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Biomedical subjects

J A Golden

Publications and source records attributed to J A Golden.

At least 19 recordsLinked to original sources
PubMed1999

Neurofibromin deficiency in mice causes exencephaly and is a modifier for Splotch neural tube defects.

Neural tube defects are common and serious human congenital anomalies. These malformations have a multifactorial etiology and can be reproduced in mouse models by mutations of numerous individual genes and by perturbation of multiple environmental factors. The identification of specific genetic interactions affecting neural tube closure will facilitate our understanding of molecular pathways regulating normal neural development and will enhance our ability to predict and modify the incidence of spina bifida and other neural tube defects. Here, we report a genetic interaction between Nf1, encoding the intracellular signal transduction protein neurofibromin, and Pax3, a transcription factor gene mutated in the Splotch mouse. Both Pax3 and Nf1 are important for the development of neural crest-derived structures and the central nervous system. Splotch is an established model of folate-sensitive neural tube defects, and homozygous mutant embryos develop spina bifida and sometimes exencephaly. Neural development is grossly normal in heterozygotes and neural tube defects are not seen. In contrast, we found a low incidence of neural tube defects in heterozygous Splotch mice that also harbored a mutation in one Nf1 allele. All compound homozygotes had severe neural tube defects and died earlier in embryogenesis than either Nf1(-/-) or Sp(-/-) embryos. We also report occasional exencephaly in Nf1(-/-) mice and identify more subtle CNS abnormalities in normal-appearing Nf1(-/-) embryos. Though other genetic loci and environmental factors affect the incidence of neural tube defects in Splotch mice, these results establish Nf1 as the first known gene to act as a modifier of neural tube defects in Splotch.

Animals↗
PubMed1999

Ectopic bone morphogenetic proteins 5 and 4 in the chicken forebrain lead to cyclopia and holoprosencephaly.

Proper dorsal-ventral patterning in the developing central nervous system requires signals from both the dorsal and ventral portions of the neural tube. Data from multiple studies have demonstrated that bone morphogenetic proteins (BMPs) and Sonic hedgehog protein are secreted factors that regulate dorsal and ventral specification, respectively, within the caudal neural tube. In the developing rostral central nervous system Sonic hedgehog protein also participates in ventral regionalization; however, the roles of BMPs in the developing brain are less clear. We hypothesized that BMPs also play a role in dorsal specification of the vertebrate forebrain. To test our hypothesis we implanted beads soaked in recombinant BMP5 or BMP4 into the neural tube of the chicken forebrain. Experimental embryos showed a loss of the basal telencephalon that resulted in holoprosencephaly (a single cerebral hemisphere), cyclopia (a single midline eye), and loss of ventral midline structures. In situ hybridization using a panel of probes to genes expressed in the dorsal and ventral forebrain revealed the loss of ventral markers with the maintenance of dorsal markers. Furthermore, we found that the loss of the basal telencephalon was the result of excessive cell death and not a change in cell fates. These data provide evidence that BMP signaling participates in dorsal-ventral patterning of the developing brain in vivo, and disturbances in dorsal-ventral signaling result in specific malformations of the forebrain.

Animals↗
PubMed1999

Effects of prenatal cocaine exposure on embryonic expression of sonic hedgehog.

Cocaine use by pregnant women may adversely affect development and behavior in the exposed infants. Sonic hedgehog (shh) is a secreted protein that induces development of many structures in the embryo, including dopaminergic cells in the ventral midbrain, the limb buds, and eyes. Because prenatal cocaine exposure has been shown to adversely affect the morphogenesis of these and other systems, the present study was undertaken to test the hypothesis that maternal cocaine treatment would alter shh mRNA expression. Cocaine HCl (60 mg/kg i.p.) was administered to pregnant mice on gestational days 6-8, the time that immediately precedes the appearance of shh. Control dams received i.p. saline. Embryos from gestational days 9-11 were examined by in situ hybridization. The temporal and spatial patterns of shh expression were indistinguishable between embryos from cocaine- and saline-treated dams. Examination of forebrain, midbrain, and midbody spinal cord coronal sections failed to reveal any differences in the dorsoventral and mediolateral localization of shh. The distribution of mRNA for patched (ptc), the membrane receptor for shh, was also indistinguishable between both groups. Chick embryos were next used to examine the direct application of cocaine into the developing brain. Shh distribution was similarly unaffected in these chick embryos. These data show that maternal cocaine treatment during early neural tube development does not significantly alter the expression patterns of shh or ptc mRNA. Thus, congenital defects and behavioral abnormalities associated with maternal cocaine use do not appear to result from altered expression of the shh-ptc pathway.

Abnormalities, Drug-Induced↗
PubMed1999

Intrapulmonary concentrations of pyrazinamide.

The objective of this study was to compare the steady-state plasma and intrapulmonary concentrations of orally administered pyrazinamide in normal volunteers and subjects with AIDS. Pyrazinamide was administered at 1 g once daily for 5 days to 40 adult volunteers (10 men with AIDS, 10 normal men, 10 women with AIDS, and 10 normal women). Subjects with AIDS and with more than four stools per day were excluded. Blood was obtained prior to administration of the first dose, 2 h after the last dose, and at the completion of bronchoscopy and bronchoalveolar lavage, which were performed 4 h after the last dose. Standardized bronchoscopy was performed without systemic sedation. The volume of epithelial lining fluid (ELF) recovered 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. Pyrazinamide was measured by high-performance liquid chromatography. The presence of AIDS or gender had no significant effect on the concentrations of pyrazinamide in plasma. The concentrations of pyrazinamide in ELF and AC were lower in the subjects with AIDS than in the subjects without AIDS, but the difference was not significant. The concentrations in plasma (mean +/- standard deviation) were 25.1 +/- 7.6 and 21.1 +/- 6.8 microg/ml at 2 and 4 h after the last dose, respectively, and were not significantly different from the concentration (17.4 +/- 16.9 microg/ml) in AC. The concentration of pyrazinamide in ELF was high (431 +/- 220 microg/ml) and was approximately 4 to 40 times the reported MIC for pyrazinamide-susceptible strains of Mycobacterium tuberculosis. The high concentration of pyrazinamide in ELF may contribute in part to the effectiveness of the drug in treating pulmonary tuberculosis.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Alveolar epithelial fluid transport capacity in reperfusion lung injury after lung transplantation.

Reperfusion lung injury is an important cause of morbidity and mortality after orthotopic lung transplantation. The purpose of this study was to investigate the function of the alveolar epithelium in the setting of reperfusion lung injury. Simultaneous samples of pulmonary edema fluid and plasma were collected from eight patients with severe post-transplantation reperfusion edema. The edema fluid to plasma protein ratio was measured, an indicator of alveolar-capillary barrier permeability. The initial edema fluid to plasma protein ratio was > 0.75 in six of eight patients, confirming the presence of increased permeability of the alveolar-capillary barrier. Graft ischemic time was positively correlated with the degree of permeability (r = 0.77, p < 0.05). In four of six patients with serial samples, there was a high rate of alveolar fluid clearance (19 +/- 9%/h, mean +/- SD). Alveolar fluid clearance was calculated from serial samples in six patients. Intact alveolar fluid clearance correlated with less histologic injury, rapid resolution of hypoxemia, and more rapid resolution of radiographic infiltrates. The two patients with no net alveolar fluid clearance had persistent hypoxemia and more severe histologic injury. This study provides the first direct evidence that increased permeability to protein is the usual cause of reperfusion edema after lung transplantation, with longer ischemic times associated with greater permeability to protein in the transplanted lung. The high rates of alveolar fluid clearance indicate that the fluid transport capacity of the alveolar epithelium may be well preserved in the allograft despite reperfusion lung injury. The ability to reabsorb fluid from the alveolar space was a marker of less severe reperfusion injury, whereas the degree of alveolar-capillary barrier permeability to protein was not. Measurement of alveolar fluid clearance may be useful to assess the severity of reperfusion lung injury and to predict outcome when pulmonary edema develops after lung transplantation.

Adult↗
PubMed1999

Persistent increases of BAL neutrophils as a predictor of mortality following lung transplant.

STUDY OBJECTIVES: To evaluate whether findings from surveillance bronchoscopy predict survival following lung transplantation. DESIGN: Retrospective review and analysis of 498 bronchoscopies with transbronchial biopsy (TBB) and BAL performed in 34 patients after lung transplantation. SETTING: University-based, tertiary referral medical center. PATIENTS: Thirty-four patients after lung transplantation. The mean age at transplantation was 49+/-9 years; 20 (59%) were female. Twenty-four (71%) underwent single and 10 (29%) underwent bilateral lung transplantation. The most common pretransplantation diagnostic groups were emphysema/COPD without concomitant alpha1-antiprotease deficiency (n = 13) and other obstructive disease processes (n = 10). INTERVENTIONS: Over follow-up, subjects underwent multiple bronchoscopies with TBB and BAL. The median number per subject was 15 (25 to 75% range 13 to 17). MEASUREMENTS AND RESULTS: We calculated the overall median BAL WBCs and median percent neutrophils (polymorphonuclear leukocytes [PMNs]) among all of the BALs performed for each subject. We then calculated the mean +/- SD of those median values. We used Cox proportionate hazards to assess mortality risk. The median overall follow-up observation period for the cohort was 560 days. There were 11 deaths during this period. Twenty-four subjects (71%) had acute rejection (AR) grades 2 to 4 (mild to severe), and nine (27%) had obliterative bronchiolitis (OB) diagnosed by TBB at any point. The mean value for BAL WBCs was 366+/-145 x 10(3) per milliliter; for percentage PMNs, the mean was 7+/-10%. Adjusting for age, gender, single vs bilateral lung transplantation, pretransplantation diagnostic group, presence of AR, presence of OB, BAL WBC concentration, and lymphocyte CD4/CD8 ratio, PMN percent was a significant predictor of mortality (p = 0.02). CONCLUSIONS: Ongoing inflammation manifested by an increased percentage PMNs over repeated bronchoscopies predicts mortality following lung transplantation. Biopsy data alone may be insufficient to identify posttransplantation patients at risk of poor outcome.

Adult↗
PubMed1999

Pulmonary function improves after expandable metal stent placement for benign airway obstruction.

STUDY OBJECTIVE: To determine whether expandable metal stent placement for benign airway lesions improves pulmonary function. DESIGN: Case series. SETTING: University medical center. PATIENTS: Nine patients who underwent balloon-mediated expandable metal stent deployment for airway obstruction due to benign etiologies. RESULTS: All nine patients had expandable stents deployed for benign airway lesions using fiberoptic bronchoscopy and fluoroscopic guidance. Pulmonary function improved after stent placement. The mean FVC increased by 388 mL (95% confidence interval [CI], 30 to 740 mL), the mean peak expiratory flow (PEF) increased by 1,288 mL (95% CI, 730 to 1,840 mL), the mean FEV1 increased by 550 mL (95% CI, 240 to 860 mL), and the mean forced expiratory flow between 25% and 50% of vital capacity (FEF25-75%) increased by 600 mL (95% CI, 110 to 1,090 mL). Corresponding relative measurements included increases in FVC (12%), PEF (95%), FEV1 (38%), and FEF25-75% (87%). The complete characterization of a benign airway obstruction generally required a multimodal approach. CONCLUSIONS: Expandable metal stent placement appears to be an effective therapy for benign airway obstruction.

Adult↗
PubMed1998

Goosecoid-like, a gene deleted in DiGeorge and velocardiofacial syndromes, recognizes DNA with a bicoid-like specificity and is expressed in the developing mouse brain.

The vast majority of patients with DiGeorge syndrome (DGS) and velocardiofacial syndrome (VCFS) have deletions of chromosomal region 22q11.2. These patients exhibit broad and variable phenotypes that include conotruncal cardiac defects, hypocalcemia, palatal and facial anomalies and developmental delay. Most of these abnormalities are thought to be due to defects in neural crest cell migration or differentiation. We have identified a homeobox-containing gene, Goosecoid-like (GSCL), that is in the region within 22q11 that is deleted most consistently in patients with DGS/VCFS. The GSCL gene is expressed in a limited number of adult tissues as well as in early human development, and is a member of a family of homeobox genes in vertebrates that includes Goosecoid and GSX. In this report, we present functional studies of the GSCL protein and determine the expression pattern of the GSCL gene in mouse embryos. We demonstrate that GSCL exhibits DNA sequence-specific recognition of sites bound by the Drosophila anterior morphogen, Bicoid. Several of these sites (TAATCCC) were found in the 5' upstream region of the GSCL gene itself, and we present evidence suggesting that GSCL might regulate its own transcription. In situ hybridization revealed that the mouse ortholog of GSCL, Gscl, is expressed in the brain starting as early as embryonic day 9.5, and expression continues in adults. This expression pattern is consistent with GSCL having either an indirect role in the development of neural crest-derived structures or a direct role in a subset of the phenotype observed in DGS/VCFS, such as learning disorders or psychiatric disease.

Abnormalities, Multiple↗
PubMed1998

Groups of histopathologic abnormalities in brains of very low birthweight infants.

The neuropathologic changes in brains of very premature infants are well recognized but relatively few studies have attempted to identify if specific neuropathologic features cluster together. These data could assist in determining pathogenetic mechanisms of immature brain injury. The goal of this study is to identify which, if any, combinations of histologic features occur together. We identified the presence or absence of 19 histologic features in the brains of 67 infants from a multicenter study of 1,665 prematurely born infants whose birthweight was 500-1,500 grams. We used clustering algorithms and factor analysis to group pathologic features that occurred together. Our results indicate that certain histopathologic features do cluster. For example, telencephalic white matter astrocytosis occurs in 2 groups: 1) associated with amphophilic globules, and, 2) in an uncorrelated group, associated with focal macrophage deposits and coagulative necroses. Parenchymal hemorrhage was not found to be associated with any telencephalic leukoencephalopathy, regardless of whether characterized by rarefaction, astrocytosis, focal coagulative necroses, or foci of macrophages in the white matter. Intraventricular hemorrhage and germinal matrix hemorrhage were not seen together more often than by chance expectation. Intraventricular hemorrhage was only marginally associated with parenchymal hemorrhage. Our data indicate that specific histopathologic features tend to preferentially cluster with each other in groups. This clustering may represent the manifestation of a common mechanism for each. These data should be valuable indicators for future research attempting to establish pathogenesis.

Algorithms↗
PubMed1998

Expandable metallic stents in benign tracheobronchial obstruction.

Expandable metallic stents offer advantages over previously available techniques for treating benign tracheobronchial stenosis or obstruction. Endoluminal stent placement offers a rapid and effective means of opening up narrowed airways, and results in excellent relief of symptoms and improvement in pulmonary function. Because they are delivered in a nonexpanded state using flexible over-wire systems, they can be placed using a flexible bronchoscope and can be located in second-order bronchial branches. Metallic stents have been used to treat benign airway obstruction caused by anastomotic narrowing after lung transplantation, infection, congenital lesions, tracheobronchial malacia, inflammatory conditions including relapsing polychondritis, Wegener granulomatosis, and acquired immunodeficiency syndrome, and external compression from benign mediastinal masses or fibrosis. The stents become epithelialized, which prevents migration and permits ciliary activity to continue. Significant complications can occur, including airway inflammation, stent migration, airway erosion, and stent fracture and collapse, but more serious complications are uncommon. Computed tomography is essential in imaging patients being considered for stent placement, as it allows 1) accurate representation of airway anatomy in three dimensions. 2) measurement of airway diameter, 3) evaluation of airway anatomy distal to a narrowed segment and invisible to bronchoscopy, 4) demonstration of dynamic changes in airway morphologic features during forced exhalation in patients with airway malacia, and 5) demonstration of focal or diffuse air trapping in lung peripheral to the abnormal airway. In patients who have had stent placement, computed tomography is valuable in assessing airway morphologic features and dynamics distal to the stent, and can be valuable in assessing stent dysfunction.

Airway Obstruction↗
PubMed1998

Surgical removal of a choroid plexus adenoma using the argon beam coagulator: technical case report.

OBJECTIVE AND IMPORTANCE: Choroid plexus tumors may be extremely vascular, limiting surgical resection. A case of a choroid plexus adenoma is presented in which the argon beam coagulator (System 6500; ConMed Corp., Utica, NY) was used as a surgical adjunct. CLINICAL PRESENTATION: A 12-year-old male patient with a giant tumor of the lateral ventricle presented with visual loss and was found to have a large intraventricular tumor. At surgery, the tumor was extremely vascular, and the pathological finding was consistent with a choroid plexus adenoma. TECHNIQUE: Because of its vascularity, the tumor was resected in stages with the aid of the argon beam coagulator. CONCLUSION: We conclude that this device may have application in selected neurosurgical operations.

Adenoma↗
PubMed1998

Möbius syndrome with oculomotor nerve paralysis without abducens paralysis.

Möbius syndrome is typified by bilateral facial nerve palsies, usually with abducens palsies. We examined an infant with Möbius syndrome who had bifacial weakness and third nerve palsies, but intact abduction of both eyes. Lower cranial nerve involvement, leading to respiratory, swallowing, and cardiac difficulties, was also present. Pathologic examination of the brainstem showed absent or hypoplastic third, seventh, tenth, and twelfth nerve nuclei. The fourth, fifth, sixth, and eighth nerve nuclei were intact. In Möbius syndrome with ocular motor palsies, rarely the sixth nerve may be spared.

Abducens Nerve↗
PubMed1997

Epilepsy and mental retardation limited to females: an X-linked dominant disorder with male sparing.

Several X-linked disorders affect females disproportionately or exclusively. These including focal dermal hypoplasia, oral-facial-digital syndrome type I (ref. 3) and epilepsy with bilateral periventricular heterotopias. X-linked dominant inheritance with male lethality is probably responsible for sex-limited expression of these disorders, as affected women have frequent spontaneous abortions and the sex ratio of their live offspring is often skewed. The same inheritance pattern has been proposed for Rett syndrome, Aicardi syndrome and microphthalmia with linear skin defects, but in these sporadic conditions, evidence of male lethality is lacking. We investigated an unusual family with epilepsy and mental retardation limited to females (EFMR, #121250 in ref. 9); this disorder is transmitted both by females and by completely unaffected carrier males. Assignment of the EFMR disease locus (EFMR) to the X chromosome indicates that selective involvement of females in X-linked disease may in some instances result from male sparing rather than male lethality.

Cerebral Cortex↗
PubMed1997

Frequency of neuropathological abnormalities in very low birth weight infants.

The occurrences of histologic changes in the central nervous system of very low birth weight infants (500 to 1500 grams) according to gestational age and postnatal age are incompletely reported. In order to better understand the abnormalities present in this patient population, the brains of 67 very low birth weight infants who died after having had at least one cranial ultrasound scan were studied. More than half the infants were born at gestational ages of 24 to 26 weeks, and only 28% died within 24 hours (h) of birth. The slides of the brains of all 67 infants were reviewed simultaneously by 3 neuropathologists who had to agree on the presence and/or absence of each histologic characteristic. Among infants who died within 24 h of birth, fully one quarter had parenchymal hemorrhage, 42% had petechial hemorrhages in the white matter, and more than 20% had hypertrophic astrocytes. These data indicate that in utero, prepartum, injury to the nervous system was common. Compared with infants who died before the sixth day, those who survived at least 6 days were twice as likely to have moderate/severe ventriculomegaly, rarefaction, amphophilic globules, hypertrophic astrocytes, macrophage foci, coagulative necrosis, and hemorrhagic necrosis than those who died before the 7th postnatal day. Parenchymal hemorrhage and moderate/severe ventriculomegaly decreased in frequency with increasing gestational age. On the other hand, the older the gestational age, the higher the likelihood of finding amphophilic globules, hypertrophic astrocytes, macrophage foci, and zones of coagulative necrosis upon neuropathologic examination. Our data indicate that several central nervous system abnormalities appear to increase with both older gestational age and older postnatal age for infants born weighing less than 1500 grams. We were unable, however, to determine the relative contribution of gestational age and postnatal age to the specific neuropathologic findings in this study.

Aging↗
PubMed1997

Cell migration in the developing chick diencephalon.

We previously reported that retrovirally marked clones in the mature chick diencephalon were widely dispersed in the mediolateral, dorsoventral and rostrocaudal planes. The current study was undertaken to define the migration routes that led to the dispersion. Embryos were infected between stages 10 and 14 with a retroviral stock encoding alkaline phosphatase and a library of molecular tags. Embryos were harvested 2.5-5.5 days later and the brains were fixed and serially sectioned. Sibling relationships were determined following PCR amplification and sequencing of the molecular tag. On embryonic day 4, all clones were organized in radial columns spanning the neuroepithelium, which was composed primarily of a ventricular zone at this age. No tangential migration was seen in the ventricular zone. On embryonic day 5, most clones remained radial with many cells located in the ventricular zone; however, a few clones had cells migrating perpendicular to the radial column, in either a rostrocaudal or dorsoventral direction. The tangential migration began just beyond the basal limit of the ventricular zone. On embryonic days 6 and 7, many clones had cells migrating perpendicular to the radial column, which spanned from the ventricular to the pial surface. The migrating cells appeared to be aligned along axes that were perpendicular to the radial column. Using a combination of DiI tracing, immunohistochemistry and electron microscopy, we have determined that axonal tracts are present and are aligned with the migrating cells, suggesting that they support the non-radial cell migration. These data indicate that migration along pathways independent of radial glia occur outside of the ventricular zone in more than 50% of the clones in the chick diencephalon.

Animals↗