Biomedical subjects

J A Golden

Publications and source records attributed to J A Golden.

At least 19 recordsLinked to original sources

PubMed2006

Dystrophic neuritic processes in epileptic cortex.

Cortical dysplasia is a frequent finding in cortical resections from children with refractory epilepsy. Diagnostic criteria and a classification scheme for cortical dysplasia has been proposed, though the relationship between specific cortical dysplasia features and their causal relationship with epilepsy is poorly understood. We reviewed 28 surgical resections from children and identified a common and easily recognized feature of cortical dysplasia: maloriented, misshapen and occasionally coarse neurofilament stained process forming a dystrophic neuritic background. The dystrophic neuritic background was associated with other features of cortical dysplasia in all 28 patients with cortical dysplasia, 26 with refractory epilepsy and 2 patients with other neurologic diagnoses. In seven children with refractory epilepsy due to other pathologic diagnosis such as vascular or glial lesions, the dystrophic neuritic background was only found in one patient with a ganglioglioma and other features suggestive of an associated cortical dysplasia. Our data indicate that a dystrophic neuritic background is a common and relatively specific neuropathologic finding in cortical dysplasia.

Adolescent↗

PubMed2003

Dysplasia: a common finding in intractable pediatric temporal lobe epilepsy.

BACKGROUND: Risk factors for temporal lobe epilepsy (TLE) include history of CNS infection, family history of epilepsy, and history of febrile convulsions (FC). Pre-existing cortical dysplasia (CD) may also predispose to refractory TLE, independent of other risk factors for epilepsy. METHODS: The authors reviewed the neuropathologic features of surgical tissue from temporal lobectomies of 33 pediatric patients with refractory TLE, with and without a history of epilepsy risk factors. RESULTS: CD was found in 64% (21/33) of all patients with refractory TLE, including 73% (11/15) patients with a history of FC, 66% (2/3) patients with CNS infections, and 83% (5/6) patients with a family history of epilepsy. Disrupted cortical lamination, dystrophic and maloriented neurons, and balloon cells characterized the CD found in the temporal neocortex. CONCLUSION: CD was seen in 21 of 33 surgical specimens from children with refractory TLE, including those with and without other epilepsy risk factors.

Brain Diseases↗

PubMed2003

AP-2 and HNK-1 define distinct populations of cranial neural crest cells.

OBJECTIVE: To determine if distinct populations of cranial neural crest cells (CNCC) exist by characterization of their divergent gene expression patterns. DESIGN: Identification of unique populations of CNCC was determined by a combination of lineage and immunohistochemical analyses. SETTING: Department of Pathology, Children's Hospital of Philadelphia and the University of Pennsylvania School of Medicine, Philadelphia, PA 19104. RESULTS: We found antibodies of two proteins previously described as identifying all CNCC, label three populations of CNCC at specific time-points. Furthermore, the activating protein 2 (AP-2) expressing CNCC become neural or mesenchymal NCC derivatives whereas the HNK-1 labeled cells do not participate in the mesenchymal lineage. CONCLUSION: These data provide molecular markers for unique CNCC fates and thus will be invaluable in the characterizing of craniofacial anomalies related to defects in NCCS. In addition, our data suggest AP-2 may function in determining the unique mesenchymal fate of CNCCs.

Animals↗

PubMed2002

Type I bone morphogenetic protein receptors are expressed on cerebellar granular neurons and a constitutively active form of the type IA receptor induces cerebellar abnormalities.

Cerebellar granular neurons are the most abundant neuronal type in the CNS. Their number and experimental accessibility have made these neurons a valuable model for investigating mechanisms of cell proliferation and differentiation in the CNS. Proliferation of granular neurons is regulated, at least in part, by the secreted protein Sonic Hedgehog, whereas induction and differentiation both appear to be controlled by bone morphogenetic protein (BMP) signaling. Given the role of BMPs in granular cell differentiation, we postulated that BMP receptors (BMPRs) would be expressed on cerebellar granular neurons and that signaling through these receptors is required for normal differentiation. We found that both BMPRIA and BMPRIB are expressed on granular neuron precursors and on mature granular neurons in the developing cerebellum. To determine if these receptors are sufficient for granular cell induction and/or differentiation in vivo, we introduced a constitutively active BMPRIA construct into the developing cerebellum. The resulting cerebelli showed a simplified folial pattern and ectopic collections of small cells located deep in the cerebellar white matter. Phenotypic analysis demonstrated that the ectopic cells are granular neurons. From these data we suggest that signaling through the type I BMPRs occurs during normal cerebellar development and ectopic activation of this pathway affects normal granular neuron development. Furthermore, the similarity of the cerebellar anomalies arising from perturbed BMPR signaling to human cerebellar malformations suggests that dysregulation of BMP signaling may play a pathogenic role in some human cerebellar abnormalities.

Amino Acid Substitution↗

PubMed2001

Brain, eye, and face defects as a result of ectopic localization of Sonic hedgehog protein in the developing rostral neural tube.

BACKGROUND: Normal development of the face, eyes, and brain requires the coordinated expression of many genes. One gene that has been implicated in the development of each of these structures encodes the secreted protein, Sonic hedgehog (Shh). During central nervous system development, Shh is required for ventral specification along the entire neural axis. To further explore the role of Shh in chick brain and craniofacial development, we overexpressed Shh in the developing rostral neural tube METHODS: In order to determine if Shh is sufficient to ventralize the forebrain, we localized ectopically recombinant Shh protein to the rostral neural tube of chick embryos. The resulting embryos were evaluated morphologically and by assaying gene expression. RESULTS: Disruption in normal gene expression patterns was observed with a reduction or loss in expression of genes normally expressed in the dorsal forebrain (wnt-3a, wnt-4, and Pax-6) and expansion of ventrally expressed genes dorsally (HNF-3beta, Ptc). In addition to the genetic alterations observed in the neural tube, a craniofacial phenotype characterized by a reduction in many cranial neural crest-derived structures was observed. The eyes of Shh-treated embryos were also malformed. They were small with expansion of the retinal pigmented epithelium, enlarged optic stalks, and a reduction of neural retina. DISCUSSION: The ectopic localization of recombinant Shh protein in the rostral neural tube resulted in severe craniofacial anomalies and alterations of gene expression predicted by other studies. The system employed appears to be a model for studying the embryogenesis of malformations that involve the brain, eyes, and face.

Abnormalities, Drug-Induced↗

PubMed2001

Cell migration and cerebral cortical development.

This annotation describes the clinical and pathological features of several conditions believed to result from a primary defect in cell migration which include the lissencephalies, pachygria, polymicrogyrias, and focal cortical dysplasia. A variety of factors must be considered in pathogeneses, including cellular proliferation, cell death, post-migrational intracortical growth and development, axonogenesis and dendritogenesis. At least two distinct types of lissencephaly exist. Classic (also known as Type I) lissencephaly is the prototypic pattern being seen in autosomal dominant Miller-Dieker syndrome, in addition to autosomal recessive and X-linked forms. The Miller-Dieker syndrome locus (LIS-1) encodes the platelet activating factor acetylhydrolase-1, beta1 subunit. The gene for an X-linked form of lissencephaly (XLIS) encodes a protein called doublecortin. Cobblestone (type II) lissencephaly is most commonly seen in patients with the Walker-Warburg syndrome, and also occurs in a group of disorders associated with congenital muscular dystrophy, including Finnish 'muscle-eye-brain' disease and Fukuyama muscular dystrophy. Controversy exits as to whether polymicrogyria is a malformation or a disruption of development. The answer is likely both. Polymicrogyria is believed to arise from defects occurring between 17 and 25 or 26 weeks gestation. Heterotopia can be sporadic, inherited as a simple Mendelian trait, or may be part of a more complex syndrome being characterized by collections of disorganized grey matter in inappropriate places. X-linked periventricular heterotopia syndrome is caused by mutations in filamin-1. In addition to those described above, many other syndromes show lissencephaly, pachygyria and polymicrogyria and many cases are not easily classified into any particular syndrome.

Brain Diseases↗

PubMed2001

Comparison of neurologic outcome after deep hypothermic circulatory arrest with alpha-stat and pH-stat cardiopulmonary bypass in newborn pigs.

OBJECTIVE: Deep hypothermic circulatory arrest for neonatal heart surgery poses the risk of brain damage. Several studies suggest that pH-stat management during cardiopulmonary bypass improves neurologic outcome compared with alpha-stat management. This study compared neurologic outcome in a survival piglet model of deep hypothermic circulatory arrest between alpha-stat and pH-stat cardiopulmonary bypass. METHODS: Piglets were randomly assigned to alpha-stat (n = 7) or pH-stat (n = 7) cardiopulmonary bypass, cooled to 19 degrees C brain temperature, and subjected to 90 minutes of deep hypothermic circulatory arrest. After bypass rewarming/reperfusion, they survived 2 days. Neurologic outcome was assessed by neurologic performance (0-95, 0 = no deficit and 95 = brain death) and functional disability scores, as well as histopathology. Arterial pressure, blood gas, glucose, and brain temperature were recorded before, during, and after bypass. RESULTS: All physiologic data during cardiopulmonary bypass were similar between groups (pH-stat vs alpha-stat) except arterial pH (7.06 +/- 0.03 vs 7.43 +/- 0.09, P <.001) and arterial PCO (2) (98 +/- 8 vs 36 +/- 8 mm Hg, P <.001). No differences existed in duration of cardiopulmonary bypass or time to extubation. Performance was better in pH-stat versus alpha-stat management at 24 hours (2 +/- 3 vs 29 +/- 17, P = 0.004) and 48 hours (1 +/- 2 vs 8 +/- 9, P =.1). Also, functional disability was less severe with pH-stat management at 24 hours (P =.002) and 48 hours (P =.053). Neuronal cell damage was less severe with pH-stat versus alpha-stat in the neocortex (4% +/- 2% vs 15% +/- 7%, P <.001) and hippocampal CA1 region (11% +/- 5% vs 33% +/- 25%, P =.04), but not in the hippocampal CA3 region (3% +/- 5% vs 16% +/- 23%, P =.18) or dentate gyrus (1% +/- 1% vs 3% +/- 6%, P =.63). CONCLUSIONS: pH-stat cardiopulmonary bypass management improves neurologic outcome with deep hypothermic circulatory arrest compared with alpha-stat bypass. The mechanism of protection is not related to hemodynamics, hematocrit, glucose, or brain temperature.

Animals↗

PubMed2001

Periventricular heterotopia may result from radial glial fiber disruption.

Periventricular heterotopia (PVH) are collections of neurons and glia heterotopically located adjacent to the ventricles. The pathogenesis of periventricular heterotopia is believed to be a failure of cells to migrate from the ventricular zone. Mutations in filamin-1 (FLN1) have recently been identified as a genetic defect that results in an X-linked dominant form of PVH. In addition to this X-linked form, PVH may be found sporadically or occasionally as part of other syndromes. The pathogenesis(es) of PVH has not been entirely elucidated for patients with or without FLN1 mutation. In an attempt to better understand the pathogenesis of PVH, we examined 5 fetuses (gestational ages 21 to 34 wk), 3 females and 2 males, with PVH. Neuropathologic examination of these 5 fetuses revealed several to multiple periventricular nodules. No case showed the extensive periventricular heterotopia most commonly found in females with FLN1 mutations. By immunohistochemistry, neurofilament-positive cells were identified within the PVH in 3 of 5 cases and glial fibrillary acidic protein-positive cells surrounded the nodules in all 5 cases, but positive cells were only found within the nodules of 3 cases. Surprisingly, small collections of CD68-positive macrophages were found at the base of the nodules in 4 of the 5 cases. Moreover, in all cases, the radial glia highlighted with vimentin, showed disorganization specifically around the nodules. These data suggest that at least one pathogenesis for PVH is a disruption of the radial glial organization, resulting in a failure of cells to migrate from the ventricular zone.

Abnormalities, Multiple↗

PubMed2001

Effects of AIDS and gender on steady-state plasma and intrapulmonary ethambutol concentrations.

Our objective was to study the steady-state plasma and intrapulmonary orally administered ethambutol concentrations in healthy volunteers and subjects with AIDS. Ethambutol (15 mg/kg of body weight) was administered orally once daily to 10 men with AIDS, 10 healthy men, 10 women with AIDS, and 10 healthy women. The mean (+/-standard deviation [SD]) CD4 cell count for the 20 subjects with AIDS was (350 +/- 169) x 10(6) cells per liter. Blood was obtained for drug assay 2 h after the last dose and at the completion of bronchoalveolar lavage, performed 4 h after the last dose. Standardized bronchoscopy was performed without systemic sedation. The volume of epithelial lining fluid (ELF) was calculated by the urea dilution method. The total number of alveolar cells (AC) was counted in a hemocytometer, and differential cell counting was performed after cytocentrifugation. Ethambutol was measured by a new, sensitive and specific liquid chromotography-mass spectrometry method. The presence of AIDS, as defined in this study, or gender was without significant effect on the concentrations of ethambutol in plasma at 2 or 4 h or in ELF at 4 h following the last dose. Plasma drug concentrations (mean +/- SD) at 2 and 4 h were 2.1 +/- 1.2 and 2.1 +/- 0.8 microg/ml, respectively, and both values were not significantly different from the concentration of ethambutol in ELF at 4 h (2.2 +/- 1.1 microg/ml). The concentration of ethambutol was significantly greater in AC in all four groups (range, 44.5 +/- 15.6 to 82.0 +/- 39.4 microg/ml) than in ELF or plasma and was approximately 30 to 240 times the reported MIC for ethambutol-susceptible strains of Mycobacterium tuberculosis. The AC ethambutol concentration (mean +/- SD) in the smoking women (97.2 +/- 32.1 microg/ml) was more than twice the concentration in all other nonsmoking subjects (45.2 +/- 16.8 microg/ml) combined (P < 0.05). Two- and 4-h concentrations of ethambutol in plasma were not affected by AIDS status or gender. The high AC/plasma and AC/ELF concentration ratios suggest that substantial antimycobacterial activity resides in these cells. The data confirm earlier observations of active transport ex vivo of ethambutol into pulmonary macrophages.

Acquired Immunodeficiency Syndrome↗

PubMed2001

Acute rejection following lung transplantation: limitations in accuracy of thin-section CT for diagnosis.

PURPOSE: To evaluate the sensitivity, specificity, predictive values, and accuracy of thin-section computed tomography (CT) for the diagnosis of acute rejection following lung transplantation and to determine whether any individual CT abnormalities are associated with histopathologically proved acute rejection. MATERIALS AND METHODS: Thin-section CT studies from 64 lung transplant recipients were retrospectively reviewed. CT studies were temporally correlated with various grades of biopsy-proved acute rejection (n = 34); 30 other CT studies were from a control group with no histopathologic evidence of acute rejection. Acute rejection was diagnosed as present or absent, and the diagnostic was calculated. RESULTS: The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of CT for the diagnosis of acute rejection were as follows: 35%, 73%, 60%, 50%, 53%, respectively. No individual CT finding was significantly associated with acute rejection. The sensitivity of CT for the detection of various grades of acute rejection was 17% for grade A1, 50% for grade A2, and 20% for grade A3. The combination of volume loss and septal thickening, with or without pleural effusion, was never seen in the absence of acute rejection. CONCLUSION: Thin-section CT has limited accuracy for the diagnosis of acute rejection following lung transplantation, and no individual CT finding is significantly associated with this diagnosis.

Acute Disease↗

PubMed2000

DM-GRASP is necessary for nonradial cell migration during chick diencephalic development.

Cell migration is fundamental to normal CNS development. Radial migration, along radial glial fibers, has been the principal pathway studied, however, nonradial or tangential cell migration has increasingly been identified at all levels of the CNS. Receptors, cell adhesion molecules, and extracellular matrix molecules have all been shown to participate in radial cell migration. In contrast, the molecular basis of nonradial cell migration has only recently begun to be elucidated. Using replication defective retroviral vectors we have determined the location and time when nonradial cell migration begins in the developing chick diencephalon. We have identified three molecules that are expressed in spatially and temporally restricted domains that are consistent with them playing a role in nonradial cell migration. One of these molecules, DM-GRASP, a transmembrane protein with five extracellular Ig domains, is expressed on the nonradially migrating cells in addition to axons. To test the hypothesis that DM-GRASP participates in guiding nonradial cell migration, we injected a replication-defective retroviral vector used for lineage tracing followed by a DM-GRASP blocking antibody. Embryos injected with the blocking antibody showed a near complete block in nonradial cell migration specifically where DM-GRASP is expressed. Furthermore, morphological analyses revealed disruption of the normal architecture of the diencephalon indicating nonradial cell migration is necessary for normal morphological development of the brain. Our data indicate that DM-GRASP is necessary for nonradial cell migration in the chick diencephalon and have provided a system to further explore the function of nonradial cell migration during CNS development.

Activated-Leukocyte Cell Adhesion Molecule↗

PubMed2000

The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues.

Proapoptotic Bcl-2 family members have been proposed to play a central role in regulating apoptosis. However, mice lacking bax display limited phenotypic abnormalities. As presented here, bak(-/-) mice were found to be developmentally normal and reproductively fit and failed to develop any age-related disorders. However, when Bak-deficient mice were mated to Bax-deficient mice to create mice lacking both genes, the majority of bax(-/-)bak(-/-) animals died perinatally with fewer than 10% surviving into adulthood. bax(-/-)bak(-/-) mice displayed multiple developmental defects, including persistence of interdigital webs, an imperforate vaginal canal, and accumulation of excess cells within both the central nervous and hematopoietic systems. Thus, Bax and Bak have overlapping roles in the regulation of apoptosis during mammalian development and tissue homeostasis.

Abnormalities, Multiple↗

PubMed2000

Neuronal migration defects of the cerebral cortex: a destination debacle.

Disruptions in neuronal migration have been postulated as the basis for many cerebral malformations including lissencephaly, cortical heterotopia, and double cortex. Recently, the genetic basis for some of these disorders has been identified. In this review, we highlight recent advances in our understanding of the molecular mechanisms of neuronal migration and its relationship to cerebral cortical development and neuronal migration disorders. This has allowed us to begin categorizing specific malformations based on their molecular etiology.

Animals↗

PubMed2000

Low-dose, dynamic, expiratory thin-section CT of the lungs using a spiral CT scanner.

Seventeen patients with lung transplants were evaluated with inspiratory, postexpiratory, and low-dose, dynamic expiratory thin-section computed tomography (CT). Region of interest measurements were performed on inspiration and expiration images with both techniques, and mean lung attenuation changes between inspiration and expiration images were calculated and compared. Dynamic expiratory thin-section CT resulted in a significantly greater increase in lung attenuation than postexpiratory thin-section CT. Dynamic expiratory thin-section CT may prove useful in the evaluation of patients with lung diseases characterized by air flow obstruction with little increase in patient radiation dose.

Air↗

PubMed2000

Incidental detection of thoracic sarcoidosis on whole-body 18fluorine-2- fluoro-2-deoxy-D-glucose positron emission tomography.

18 Fluorine-2- Fluoro-2-Deoxy-D-Glucose positron emission tomography (18FDG PET) allows imaging of sites with increased metabolic activity. Increased metabolic activity in mediastinal nodes in sarcoidosis has been described. We report the prospective diagnosis of thoracic sarcoidosis on 18FDG PET based on extensive, peripheral, upper lobe parenchymal, and mediastinal nodal tracer uptake.

Female↗

PubMed2000

Single-dose intrapulmonary pharmacokinetics of rifapentine in normal subjects.

The intrapulmonary pharmacokinetics of rifapentine were studied in 30 volunteers who received a single, oral dose of rifapentine (600 mg). Subgroups of five subjects each underwent bronchoscopy and bronchoalveolar lavage (BAL) at timed intervals following drug administration. Drug concentrations, including the concentration of the primary metabolite 25-desacetyl rifapentine, were determined in plasma, BAL fluid, and alveolar cells (AC) by high-pressure liquid chromatography. The concentrations in epithelial lining fluid (ELF) were calculated by the urea diffusion method. The concentration-time data were fit to two-compartment (plasma) or one-compartment (AC and ELF) models. The peak concentrations in plasma, ELF, and AC, 26.2, 3. 7, and 5.3 microg/ml, respectively, occurred at 5, 5, and 7 h after drug administration, respectively. The half-lives and areas under the curve for plasma, ELF, and AC were 18.3 h and 520 microg. h/ml, 20.8 h and 111 microg. h/ml, and 13.0 h and 133 microg. h/ml, respectively. Although the intrapulmonary rifapentine concentrations were less than the plasma rifapentine concentrations at all time periods, they remained above the proposed breakpoint for M. tuberculosis (0.5 microg/ml) for the 48-h observation period. These data provide a pharmacokinetic rationale for extended-interval dosing. The optimum dosing regimen for rifapentine will have to be determined by controlled clinical trials.

Adolescent↗

PubMed2000

Effects of AIDS and gender on steady-state plasma and intrapulmonary ethionamide concentrations.

Ethionamide, 250 mg every 12 h for a total of nine doses, was administered to 40 adult volunteers (10 men with AIDS, 10 healthy men, 10 women with AIDS, and 10 healthy women). Blood was obtained for drug assay prior to administration of the first dose, 2 h after the last dose, and at the completion of standardized bronchoscopy and bronchoalveolar lavage, which were performed 4 h after the last dose. Ethionamide was measured in epithelial lining fluid (ELF) and alveolar cells (AC) using a new mass spectrometric method. The presence of AIDS or gender was without significant effect on the concentrations of ethionamide in plasma, AC, or ELF. Plasma concentrations (mean +/- standard deviation [SD]) were 0.97 +/- 0.65 and 0.65 +/- 0.35 microg/ml at 2 and 4 h after the last dose, respectively, and both values were significantly greater than the concentration of ethionamide in AC (0.38 +/- 0.47 microg/ml) (P < 0. 05). The concentration of ethionamide was significantly greater in ELF (5.63 +/- 3.8 microg/ml) than in AC or plasma at 2 and 4 h and was approximately 10 to 20 times the reported MIC for ethionamide-susceptible strains of Mycobacterium tuberculosis. For all 40 subjects, the ELF/plasma concentration ratios (mean +/- SD) at 2 and 4 h were 8.7 +/- 11.7 and 9.7 +/- 5.6, respectively. We conclude that the absorption of orally administered ethionamide, as measured in this study, was not affected by gender or the presence of AIDS. Ethionamide concentrations were significantly greater in ELF than in plasma or AC, suggesting that substantial antimycobacterial activity resides in this compartment.

Acquired Immunodeficiency Syndrome↗

PubMed2000

Early bronchiolitis obliterans following lung transplantation: accuracy of expiratory thin-section CT for diagnosis.

PURPOSE: To evaluate the accuracy of thin-section computed tomography (CT) with expiratory scans in diagnosing early bronchiolitis obliterans after lung transplantation. MATERIALS AND METHODS: Thin-section CT scans were reviewed by two observers blinded to the diagnoses in seven consecutive lung transplant recipients with histopathologically proved bronchiolitis obliterans (group A) and 21 with normal biopsy findings (group B). All patients had normal biopsy and stable pulmonary function test (PFT) results 2-36 weeks prior to CT. Patients with normal biopsy results were placed into subgroups based on abnormal (group B1) or stable (group B2) PFT results. Air-trapping extent on expiratory scans was scored on a 24-point scale. RESULTS: The mean air-trapping score in group A (6.6) was not significantly different from that in group B (4.5, P =. 17). The air-trapping score was significantly higher in groups A and B1 than in group B2 (6.2 and 2.6, respectively; P =.03). The frequency of an air-trapping score of 3 or more in groups A and B1 was significantly higher than that in group B2 (P =.03). By using a score of 3 or more to indicate air trapping, the sensitivity of expiratory CT was 74%, specificity was 67%, and accuracy was 71%. CONCLUSION: Thin-section CT, including expiratory scans, is of limited accuracy in diagnosing early bronchiolitis obliterans after lung transplantation.

Adult↗