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Biomedical subjects

M Brenner

Publications and source records attributed to M Brenner.

At least 37 records · Page 2Linked to original sources
PubMed1994

Concentric sclerosis (Baló): morphometric and in situ hybridization study of lesions in six patients.

Brain tissues from 6 patients with concentric sclerosis (Baló) were examined by in situ hybridization, immunocytochemistry, morphometry, and histological methods. The patients were 24 to 48 years old and had progressive cerebral symptoms and signs that lasted 15 to 100 days. Large demyelinative lesions, most frequent in the frontal white matter, contained alternating bands of demyelinated and partly myelinated white matter that were arranged in concentric or mosaic patterns. In the areas of demyelination, axons were relatively well preserved and there were perivascular inflammatory infiltrates. In 2 specimens, lesions contained regions with the characteristic appearance of actively demyelinating multiple sclerosis plaques. Oligodendroglial densities were highest in normal-appearing white matter, lower in partially myelinated areas, and lowest in demyelinated areas, which also contained many hypertrophic astrocytes closely associated with oligodendroglia. Messenger RNA levels for myelin-related proteins followed the same pattern; they were lowest in demyelinated areas, higher in partially myelinated areas, and highest in normal-appearing white matter beyond lesion margins. Our findings suggest that concentric sclerosis is a variant of multiple sclerosis, that oligodendroglial loss is important in the pathogenesis of demyelination, and that partially myelinated areas probably represent stages of ongoing myelin breakdown rather than remyelination of previously demyelinated areas.

Adult↗
PubMed1994

Expression of insulin-like growth factor-I and related peptides during motoneuron regeneration.

The regulation of insulin-like growth factor-I (IGF-I) and related peptides during motoneuron regeneration was examined in the facial nerve following facial nerve transection. One to 39 days after axotomy, the mRNAs and peptides of IGF-I, type-I insulin-like growth factor receptor (IGFR), insulin-like growth factor binding proteins 1-5 (IGFBP-1-5), and glial fibrillary acidic protein (GFAP) were assayed in brain stem sections by in situ hybridization and immunohistochemistry. Relative mRNA levels of IGF-I, IGFR, IGFBP-2, and GFAP in the ipsilateral facial nucleus were highest 4-7 days after transection and declined thereafter. Double immunostaining experiments showed that both IGF-I and IGFBP-2 were localized in GFAP-positive astrocytic processes, many of which were perineuronal. Peak staining intensity was found 4-7 days after transection and immunoreactivity still was present after 21-35 days. IGFR mRNA was found in some regenerating neurons; however, IGFR peptide was not detected in these neurons or in any other cells in the facial nucleus. Our findings suggest that astrocytic production of IGF-I and IGFBP-2 may accompany regeneration of neurons undergoing retrograde changes induced by axotomy.

Animals↗
PubMed1994

Astrocytes express insulin-like growth factor-I (IGF-I) and its binding protein, IGFBP-2, during demyelination induced by experimental autoimmune encephalomyelitis.

To assess the distribution of insulin-like growth-factor-related proteins during autoimmune CNS demyelination and remyelination, experimental autoimmune encephalomyelitis was produced by injecting Lewis rats with an emulsion containing guinea pig spinal cord and complete Freund's adjuvant. Tail weakness appeared at 10-12 days and was followed by hind and forelimb weakness. Paraplegia and incontinence were observed in some animals. From 8-40 days postinoculation (dpi), spinal cord sections were used to correlate lesion location and severity with mRNA distributions of insulin-like growth factor I (IGF-I), IGF-binding protein 2 (IGFBP-2), IGF-I-receptor (IGFR-I), glial fibrillary acidic protein (GFAP), and myelin basic protein (MBP). These were determined semiquantitatively by in situ hybridization. Fourteen dpi, there were inflammatory infiltrates and demyelination in both white matter (WM) and grey matter (GM). IGF-I and GFAP mRNAs were increased in these lesions and transcripts encoding myelin basic protein (MBP) were greatly reduced. Large lesions with extensive demyelination were evident in both WM and GM when mRNA levels of GFAP and IGF-I peaked 26 dpi. MBP mRNA levels began increasing 21 dpi and peaked 26 dpi, when a few thin regenerating myelin sheaths were found morphologically. Astrocytes, identified by their morphology and GFAP immunoreactivity, expressed very low levels of IGFBP-2 mRNA and peptide in normal controls; their levels were significantly higher 14 dpi, peaked 26 dpi, and then gradually decreased. Some neurons, as well as oligodendroglia in areas undergoing remyelination, expressed IGFR-I. Although levels of IGF-I, IGFBP-2, and GFAP mRNAs were highest in lesion areas, levels were also elevated around lesions and in some normal-appearing areas of WM and GM 14-40 dpi. The gene expression of both IGF-I and IGFBP-2 by hypertrophic GFAP-positive astrocytes was demonstrated 14-40 dpi by combined in situ hybridization and immunocytochemistry as well as by double immunostaining. Coexpression of IGF-I and IGFBP-2 in the same astrocyte was a frequent finding. Relative increases in both IGF-I, GFAP, IGFBP-2, IGFR-I, and MBP mRNAs peaked at about the same time. This suggests that during lesion progression and recovery, astrocytic expression of IGF-I-related peptides may reduce immune-mediated myelin injury. We also suggest that astrocytic IGFBP-2 in lesions may help target IGF-I to IGFR-I-expressing oligodendrocytes and promote remyelination of demyelinated axons.

Animals↗
PubMed1994

Cyclic AMP decreases the expression of a neuronal marker (GAD67) and increases the expression of an astroglial marker (GFAP) in C6 cells.

C6 cells express proteins and mRNAs that are characteristic of both glia and neurons. Agents that increase intracellular levels of cyclic AMP (cAMP) decrease the enzymatic activity of glutamate decarboxylase (GAD), a neuronal marker, and the mRNA levels for one of the two GAD isoenzymes, GAD67. This reduction is accompanied by increased levels of glial fibrillary acidic protein (GFAP) mRNA, an astrocyte marker. Transient transfection assays, in which a 2-kb upstream regulatory region of the human GFAP gene was linked to a reporter gene, indicate that at least some of the cAMP-mediated increase of GFAP mRNA levels is due to increased transcription. Increases in intracellular cAMP appear to induce differentiation of C6 cells toward a more mature astrocyte phenotype.

Actins↗
PubMed1994

Measuring oxygen uptake and carbon dioxide production in critically ill patients using a standard blood gas analyzer.

OBJECTIVE: The measurement of oxygen uptake and CO2 production in critically ill patients requires invasive monitoring or complex analysis equipment. This study investigates the hypothesis that oxygen uptake and CO2 production can be accurately determined by measuring oxygen and CO2 concentrations in samples from inspiratory and expiratory ventilator circuitry, using a standard blood gas analyzer. DESIGN: Prospective comparison of CO2 production and oxygen uptake measurements determined by use of a blood gas analyzer vs. a mass spectrometer. SETTING: University teaching hospital medical and surgical intensive care units (ICUs). PATIENTS: Critically ill patients (n = 46) receiving mechanical ventilation in the ICUs. INTERVENTIONS: PO2 and PCO2 were obtained with two new techniques and compared simultaneously with measurements on a mass spectrometer in critically ill, mechanically ventilated patients. Two methods were evaluated: a) arterial blood gas analyzer measurements of PO2 and PCO2 from fluid collected in traps on the inspiratory and expiratory limbs of the ventilator circuitry; b) PO2 and PCO2 measurements of inspiratory and expiratory gas samples collected in bags and injected directly into an arterial blood gas analyzer. Oxygen consumption and CO2 production were compared, using both methods of gas measurements. MEASUREMENTS AND MAIN RESULTS: Direct injection of gas samples collected in a bag from inspiratory and expiratory limbs of a breathing circuit into the arterial blood gas analyzer correlated very closely with mass spectrometer measurements for all variables (n = 32 sample measurements in 25 patients): fractional oxygen (r2 = .99, slope = 1.02, bias = 0.37%, precision = 0.54), fractional expired CO2 (r2 = .90, slope = 0.86, bias = -0.10%, precision = 0.15), oxygen uptake (r2 = .87, slope = 0.99, bias = 21.6 mL/min, precision = 38.0), and CO2 production (r2 = .98, slope = 0.95, bias = 7.90 mL/min, precision = 15.3). In contrast, although fractional oxygen and CO2 concentrations were approximated by analysis of fluid collected from inspiratory and expiratory traps, the values did not correlate well enough with mass spectrometer values to yield reasonable oxygen uptake or CO2 production results. CONCLUSION: We have demonstrated that direct Fick oxygen uptake and CO2 production can be accurately determined in mechanically ventilated patients, using direct injection of collected gas samples into standard blood gas analyzers. This simple, inexpensive technique can be performed using equipment readily available in any hospital.

Bias↗
PubMed1994

Structure and transcriptional regulation of the GFAP gene.

Transcriptional regulation of the GFAP gene is intimately connected with astrocyte function: its initial activation marks the differentiation of astrocytes, and its up-regulation accompanies the reactive response to CNS injury. Studies of GFAP transcription should thus provide insights into multiple regulatory pathways operating in these cells. In addition, they should identify DNA elements that could be used to direct synthesis of other proteins to astrocytes in transgenic animals, permitting creation of disease models, and the testing of cause and effect relationships. This review describes several GFAP cDNA and genomic clones that have been isolated, including homology comparisons of the encoded RNAs and proteins. Cell transfection studies by several laboratories are summarized that have identified a DNA segment immediately upstream of the RNA start site that is essential for transcriptional activity, but which have yielded conflicting results concerning the importance of other segments located both further upstream and downstream of the RNA start site. Two procedures are recounted that have led to the successful expression of GFAP-transgenes in astrocytes in mice. One of these incorporates the transgene into the first exon of a fragment spanning the entire GFAP gene, while the other links it to a 2 kb 5'-flanking segment. Results already produced by GFAP-transgenic studies include demonstration of a neurotoxic effect of the HIV-1 gp120 coat protein, and creation of a hydrocephalic mouse model.

Animals↗
PubMed1994

Measurement of transfer factor during constant exhalation.

BACKGROUND: Transfer factor of the lung for carbon monoxide (TLCO) was measured by a new method based on analysis of the ratio of the concentrations of carbon monoxide to an inert gas (methane) relative to lung volume during a constant exhalation. Since this new technique is based solely upon exhalation, anomalies associated with inspiration and breath holding do not affect results. Additionally, because prolonged breath holding is not required, measurements can readily be made in dyspnoeic patients. METHODS: Exhalation TLCO (TLCO,ex) was compared with the standard (Jones and Meade) 10 second breath holding TLCO (TLCO,bh) in 100 consecutive patients. Patients did not practise the exhalation manoeuvre prior to testing. RESULTS: The comparative results were very close; mean difference (bias) +/- standard deviation (precision) was 0.05 (0.84) mmol/min/kPa. The relation was equally strong in patients with severe pulmonary disease; for patients with FEV1 < 1.51 the mean difference was 0.21 (0.80) mmol/min/kPa. CONCLUSIONS: Since the results were essentially identical between the techniques, it seems that comparable pathophysiological factors affect TLCO during breath holding and constant exhalation. Constant exhalation may therefore be a useful alternative to the breath holding technique for clinical measurement of TLCO.

Adult↗
PubMed1994

Investigation of computer lung model-predicted DLCO during single-breath maneuvers.

A computer model based on the theoretical gas absorption equations of Martonen and Wilson (J. Math. Biol. 14: 203-220, 1982) was developed to predict changes in single-breath diffusing capacity of the lung for carbon monoxide (DLCO) with alterations in anatomic dead space, alveolar volume, and inspiratory time. The computer model predictions were compared with results obtained from normal subjects performing DLCO maneuvers under correspondingly altered conditions to assess the validity of the Martonen-Wilson equations. In normal subjects, a theoretical "ideal" single-breath DLCO was derived from measured DLCO and adjusted to instantaneous inspiratory and expiratory times with this three-phase computer model. Clinical single-breath DLCO measurements with increased external dead space and inspiratory and expiratory times in normal subjects correlated well with our mathematical model predictions (all r > 0.80, P < 0.001) but did not correlate closely with the predicted effects of alveolar volume on DLCO. This study demonstrates that uniform gas absorption equations of Martonen and Wilson closely predict changes in observed DLCO with systematic variation of inspiratory and expiratory time in normal subjects at full lung volume and appear to be a reasonable estimation of normal physiological events during single-breath carbon monoxide absorption.

Adult↗
PubMed1994

Immunomodulatory effects of human neuroblastoma cells transduced with a retroviral vector encoding interleukin-2.

We have investigated whether retroviral mediated transfer of the IL-2 gene renders human neuroblastoma cells immunogenic, justifying their use in a clinical tumor immunization study. Fourteen neuroblastoma cell lines were established from patients with disseminated neuroblastoma and transduced with the vector G1Ncvl2, which contains the neomycin phosphotransferase gene and the cDNA of the human interleukin-2 gene. Clones secreting > 150 pg/10(6) cells/24 h of IL-2 were selected for further study. Secretion of IL-2 was maintained for at least 3 weeks in nonselective media, implying that production of the cytokine would continue under in vivo conditions. Co-culture of IL-2 transduced cell lines with patient lymphocytes induced potent cytotoxic activity against both transduced and parental neuroblastoma cell lines. This activity was HLA unrestricted, and predominantly mediated by CD16+ or CD56+ and CD8- lymphocytes. These data form the preclinical justification for our current immunization protocol for patients with relapsed or resistant neuroblastoma.

Antibodies, Monoclonal↗
PubMed1994

[Corticobasal degeneration. The significance of clinical criteria for establishing the diagnosis].

Neuropathological studies show that about 20% of all patients suffering from an acinetic-rigid syndrome can not be given the diagnosis of idiopathic Parkinson's disease. Among these non-idiopathic Parkinson-syndromes the corticobasal degeneration (CBD) can be regarded as a separate disease entity. The pathological findings of moderate predominantly frontal and parietal cerebral atrophy, cortical Pick-cells and specific corticobasal inclusion bodies are considered valuable features which support the diagnosis. The clinical Characteristics of CBD are demonstrated in 3 patients including an acinetic-rigid syndrome, limb apraxia and "alien limb"-syndrome, as well as reflex myoclonus. Eye movement disorders, dementia and other rare symptoms may also be present. Electrophysiological reflex-testing helps to corroborate diagnosis. These findings and a summary which includes the previously published cases of CBD show that CBD in most cases can be diagnosed intra vitam.

Aged↗
PubMed1994

Speech measures indicating workload demand.

Heart rate and six speech measures were evaluated using a manual tracking task under different workload demands. Following training, 17 male subjects performed three task trials: a difficult trial, with a $50 incentive for successful performance at a very demanding level; an easy trial, with a $2 incentive for successful performance at a simple level; and a baseline trial, in which there was physiological monitoring but no tracking performance. Subjects counted aloud during the trials. It was found that heart rate, speaking fundamental frequency (pitch), and vocal intensity (loudness) increased significantly with workload demands. Speaking rate showed a marginal increase, while vocal jitter and vocal shimmer did not show reliable changes. A derived speech measure, which statistically combined information from all other speech measures except shimmer, was also evaluated. It increased significantly with workload demands and was surprisingly robust in showing differences for individual subjects. It appears that speech analysis can provide practical workload information.

Adult↗
PubMed1994

GFAP promoter directs astrocyte-specific expression in transgenic mice.

Glial fibrillary acidic protein (GFAP) is an intermediate-filament protein expressed abundantly and almost exclusively in astrocytes of the CNS. We are studying transcriptional regulation of the GFAP gene to gain insight into astrocyte function and also to develop an astrocyte-specific expression system for manipulating brain physiology. In this work, we have produced transgenic mice carrying the bacterial lacZ reporter gene linked to a 2.2 kilobase 5'-flanking sequence derived from the human GFAP gene that previously was shown to direct astrocyte-specific transcription in cultured cells. We report that this promoter directs expression to astrocytes in the CNS. In addition, the upregulation of GFAP gene activity that follows injury to the brain was mimicked by the transgene. One of the transgenes was found to be X-linked and appeared to undergo the usual random inactivation that achieves gene dosage compensation in females. The brains of hemizygous females stained uniformly rather than displaying mosaic patches, indicating that astrocytes intermingle following their formation. The specific expression of the GFAP-lacZ transgene means that it is now possible to target expression of other heterologous genes to astrocytes in vivo, and to study the mechanisms for reactive gliosis at the DNA level.

Animals↗
PubMed1994

Thoracoscopic laser ablation of pulmonary bullae. Radiographic selection and treatment response.

The purpose of this study was to develop objective preoperative selection methods for predicting outcome in patients undergoing thoracoscopic laser ablation of emphysematous pulmonary bullae. Initial radiographic presentation was correlated with physiologic function both before and after the operation in 24 patients entered into a prospective clinical protocol for evaluation of carbon dioxide laser treatment of emphysematous pulmonary bullae. Nineteen surviving patients underwent follow-up evaluation 1 to 3 months after the operation. Pulmonary function test results showed improvements in spirometry (forced vital capacity increased 0.82 +/- 0.125 L, forced expiratory volume in 1 second increased 0.36 +/- 0.07 L, and maximum voluntary ventilation increased 11.69 +/- 2.6 L/m; p < 0.002); airway resistance decreased by 0.9 +/- 0.35 cm of water/L per second, and specific conductance increased 0.019 +/- 0.006 L/cm H2O per second (p < 0.02). Lung volumes improved (residual volume decreased 1.25 +/- 0.23 L, p < 0.001) without significant change in resting gas exchange. Quantitative radiographic grading of extent of preoperative pulmonary bullae correlated well with response to laser treatment in patients with preoperative and postoperative studies. Patients with large bullae accompanied by crowding of adjacent lung structures, upper lobe predominance, and minimal underlying emphysema had greatest improvement in pulmonary function results with laser bullae ablation (p < 0.05). However, some patients with multiple smaller bullae and diffuse emphysema also demonstrated objective improvement after operation. Quantitative radiographic analysis of the extent of bullous disease and the degree of associated emphysema can be used to determine short-term postoperative pulmonary response and may be useful in selecting future thoracoscopic laser bullae ablation candidates. Additional follow-up will be necessary to further improve selection criteria and help define the long-term role of thoracoscopic laser treatment of bullous emphysema.

Aged↗
PubMed1993

Continuous infusion of interleukin-2 in children with refractory malignancies.

BACKGROUND: The toxicity of interleukin-2 (IL-2) administered by continuous infusion has not been investigated in children. METHODS: This study enrolled 10 boys and 7 girls with refractory malignancy. Recombinant IL-2 was infused continuously for cycles of 120 hours at doses escalating from 3 to 30 x 10(6) IU/m2 per day. RESULTS: A total of 45 cycles was administered. The most common toxicities included fever, anemia, hypotension (usually responsive to fluid bolus), hyponatremia, oliguria, hypoalbuminemia, nausea, thrombocytopenia, vomiting, and weight gain. Most side effects were correlated significantly with a dosage of 18 x 10(6) IU/m2 or more per day. Respiratory distress was infrequent. Two cycles were interrupted due to severe toxicity (hypotension in one case and confusion in another), but there were no fatalities. During infusion, there was a significant nondose-related increase in serum IL-2 receptor levels. Despite this evidence of immunomodulation, no objective tumor response was noted. CONCLUSIONS: Continuous infusion of IL-2 at doses up to 30 x 10(6) IU/m2 per day can be administered safely to children by this method.

Adolescent↗
PubMed1993

Measurement of cardiac output by automated single-breath technique, and comparison with thermodilution and Fick methods in patients with cardiac disease.

Accurate noninvasive methods are needed for determination of cardiac output. Current methods are generally complex or may be unreliable. A previously described method, based on absorption of acetylene gas during a constant exhalation that enables calculation of cardiac output by estimating pulmonary capillary circulation, is incorporated in a new, automated commercial product (SensorMedics 2200). In this study, cardiac output by single-breath acetylene blood flow measured with this device was compared with the standard thermodilution and direct Fick methods in 20 patients undergoing cardiac or pulmonary artery catheterization. Patients inhaled test gas mixture to total lung capacity and exhaled at a constant rate through an adjustable resistor. Lung volumes and noninvasive acetylene blood flow value were calculated automatically. Correlation between the automated single-breath technique and both thermodilution and Fick cardiac output determinations was very high (correlation coefficients were 0.90 and 0.92, respectively), regression slopes were close to identity (0.98 and 0.90), and bias (-0.39 and -0.79 liter/min) and precision (0.94 and 1.02) were good; when shunt correction was applied, bias was reduced to 0.06 and 0.35 liter/min, respectively. Rapid, accurate, noninvasive measurement of cardiac output was easily obtained using the automated device. This technique may have a wide applicability for noninvasive evaluation of patients with cardiac disease and for monitoring effects of therapeutic interventions.

Absorption↗
PubMed1993

Measurement of red blood cell-vitamin B12: a study of the correlation between intracellular B12 content and concentrations of plasma holotranscobalamin II.

We have recently reported a new and rapid assay to measure plasma holotranscobalamin II (holo TC II) as a means of exploring vitamin B12 status. In order to further evaluate the significance of plasma holoTC II in determining tissue cobalamin, we have chosen the red blood cell-vitamin B12 (RBC-B12) assay as a measure of tissue vitamin B12 content and studied the relationship between RBC-B12 and plasma holoTC II levels. Plasma holoTC II and RBC-B12 concentrations were concomitantly assayed in 20 hematologically normal controls and cancer patients. In our groups of controls, the mean value of RBC-B12 was determined as 241 +/- 51 pg/ml of packed erythrocytes (PE) with a range varying from 180 to 355 pg/ml PE. Preliminary results obtained in 32 cancer patients revealed lower holoTC II and RBC-B12 levels than the control group and a required threshold value of 70 pg/ml of holoTC II in order to maintain a normal RBC-B12 greater than 180 pg/ml PE.

Erythrocytes↗