglioside and darkly staining neurons in brains of rats subjected to neonatal hypoxia-ischemia.

  Authors: L Aguis, M Hadjiconstantinou, Z X Qu, N H Neff, D K Pearl, A J Yates

  International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience. 12/1994; 12(7):623-30.

  Rat pups, seven days old, with right carotid artery ligations were exposed to an atmosphere of oxygen 8% remainder nitrogen for 2 hr. The animals that survived for three weeks after theRat pups, seven days old, with right carotid artery ligations were exposed to an atmosphere of oxygen 8% remainder nitrogen for 2 hr. The animals that survived for three weeks after the hypoxic-ischemic episode had clusters of darkly stained (hematoxylin-eosin) neurons in the cortex and reduced uptake of dopamine (frontal cortex) and choline (frontal cortex, hippocampus and striatum) in preparations of synaptosomes. Treatment with GM1 ganglioside partially corrected the loss of uptake activity and increased the number of darkly stained neurons.