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Biomedical subjects

M Brenner

Publications and source records attributed to M Brenner.

At least 73 records · Page 4Linked to original sources
PubMed1999

Lung function 4 years after lung volume reduction surgery for emphysema.

STUDY OBJECTIVES: Current data for patients > 2 years after lung volume reduction surgery (LVRS) for emphysema is limited. This prospective study evaluates pre-LVRS baseline data and provides long-term results in 26 patients. INTERVENTION: Bilateral targeted upper lobe stapled LVRS using video thoracoscopy was performed in 26 symptomatic patients (18 men) aged 67 +/- 6 years (mean +/- SD) with severe and heterogenous distribution of emphysema on lung CT. Lung function studies were measured before and up to 4 years after LVRS unless death intervened. RESULTS: No patients were lost to follow-up. Baseline FEV(1) was 0.7 +/- 0.2 L, 29 +/- 10% predicted; FVC, 2.1 +/- 0.6 L, 58 +/- 14% predicted (mean +/- SD); maximum oxygen consumption, 5.7 +/- 3.8 mL/min/kg (normal, > 18 mL/min/kg); dyspneic class > or = 3 (able to walk < or = 100 yards) and oxygen dependence part- or full-time in 18 patients. Following LVRS, mortality due to respiratory failure at 1, 2, 3, and 4 years was 4%, 19%, 31%, and 46%, respectively. At 1, 2, 3, and 4 years after LVRS, an increase above baseline for FEV(1) > 200 mL and/or FVC > 400 mL was noted in 73%, 46%, 35%, and 27% of patients, respectively; a decrease in dyspnea grade > or = 1 in 88%, 69%, 46%, and 27% of patients, respectively; and elimination of oxygen dependence in 78%, 50%, 33%, and 22% of patients, respectively. The mechanism for expiratory airflow improvement was accounted for by the increase in both lung elastic recoil and small airway intraluminal caliber and reduction in hyperinflation. Only FVC and vital capacity (VC) of all preoperative lung function studies could identify the 9 patients with significant physiologic improvement at > 3 years after LVRS, respectively, from 10 patients who responded < or = 2 years and died within 4 years (p < 0.01). CONCLUSIONS: Bilateral LVRS provides clinical and physiologic improvement for > 3 years in 9 of 26 patients with emphysema primarily due to both increased lung elastic recoil and small airway caliber and decreased hyperinflation. The 9 patients had VC and FVC greater at baseline (p < 0.01) when compared to 10 short-term responders who died < 4 years after LVRS.

Aged↗
PubMed1999

Nonlethal detection of transgene expression in the CNS of founder mice.

Determining whether transgenes targeted to the central nervous system (CNS) are expressed has previously required sacrificing the animal; thus, if a line was to be maintained, it was necessary to generate offspring from the original founder mouse before assay. We describe a method for assaying for the expression of a variety of CNS-targeted transgenes that allows for the survival of the founder mice. Many CNS genes are expressed in the retina, which can be obtained from a mouse by simple survival surgery. We demonstrate that reverse transcription PCR of RNA isolated from a single eye can detect the mRNAs for glial fibrillary acidic protein (GFAP), vimentin, neurofilament light chain (NF-68) and Thy-1, all of whose promoters have been used to direct transgene expression in the CNS. We also show that this method readily detects expression of an astrocyte-specific GFAP-driven lacZ transgene and a neuron-specific L7-driven lacZ transgene.

Animals↗
PubMed1999

BIIR 561 CL: a novel combined antagonist of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and voltage-dependent sodium channels with anticonvulsive and neuroprotective properties.

Antagonists of glutamate receptors of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype, as well as of voltage-gated sodium channels, exhibit anticonvulsive and neuroprotective properties in vivo. One can postulate that a compound that combines both principles might be useful for the treatment of disorders of the central nervous system, like focal or global ischemia. Here, we present data on the effects of dimethyl-(2-[2-(3-phenyl-[1,2, 4]oxadiazol-5-yl)-phenoxy]ethyl)-amine hydrochloride (BIIR 561 CL) on neuronal AMPA receptors and voltage-dependent sodium channels. BIIR 561 CL inhibited AMPA receptor-mediated membrane currents in cultured cortical neurons with an IC50 value of 8.5 microM. The inhibition was noncompetitive. In a cortical wedge preparation, BIIR 561 CL reduced AMPA-induced depolarizations with an IC50 value of 10.8 microM. In addition to the effects on the glutamatergic system, BIIR 561 CL inhibited binding of radiolabeled batrachotoxin to rat brain synaptosomal membranes with a Ki value of 1.2 microM. The compound reduced sodium currents in voltage-clamped cortical neurons with an IC50 value of 5.2 microM and inhibited the veratridine-induced release of glutamate from rat brain slices with an IC50 value of 2.3 microM. Thus, BIIR 561 CL inhibited AMPA receptors and voltage-gated sodium channels in a variety of preparations. BIIR 561 CL suppressed tonic seizures in a maximum electroshock model in mice with an ED50 value of 2.8 mg/kg after s.c. administration. In a model of focal ischemia in mice, i.p. administration of 6 or 60 mg/kg BIIR 561 CL reduced the area of the infarcted cortical surface. These data show that BIIR 561 CL is a combined antagonist of AMPA receptors and voltage-gated sodium channels with promising anticonvulsive and neuroprotective properties.

Animals↗
PubMed1999

Alternative pathway of complement is activated during in vitro ventricular assist.

BACKGROUND: Although ventricular assist devices (VAD) have improved survival in selected patients, their use continues to be complicated by thromboembolism and end-organ failure. Complement activation may play a role in the pathogenesis of these complications. Previous studies have found that the complement common terminal pathway is activated during VAD circulation. C3a levels rise dramatically during VAD use. Because the C3a fragment is generated by either the alternative or classical pathway, the purpose of this study is to determine the relative importance of the respective pathways in complement activation during in vitro VAD circulation. METHODS: Six in vitro VAD circuits were simulated for 3 days using 450 mL of human blood. Temperature, activated clotting time, pH, pCO2, pO2, Ca2+, and glucose were maintained at physiologic levels. Enzyme immunoassays were used to measure concentrations of fragment Bb to indicate alternative pathway activation and fragment C4d to indicate classical pathway activation. RESULTS: Fragment Bb concentrations rise from 1.92 to 10.77 micrograms/mL during the first 6 hours of circulation. Thereafter, Bb levels plateau. C4d concentrations slowly rise from a baseline of 1.49 to 6.84 micrograms/mL in 72 hours. CONCLUSIONS: These findings suggest that both the alternative and classical pathways of complement are activated during VAD circulation. Alternative pathway activation precedes classical pathway activation during in vitro VAD circulation and may be of greater clinical importance during clinical VAD circulation.

Assisted Circulation↗
PubMed1998

Suppression of protein synthesis in brain during hibernation involves inhibition of protein initiation and elongation.

Protein synthesis (PS) has been considered essential to sustain mammalian life, yet was found to be virtually arrested for weeks in brain and other organs of the hibernating ground squirrel, Spermophilus tridecemlineatus. PS, in vivo, was below the limit of autoradiographic detection in brain sections and, in brain extracts, was determined to be 0.04% of the average rate from active squirrels. Further, it was reduced 3-fold in cell-free extracts from hibernating brain at 37 degreesC, eliminating hypothermia as the only cause for protein synthesis inhibition (active, 0.47 +/- 0.08 pmol/mg protein per min; hibernator, 0.16 +/- 0.05 pmol/mg protein per min, P < 0.001). PS suppression involved blocks of initiation and elongation, and its onset coincided with the early transition phase into hibernation. An increased monosome peak with moderate ribosomal disaggregation in polysome profiles and the greatly increased phosphorylation of eIF2alpha are both consistent with an initiation block in hibernators. The elongation block was demonstrated by a 3-fold increase in ribosomal mean transit times in cell-free extracts from hibernators (active, 2.4 +/- 0.7 min; hibernator, 7.1 +/- 1.4 min, P < 0.001). No abnormalities of ribosomal function or mRNA levels were detected. These findings implicate suppression of PS as a component of the regulated shutdown of cellular function that permits hibernating ground squirrels to tolerate "trickle" blood flow and reduced substrate and oxygen availability. Further study of the factors that control these phenomena may lead to identification of the molecular mechanisms that regulate this state.

Adenosine Diphosphate Ribose↗
PubMed1998

Selective killing of glioma cell lines using an astrocyte-specific expression of the herpes simplex virus-thymidine kinase gene.

Gene therapy using the herpes simplex virus thymidine kinase gene (HSV-TK) is a promising new approach for the treatment of gliomas, a tumor type with a poor prognosis. To limit the toxic effects of this procedure, it is desirable to restrict expression of the HSV-TK gene to the target cells. This can be accomplished by use of the promoter of the glial fibrillary acidic protein gene, an intermediate filament protein expressed primarily in astrocytes. A plasmid containing the HSV-TK gene, driven by the human glial fibrillary acidic protein promoter gfa2, was lipofected into glioma cell lines and into an ovarian cancer cell line. Treatment with ganciclovir showed efficient killing of glioma cells, with no effect on the ovarian cells. Thus, the gfa2 promoter is a promising candidate for directing expression of toxic genes to gliomas.

Astrocytes↗
PubMed1998

IL-2 adenovector-transduced autologous tumor cells induce antitumor immune responses in patients with neuroblastoma.

In many different murine models, the immunogenicity of tumor cells can be increased by transduction with a range of immunostimulatory genes, inducing an immune response that causes regression of pre-existing unmodified tumor cells. To investigate the relevance of these animal models to pediatric malignancy, we used autologous unirradiated tumor cells transduced with an adenovirus-IL-2 to immunize 10 children with advanced neuroblastoma. In a dose-escalation study, we found that this tumor immunogen induced a moderate local inflammatory response consisting predominantly of CD4(+) T lymphocytes, and a systemic response, with a rise in circulating CD25(+) and DR+ CD3(+) T cells. Patients also made a specific antitumor response, manifest by an IgG antitumor antibody and increased cytotoxic T-cell killing of autologous tumor cells. Clinically, five patients had tumor responses after the tumor immunogen alone (one complete tumor response, one partial response, and three with stable disease). Four of these five patients were shown to have coexisting antitumor cytotoxic activity, as opposed to only one of the patients with nonresponsive disease. These results show a promising correlation between preclinical observations and clinical outcome in this disease, and support further exploration of the approach for malignant diseases of children.

Adenoviridae↗
PubMed1998

Astrocytes cultured from transgenic mice carrying the added human glial fibrillary acidic protein gene contain Rosenthal fibers.

Mice carrying copies of the human glial fibrillary acidic protein (hGFAP) gene driven by its own promoter have been generated that express the human transgene at different levels (Messing et al.: 152:391-398, 1998). Lines that expressed high levels of the gene died shortly after birth. Astrocyte cultures prepared from a low overexpressor (Tg73.2) exhibited abnormal cytoplasmic inclusions identical to those seen in vivo in the high overexpressors. Astrocytes in the Tg73.2 cultures appear odd-shaped and enlarged, express increased levels of GFAP (both human and mouse), and express alphaB crystallin protein, Hsp27 protein, and vimentin protein. At the light microscopic level, the Tg73.2 astrocytes are filled with eosinophilic deposits surrounded by positive GFAP immunostain. Ultrastructurally, the Tg73.2 astrocytes contain osmophilic deposits on a bed of intermediate filaments identical to Rosenthal fibers found in the brain in Alexander's disease. It seems that Tg73.2 mouse astrocytes in culture do not require additional stress from external sources or contact with other neuroectodermal cells to produce Rosenthal fibers. This suggests that the added hGFAP gene is sufficient to induce Rosenthal fibers and that an excess of GFAP in astrocytes may be detrimental to normal function. We hypothesize that the normal mechanism for GFAP turnover may be insufficient to handle the excess GFAP, thus causing an accumulation of stress proteins. The increased amounts of stress proteins and GFAP results in the formation of Rosenthal fibers, similar to those found in Alexander's disease.

Animals↗
PubMed1998

Interleukin-2 gene-modified allogeneic tumor cells for treatment of relapsed neuroblastoma.

Tumor cells that have been genetically modified to express immunostimulatory genes will induce effective antitumor responses in a range of syngeneic animal models. For human applications, transduced autologous tumor cell lines are often difficult or impossible to prepare, so that there are strong incentives for substituting a standardized allogeneic tumor cell line. However, such lines may be inferior immunogens if they differ from host tumors in the antigens they express. We have evaluated the safety, immunostimulatory, and antitumor activity of an interleukin-2-secreting allogeneic neuroblastoma cell line in 12 children with relapsed stage IV neuroblastoma. They received two to four subcutaneous injections of cells in a dose-escalating schedule, up to a maximum of 10(8) cells per injection. There was induration and pruritus at the injection site, and skin biopsies revealed mild panniculitis with CD3+ cells surrounding scanty residual tumor cells. There was a limited but significant peripheral monocytosis. No patient showed any increase in direct cytotoxic effector function against the immunizing cell line, but 3 patients had a rise in the frequency of neuroblastoma-reactive cytotoxic T lymphocyte precursor cells. One child had > 90% tumor response (PR), 7 had stable disease, and 4 had progressive disease in response to vaccine alone. Although these results offer some encouragement for the continued pursuit of allogeneic vaccine strategies in human cancer, the antitumor immune responses we observed are inferior to those obtained in an earlier immunization study using autologous neuroblastoma cells. Hence, we suggest that this earlier approach remains preferable, its difficulties notwithstanding.

Cancer Vaccines↗
PubMed1998

Mice lacking GFAP are hypersensitive to traumatic cerebrospinal injury.

Glial fibrillary acidic protein (GFAP) is an intermediate filament protein expressed primarily in astrocytes. We have tested whether GFAP protects against mechanical stress by inducing percussive head injury in GFAP-null mice with a weight drop device. When mice were positioned on a foam bed which allowed head movement at impact, all 14 wild-type mice tested survived, but 12 of 15 GFAP-null mice died within a few minutes. The cause of death appeared to be upper cervical spinal cord injury resulting in respiratory arrest. When the foam bed was replaced by a firm support, both GFAP-null and wild-type mice survived. These results indicate that mice lacking GFAP are hypersensitive to cervical spinal cord injury caused by sudden acceleration of the head.

Animals↗
PubMed1998

Differentiation-dependent expression of transgenes in engineered astrocyte cell lines.

The utility of transgenes for both basic and applied studies has been augmented by the recent advent of versions that can be regulated by the addition of suitable activators. However, still more convenient would be transgenes whose expression responded appropriately to endogenous signals. The promoter of the glial fibrillary acidic protein (GFAP) gene is a candidate for this role in the central nervous system (CNS) since the GFAP gene is specifically expressed in astrocytes in the CNS and its activity is upregulated in response to almost any CNS injury. As a feasibility study, we isolated a C6 rat glioma cell line stably transfected with a lacZ reporter gene driven by the gfa2 human GFAP promoter fragment. We find that the activity of the transgene indeed responds to an environmental signal, forskolin, that induces astrocyte-like differentiation of C6 cells. We also isolated a C6 line carrying a transgene in which the gfa2 promoter directs expression of a cDNA for tyrosine hydroxylase (TH), the rate-limiting enzyme for catecholamine synthesis. This transgene should be of considerable interest for gene therapy for Parkinson's disease. We show that in this cell line both TH mRNA and protein are upregulated by forskolin. Finally, we note that the growth rate of C6 cells is severely depressed by forskolin, suggesting that predifferentiation of these cells prior to implant may retard their tumor forming capacity, prolonging the time that they can be used in animal models in vivo.

Animals↗
PubMed1998

Effect of lung volume reduction surgery on pulmonary diffusion capacity in a rabbit model of emphysema.

BACKGROUND: While there is renewed interest in lung volume reduction surgery (LVRS) for treatment of emphysema, many aspects of the operation such as patient selection and surgical end points of excision are uncertain. We studied the effects of LVRS on measured lung volumes and diffusion capacity in an animal model to investigate optimal resection volumes. METHODS: Emphysema was induced in 32 New Zealand white (NZW) rabbits using aerosolized elastase. Helium dilution lung volumes and single breath DLCO were measured concurrently at baseline, following induction of emphysema (preop), and 1 week postoperatively (postop) following LVRS. Bilateral upper and middle lobe stapled lung resections were performed through midline sternotomies with excision of variable amounts of lung tissue from 1.8 to 5.8 g. RESULTS: FRC increased following induction of emphysema and decreased postoperatively. DLCO improved with increasing lung tissue resection up to 3 g of tissue and then decreased as even greater amounts were removed (r = 0.54). CONCLUSIONS: Measured lung volumes increase with development of emphysema and appropriately decrease in response to LVRS in this rabbit model. DLCO improves with moderate resection but then decreases with excessive excision of lung quantities and may help define one physiologic operative end point. In this rabbit model, excision of approximately 30% of lung volume was optimal and prevented further decrease in diffusion capacity.

Animals↗
PubMed1998

Is lobectomy by video-assisted thoracic surgery an adequate cancer operation?

BACKGROUND: Although the public perceives video-assisted thoracic surgery (VATS) as advantageous because it is less invasive than a thoracotomy, the medical community has questioned the safety of VATS lobectomy and its adequacy as a cancer operation. Reported series have not been able to address these issues because follow-up has been only short-term. METHODS: A multiinstitutional, retrospective review was performed in 298 consecutive patients who underwent VATS for a standard anatomic lobectomy with lymph node dissection for lung cancer. Pathologic staging was I in 233 (78%), II in 27 (9%), and IIIA in 38 (13%) patients. Kaplan Meier survival analysis was performed. RESULTS: The conversion rate from VATS lobectomy to thoracotomy was 6%, but none were for massive intraoperative bleeding. The only death (0.3%) was because of mesenteric venous thrombosis. Forty minor complications occurred in 38 patients (12.8%) undergoing VATS. The mean and median lengths of stay were 5+/-3.39 and 4 days, respectively. Recurrence in an incision occurred in 1 patient (0.3%). The Kaplan Meier 4-year survival for stage I was 70%+/-5%. CONCLUSION: The VATS lobectomy for bronchogenic carcinoma appears to be a safe operation, with the same survival as expected for a lobectomy done by thoracotomy.

Aged↗
PubMed1998

Changes in pulmonary physiology after lung volume reduction surgery in a rabbit model of emphysema.

OBJECTIVE: The purpose of this study is to investigate the effects of lung volume reduction surgery on pulmonary compliance, airway flow, and helium lung volumes in an elastase-induced emphysema animal model. METHODS: A 15,000-unit bolus of elastase was aerosolized through an endotracheal tube in 14 New Zealand White rabbits to induce emphysema. Stapled lung volume reduction of bilateral upper and middle lobes was performed through a midline sternotomy at 4 weeks after induction of emphysema. Lung functions were measured at baseline before induction of emphysema, preoperatively at 4 weeks, and 1 week postoperatively. RESULTS: Compliance increased after induction of emphysema and decreased in response to lung volume reduction surgery. Functional residual capacity decreased after lung volume reduction surgery in proportion to the amount of excised lung tissue. Expired flows suggested improvement in response to lung volume reduction surgery. Histologic examination confirmed presence of diffuse heterogeneous emphysema in each animal at necropsy. CONCLUSIONS: The decreased compliance and increased airway flow after volume reduction surgery in this model parallels findings in human studies and suggests that similar mechanisms of increased elastic recoil and airway support contribute to improvement.

Animals↗
PubMed1998

Astrocyte-specific expression of tyrosine hydroxylase after intracerebral gene transfer induces behavioral recovery in experimental parkinsonism.

Parkinson's disease is a neurodegenerative disorder characterized by the depletion of dopamine in the caudate putamen. Dopamine replacement with levodopa, a precursor of the neurotransmitter, is presently the most common treatment for this disease. However, in an effort to obtain better therapeutic results, tissue or cells that synthesize catecholamines have been grafted into experimental animals and human patients. In this paper, we present a novel technique to express tyrosine hydroxylase (TH) in the host's own astrocytes. This procedure uses a transgene in which the expression of a TH cDNA is under the control of a glial fibrillary acidic protein (GFAP) promoter, which confers astrocyte-specific expression and also increases its activity in response to brain injury. The method was tested in a rat model of Parkinson's disease produced by lesioning the striatum with 6-hydroxydopamine. Following microinjection of the transgene into the denervated striatum as a DNA-liposome complex, expression of the transgene was detected by RT-PCR and TH protein was observed specifically in astrocytes by using double-labeling immunofluorescence for GFAP and TH coupled with laser confocal microscopy. Efficacy was demonstrated by significant behavioral recovery, as assessed by a decrease in the pharmacologically induced turning behavior generated by the unilateral denervation of the rat striatum. These results suggest this is a valuable technique to express molecules of therapeutic interest in the brain.

Animals↗