Biomedical subjects

Jeffrey A Golden

Publications and source records attributed to Jeffrey A Golden.

11 recordsLinked to original sources

PubMed2003

Traumatic brain injury in piglets of different ages: techniques for lesion analysis using histology and magnetic resonance imaging.

Quantitation of lesions in large gyrencephalic brains presents a variety of technical challenges. Specific techniques are required when comparing lesions in subjects of different ages in order to assess maturational effects. We have modified existing techniques to attain reliable, consistent and reproducible paraffin-embedded histological sections for volumetric lesion analysis and correlation with magnetic resonance imaging (MRI) in piglets of different ages following focal traumatic brain injury. Twenty-four Yorkshire domestic piglets at three different ages (5 days, 1 month, and 4 months old) underwent scaled cortical impact injury to the fronto-parietal cortex. This contusion model utilizes a rapid volume of indentation scaled proportionally to the growth of the brain, allowing for examination of maturational influences on the brain's response to focal mechanical trauma. To overcome problems with differential processing and embedding of brains ranging from 43 to 107 g, we developed a piglet parallel brain slicing apparatus. Along with specific methods for processing, embedding, mounting, and slide preparation, these techniques enabled excellent quality 10-microm serial coronal sections to be obtained for histology and immunohistochemical analysis. Accurate co-registration of histologic, immunohistochemical and radiologic images at different ages was possible, which may enhance understanding of developmental aspects of brain injury pathophysiology.

Age Factors↗

PubMed2003

Loss of murine Na+/myo-inositol cotransporter leads to brain myo-inositol depletion and central apnea.

myo-Inositol (Ins) and its polyphosphoinositide derivatives that are important in membrane signaling have long been held to play a special role in brain metabolism. As polyphosphoinositides turn over rapidly and are exceptionally abundant in nervous tissue, high Ins levels in the range of 2-15 mm that have been observed in brain may be necessary to maintain the rates of phosphoinositide synthesis in diverse membrane locations within neurons. Cellular concentration gradients of this magnitude indicate a dependence on active Ins transport, especially at the time of growth and differentiation. The Na(+)/myo-inositol cotransporter (SMIT1 or SLC5A3) gene is highly expressed prenatally in the central nervous system and placenta. To gain more insight into brain Ins metabolism, while ascertaining the importance of SMIT1 as a transporter, we generated mice with a homozygous targeted deletion of this gene. Newborn SMIT1(-/-) animals have no evidence of SMIT1 mRNA, a 92% reduction in the level of brain Ins, an 84% reduction in whole body Ins, and expire shortly after birth due to hypoventilation. Gross pathologic and light microscopic examinations of each organ, as well as the placenta, of embryonic day 18.5 fetuses at near term gestation were normal. Based on [(3)H]acetate incorporation into phospholipids of lung tissue explants, immunostaining of lung tissue for surfactant protein A, B, and C, and electron microscopic examination of alveolar cells, there was no evidence of abnormal pulmonary surfactant production by type 2 pneumocytes in lung. Although no histologic lesions were detected in the nervous system, electrophysiological studies of the brainstem pre-Bötzinger respiratory control center demonstrated an abnormal rhythm discharge with periods of central apnea. The cause of death can be explained by the regulatory defect in brainstem control of ventilation. This model demonstrates the critical importance of SMIT1 in the developing nervous system. The high affinity SMIT1 transporter is responsible for the Ins concentration gradient in the murine fetal-placental unit.

Alleles↗

PubMed2003

Modified ultrafiltration may not improve neurologic outcome following deep hypothermic circulatory arrest.

OBJECTIVE: Modified ultrafiltration (MUF) improves systolic blood pressure and left ventricular performance, as well as lowering transfusion requirements, after cardiopulmonary bypass (CPB). MUF has also been shown to enhance acute cerebral metabolic recovery after deep hypothermic circulatory arrest (DHCA), but whether this improves neurologic outcome is unknown. METHODS: Sixteen neonatal piglets underwent CPB and 90 min of DHCA. The hematocrit was maintained between 25 and 30%. Alpha-stat blood gas management was used. After separation from CPB, animals were randomized to 15 min of MUF (n = 8) or no intervention (n = 8). Neurologic injury was assessed with behavior scores and histologic examination. Standardized behavior scores were obtained on post-operative days 1, 3, and 6 (0 = no deficit to 95 = brain death). The percentage of injured neurons by hematoxylin and eosin staining and the degree of reactive astrocytosis by glial filbrillary acidic protein (GFAP) immunohistochemistry were assessed to determine histologic scores in the neocortex and hippocampus (0 = no injury to 4 = diffuse injury). RESULTS: There were no statistically significant differences between groups during CPB. After MUF, the hematocrit was significantly higher (40% +/- 5.7 vs. 28% +/- 3.9, P < 0.001). There were no significant differences in behavior scores between groups (p > 0.1). There was resolution of deficits by day 6 in all animals. Neuronal injury was present in 81% (13/16) of the animals with no statistically significant differences between groups in incidence or severity. CONCLUSIONS: Use of MUF after DHCA does not prevent neuronal injury or improve neurologic outcome in this neonatal swine model.

Animals↗

PubMed2002

Expression pattern of cLhx2b, cZic1 and cZic3 in the developing chick diencephalon.

The diencephalon is the caudal part of the developing forebrain that gives rise to the epithalamus, thalamus, hypothalamus and retina. The mature diencephalon is functionally and anatomically parceled into well-defined nuclei. In an effort to understand how this region of the brain develops we examined the expression of several transcription factors during development. We find that the LIM homeodomain transcription factor, cLhx2b, and the zinc finger transcription factors, cZic1 and cZic3, are predominantly expressed in partially overlapping domains of the chick dorsal diencephalon. Interestingly, a correlation exists between their expression in neuroepithelial progenitor cells at early stages and in the differentiated nuclei at progressively more advanced stages of development.

Animals↗

PubMed2002

Neuronal migration, cerebral cortical development, and cerebral cortical anomalies.

Cerebral cortical malformations are relatively common anomalies identified by neuroimaging and pathologically in patients with epilepsy and mental retardation. A disruption in neuronal migration during central nervous system development has been postulated as the pathogenesis for many of these disorders. Recently, the cell migration hypothesis has been proven accurate for lissencephaly, subcortical band heterotopia, and periventricular nodular heterotopia. Furthermore, advances in cellular and molecular biology have begun elucidating the fundamental mechanisms underlying these migration disorders. These data have resulted in redefining and recategorizing specific malformations based on their molecular genetic abnormality. In this review we shall discuss the current understanding of neuronal migration in the developing cerebral cortex, the evaluation of these patients, and attempt to describe the pathogenesis for several well-characterized human disorders of cell migration.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

PubMed2002

Should thrombolysis be contraindicated in patients with cerebral arteriovenous malformations?

OBJECTIVES: To report the successful and uncomplicated use of systemic thrombolysis for massive pulmonary embolism in a patient with a known cerebral arteriovenous malformation and to suggest that the presence of an unruptured arteriovenous malformation or aneurysm should not be considered an absolute contraindication to systemic thrombolysis. DESIGN: Case report. SETTING: A 16-bed adult neurologic/medical intensive care unit in a university hospital. PATIENTS: A patient developed a massive pulmonary embolism the morning after elective cerebral embolization of a large unruptured cerebral arteriovenous malformation. INTERVENTION: Radial artery catheterization, arterial blood gas measurements, mechanical ventilation, vasopressors, pulmonary perfusion scan, echocardiogram, head computed tomography, heparin therapy, and systemic recombinant tissue plasminogen activator therapy. MEASUREMENT AND MAIN RESULTS: The patient required emergent mechanical ventilation and vasopressor support for respiratory and hemodynamic failure. Echocardiogram showed acute right heart failure, and pulmonary perfusion scan demonstrated massive pulmonary embolism. Despite intravenous heparin therapy, the patient had worsening hypotension and acidosis and we therefore treated with recombinant tissue plasminogen activator. Within the next day the patient was weaned from vasopressor support and extubated. Neurologic examination remained normal, and follow-up head computed tomography revealed no evidence of intracranial hemorrhage. CONCLUSION: Known arteriovenous malformations or aneurysms are considered a contraindication to thrombolysis, although the true risk of thrombolysis-precipitated intracranial hemorrhage is unknown. We believe that this risk is low in the setting of a previously unruptured arteriovenous malformation or aneurysm. The decision to use systemic thrombolysis in a patient with a known vascular malformation should be individualized.

Contraindications↗

PubMed2002

Hard metal interstitial lung disease: high-resolution computed tomography appearance.

Hard metal interstitial lung disease (HM-ILD) is a rare form of interstitial lung disease caused by aerosolized particulates containing cobalt inhaled during the manufacture or grinding of hard metal. The high-resolution computed tomography (HRCT) appearance of HM-ILD includes reticulation, traction bronchiectasis, and large peripheral cystic spaces in a mid and upper lung distribution. This appearance, along with a consistent occupational exposure, should specifically suggest the diagnosis of HM-ILD.

Adult↗

PubMed2002

Intrapulmonary pharmacokinetics of linezolid.

In this study, our objective was to determine the steady-state intrapulmonary concentrations and pharmacokinetic parameters of orally administered linezolid in healthy volunteers. Linezolid (600 mg every 12 h for a total of five doses) was administered orally to 25 healthy adult male subjects. Each subgroup contained five subjects, who underwent bronchoscopy and bronchoalveolar lavage (BAL) 4, 8, 12, 24, or 48 h after administration of the last dose. Blood was obtained for drug assay prior to administration of the first dose and fifth dose and at the completion of bronchoscopy and BAL. Standardized bronchoscopy was performed without systemic sedation. The volume of epithelial lining fluid (ELF) recovered was calculated by the urea dilution method, and the total number of alveolar cells (AC) was counted in a hemocytometer after cytocentrifugation. Linezolid was measured in plasma by a high-pressure liquid chromatography (HPLC) technique and in BAL specimens and AC by a combined HPLC-mass spectrometry technique. Areas under the concentration-time curves (AUCs) for linezolid in plasma, ELF, and AC were derived by noncompartmental analysis. Half-lives for linezolid in plasma, ELF, and AC were calculated from the elimination rate constants derived from a monoexponential fit of the means of the observed concentrations at each time point. Concentrations (means +/- standard deviations) in plasma, ELF, and AC, respectively, were 7.3 +/- 4.9, 64.3 +/- 33.1, and 2.2 +/- 0.6 microg/ml at the 4-h BAL time point and 7.6 +/- 1.7, 24.3 +/- 13.3, and 1.4 +/- 1.3 microg/ml at the 12-h BAL time point. Linezolid concentrations in plasma, ELF, and AC declined monoexponentially, with half-lives of 6.9, 7.0, and 5.7 h, respectively. For a MIC of 4, the 12-h plasma AUC/MIC and maximum concentration/MIC ratios were 34.6 and 3.9, respectively, and the percentage of time the drug remained above the MIC for the 12-h dosing interval was 100%; the corresponding ratios in ELF were 120 and 16.1, respectively, and the percentage of time the drug remained above the MIC was 100%. The long plasma and intrapulmonary linezolid half-lives and the percentage of time spent above the MIC of 100% of the dosing interval provide a pharmacokinetic rationale for drug administration every 12 h and indicate that linezolid is likely to be an effective agent for the treatment of pulmonary infections.

Acetamides↗

PubMed2002

Effects of gender, AIDS, and acetylator status on intrapulmonary concentrations of isoniazid.

The objective of the present study was to evaluate the effects of gender, AIDS, and acetylator status on the steady-state concentrations of orally administered isoniazid in plasma and lungs. Isoniazid was administered at 300 mg once daily for 5 days to 80 adult volunteers. Subjects were assigned to eight blocks according to gender, presence or absence of AIDS, and acetylator status. Blood was obtained prior to administration of the first dose, 1 h after administration of the last dose, and at the completion of bronchoscopy and bronchoalveolar lavage (BAL), which was performed 4 h after administration of the last dose. The metabolism of caffeine was used to determine acetylator status. Standardized bronchoscopy was performed without systemic sedation. The volume of epithelial lining fluid (ELF) recovered was calculated by the urea dilution method. Isoniazid concentrations in plasma, BAL fluid, and alveolar cells (ACs) were measured by high-performance liquid chromatography. AIDS status or gender had no significant effect on the concentrations of isoniazid in plasma at 1 or 4 h. Concentrations in plasma at 4 h and concentrations in ELF were greater in slow acetylators than fast acetylators. The concentration in plasma (1.85 +/- 1.60 microg/ml [mean +/- standard deviation; n = 80]) at 1 h following administration of the last dose was not significantly different from that in ELF (2.25 +/- 3.50 microg/ml) or ACs (2.61 +/- 5.01 microg/ml). For the entire study group, concentrations in plasma at 1 h were less than 1.0, 2.0, and 3.0 microg/ml for 34.7, 60, and 82.7% of the subjects, respectively; concentrations in ELF were less than 1.0, 2.0, and 3.0 microg/ml in 30 (37.5%), 53 (66.0%), and 58 (72.5%) of the subjects, respectively; and concentrations in ACs were less than 1.0, 2.0, and 3.0 microg/ml in 43 (53.8%), 59 (73.8%), and 65 (81.3%) of the subjects, respectively. The concentrations of orally administered isoniazid in plasma were not affected by gender or the presence of AIDS. The concentrations in plasma at 4 h and the concentrations in ELF, but not the concentrations in ACs, were significantly greater in slow acetylators than fast acetylators. Concentrations in plasma and lungs were low compared to recommended therapeutic concentrations in plasma and published MICs of isoniazid for Mycobacterium tuberculosis. The optimal concentrations of isoniazid in ACs and ELF are unknown, but these data suggest that the drug enters these compartments by passive diffusion and achieves concentrations similar to those found in plasma.

Acetylation↗

PubMed2002

Tracheal compression by the stomach following gastric pull-up: diagnosis with CT and treatment with expandable metallic stent placement.

Surgical treatment of recurrent achalasia includes esophagectomy with gastric pull-up. A MEDLINE search yielded no articles describing an adverse effect of this surgery on pulmonary function. We report the first case of acute ventilatory failure caused by gastric pull-up. An evaluation by flexible bronchoscopy, spirometry with flow-volume loops, and dynamic CT scanning revealed extrinsic compression of the trachea by the stomach causing obstruction. Endotracheal placement of a self- expanding stent resulted in the rapid extubation of the patient with normalization of the flow-volume loop and dramatic improvement in the FVC, FEV(1), and peak expiratory flow.

Constriction, Pathologic↗

PubMedDate not supplied

Benign tracheobronchial stenoses: changes in short-term and long-term pulmonary function testing after expandable metallic stent placement.

PURPOSE: To determine the short- and long-term improvement in airflow dynamics in patients undergoing tracheobronchial stent placement for benign airway stenoses. METHODS: Twenty-two patients underwent 34 tracheal and/or bronchial stent placement procedures for benign airway stenoses and had the results of pulmonary function tests available. Stent placement indications included bronchomalacia after lung transplantation (n = 11), postintubation stenoses (n = 6), relapsing polychondritis (n = 2), and 1 each of tracheomalacia, tracheal compression, and histoplasmosis. Six patients underwent more than one stent placement procedure (range: 2-7 procedures). The mean forced expiratory volume in one second (FEV(1) ), forced expiratory flow rate in the midportion of the forced vital capacity curve (FEF(25-75) ), forced vital capacity, and peak flow (PF) rate obtained before stent placement were compared with those immediately after stent placement and with those measurements most remote from stent placement using the paired two-tailed test. RESULTS: All patients reported improved respiratory function immediately after stent placement. The mean FEV(1), FEF(25-75), and PF rate improved significantly (p < 0.001, p = 0.002, and p = 0.009, respectively) after stent placement. On long-term follow-up averaging 15 months after stent placement, these parameters declined despite patients' subjective sense of improvement. Segregating the population into transplant and nontransplant airway stenosis etiologies, however, FEF(25-75) and PF rate remained significantly improved (p = 0.045, p = 0.027, respectively), over the long term for the latter. FEV increased after subsequent stent placements for patients receiving multiple stents. CONCLUSION: Stent placement for benign tracheobronchial stenoses provides significant immediate improvement in airflow dynamics. Long-term improvement in airflow obstruction may be expected, and additional stent placements may further improve pulmonary function.

Adult↗