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M Brenner

Publications and source records attributed to M Brenner.

At least 37 records · Page 2Linked to original sources
PubMed2001

Lung volume reduction surgery for chronic obstructive pulmonary disease: where do we stand?

Lung volume reduction surgery (LVRS) is a promising new treatment for selected patients with moderate to severe symptoms of emphysema. Medical management, including pulmonary rehabilitation, has been shown to reduce oxygen requirements during exercise and probably to reduce hospitalization for patients with severe emphysema, but it does not improve pulmonary function. By improving the elastic recoil of the lung, LVRS is the first treatment to demonstrate substantial improvement in pulmonary function and quality of life for selected patients with emphysema. The most important selection factor for LVRS is the presence of a heterogeneous pattern of emphysema. Because it is found in only 20% of patients with emphysema, only a small number of patients are candidates for the procedure. Published reports indicate that the optimal operative technique appears to be a bilateral staple operation during a single anesthetic. This procedure offers a 68% chance of oxygen independence, 85% chance of prednisone independence, and 60% to 70% improvement in pulmonary function for patients with an upper lobe distribution of emphysema. The long-term benefits of the procedure are currently unknown, so several randomized, prospective studies are now comparing LVRS with maximal medical management.

Contraindications↗
PubMed2001

Adenovector-induced expression of human-CD40-ligand (hCD40L) by multiple myeloma cells. A model for immunotherapy.

OBJECTIVE: CD40L restores the antigen-presenting cell (APC) function of some B-cell tumors and induces professional APC maturation. We therefore evaluated the effects of transgenic CD40L expression on the behavior and immunogenicity of human multiple myeloma (MM) cells. MATERIALS AND METHODS: CD40L expression was induced in a CD40(+) (RPMI 8226) and a CD40(-) (U266B1) human myeloma cell line (HMCL) by adenoviral vector gene transfer. The viability and proliferative activity of control HMCL and HMCL/CD40L were determined by daily trypan blue staining and methyl-3H-thymidine incorporation. Mixed lymphocyte reaction (MLR) with allogeneic mononuclear cells (MNCs) and coculture of allogeneic dendritic cells (DCs) with HMCL expressing transgenic CD40L were used to evaluate the APC function of modified HMCL as well as the role of bystander DCs in inducing an anti-tumor immune response. RESULTS: CD40L expression significantly inhibited the growth of the CD40(+) HMCL and induced apoptosis. These effects were less evident for the CD40(-) HMCL. There was no upregulation of costimulatory molecules on either HMCL following CD40L expression. Both HMCL expressing transgenic CD40L induced maturation of bystander DCs and enhanced their ability to stimulate the proliferation of MNCs. DCs cultured with the poorly immunogenic RPMI 8226 expressing CD40L upregulated T-lymphocyte release of IFN-gamma and other Th1 cytokines (interleukin-2, tumor necrosis factor-alpha). CONCLUSIONS: Our data suggest that transgenic expression of CD40L exerts a dual effect favoring generation of an immune response to human MM. Where the tumor cells are CD40(+), the engagement of CD40 antigen by CD40L on tumor cells induces their apoptosis, allowing uptake of tumor-associated antigen by professional APC. Independently of tumor-cell expression of CD40, transgenic expression of CD40L on tumor cells allows them to stimulate CD40(+) APC, to increase their maturation and their capacity to stimulate cytotoxic T lymphocytes (CTL) that recognize the tumor-derived antigens the APC may have engulfed.

Adenoviridae↗
PubMed2001

Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease.

Alexander disease is a rare disorder of the central nervous system of unknown etiology. Infants with Alexander disease develop a leukoencephalopathy with macrocephaly, seizures and psychomotor retardation, leading to death usually within the first decade; patients with juvenile or adult forms typically experience ataxia, bulbar signs and spasticity, and a more slowly progressive course. The pathological hallmark of all forms of Alexander disease is the presence of Rosenthal fibers, cytoplasmic inclusions in astrocytes that contain the intermediate filament protein GFAP in association with small heat-shock proteins. We previously found that overexpression of human GFAP in astrocytes of transgenic mice is fatal and accompanied by the presence of inclusion bodies indistinguishable from human Rosenthal fibers. These results suggested that a primary alteration in GFAP may be responsible for Alexander disease. Sequence analysis of DNA samples from patients representing different Alexander disease phenotypes revealed that most cases are associated with non-conservative mutations in the coding region of GFAP. Alexander disease therefore represents the first example of a primary genetic disorder of astrocytes, one of the major cell types in the vertebrate CNS.

Adolescent↗
PubMed2001

In vivo pharmacology of BIIR 561 CL, a novel combined antagonist of AMPA receptors and voltage-dependent Na(+) channels.

Glutamate receptors of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype and voltage-gated Na(+) channels are associated with diseases of the central nervous system characterized by neuronal over-excitation as in epilepsy or cerebral ischaemia. In animal models, AMPA receptor antagonists and Na(+) channel blockers provide protection in these conditions. Dimethyl-[2-[2-(3-phenyl-[1,2,4]oxadiazol-5-yl)-phenoxyl]-ethyl]-amine hydrochloride (BIIR 561 CL) combines both, AMPA receptor - and Na(+) channel blocking properties in one molecule. Here, BIIR 561 CL was investigated in vivo. BIIR 561 CL protected mice against AMPA-induced toxicity with an ED(50) value of 4.5 mg kg(-1) following subcutaneous (s.c.) administration. A 0.1% solution of BIIR 561 CL provided local anaesthesia in the corneal reflex test in rabbits. In mice, the compound prevented tonic seizures in the maximal electroshock (MES) model with an ED(50) value of 3.0 mg kg(-1) s.c. In amygdala-kindled rats, BIIR 561 CL inhibited seizures at doses of 3 and 11 mg kg(-1) following intraperitoneal (i.p.) injection. The data show that the combination of blocking AMPA receptor- and voltage-gated Na(+) channels in one molecule induces effective protection in animal models of neuronal over-excitation.

Animals↗
PubMed2001

Efficient infection of primitive hematopoietic stem cells by modified adenovirus.

Almost all studies of adenoviral vector-mediated gene transfer have made use of the adenovirus type 5 (Ad5). Unfortunately, Ad5 has been ineffective at infecting hematopoietic progenitor cells (HPC). Chimeric Ad5/F35 vectors that have been engineered to substitute the shorter-shafted fiber protein from Ad35 can efficiently infect committed hematopoietic cells and we now show highly effective gene transfer to primitive progenitor subsets. An Ad5GFP and Ad5/F35GFP vector was added to CD34(+) and CD34(-)lineage(-) (lin(-)) HPC. Only 5-20% of CD34(+) and CD34(-)lin(-) cells expressed GFP after Ad5 exposure. In contrast, with the Ad5/F35 vector, 30-70% of the CD34(+), 50-70% of the CD34(-)lin(-) and up to 60% of the CD38(-) HPC expressed GFP and there was little evident cellular toxicity. Because of these improved results, we also analyzed the ability of Ad5/F35 virus to infect the hoechst negative 'side population' (SP) of marrow cells, which appear to be among the very earliest multipotent HPC. Between 51% and 80% of marrow SP cells expressed GFP. The infected populations retained their ability to form colonies in two short-term culture systems, with no loss of viability. We also studied the transfer and expression of immunomodulatory genes, CD40L (cell surface expression) and interleukin-2 (secreted). Both were expressed at immunomodulatory levels for >5 days. The ability of Ad5/F35 to deliver transgenes to primitive HPC with high efficiency and low toxicity in the absence of growth factors provides an improved means of studying the consequences of transient gene expression in these cells.

Adenoviridae↗
PubMed2001

Alexander disease: new insights from genetics.

Prior to finding that GFAP mutations underlie many cases of Alexander disease, it was unclear whether the disease originated in astrocytes or if the formation of Rosenthal fibers was a response to an external insult. It was also unclear whether the etiology of the disease was environmental or genetic. For many cases of Alexander disease, these questions have now been answered. An immediate clinical benefit of this discovery is the possibility of diagnosing most cases of Alexander disease through analysis of patient DNA samples, rather than resorting to brain biopsy. In addition, fetal testing is now an option for parents who have had an Alexander disease child with an identified mutation and who wish to have additional children. For the future, these mutations should provide a unique window for illuminating the mechanism of the disease.

Brain↗
PubMed2001

Lung function 5 yr after lung volume reduction surgery for emphysema.

Current datum more than 2 yr after lung volume reduction surgery (LVRS) for emphysema is limited. This prospective study evaluates pre-LVRS baseline and 5-yr results in 26 symptomatic patients (mean age 67 +/- 6 yr) (mean +/- SD) who underwent bilateral, targeted upper lobe stapled LVRS using video-assisted thoracoscopy. Baseline forced expiratory volume in 1 s (FEV(1)) was 0.7 +/- 0.2 L (mean +/- SD), 29 +/- 10% predicted. Following LVRS, with none lost to follow-up, mortality due to respiratory failure at 0.5, 1, 2, 3, 4, and 5 yr was 4%, 4%, 19%, 31%, 46%, and 58%, respectively. Increase above baseline for FEV(1) > 200 ml and/or FVC > 400 ml at 1, 2, 3, 4, and 5 yr post-LVRS was noted in 73%, 46%, 35%, 27%, and 8% of all patients; decrease in dyspnea grade >/= 1 in 88%, 69%, 46%, 27%, and 15%; and elimination of initial oxygen dependence in 18 patients in 78%, 50%, 33%, 22%, and 0%, respectively. Expiratory airflow improved due to the increase in both lung elastic recoil and small airway intraluminal caliber. Five patients decreased FEV(1) 141 +/- 60 ml/yr and FVC 102 +/- 189 ml/yr over 3.8 +/- 1.2 yr post-LVRS, similar to their pre-LVRS rate of decline. In the 11 patients who survived 5 yr, at 0.5-1.0 yr post-LVRS peak increase in FEV(1) was 438 +/- 366 ml, with a decline of 149 +/- 157 ml the following year and 78 +/- 59 ml/yr over 4.0-4.5 yr. Bilateral LVRS provided palliative clinical and physiological improvement in 9 of 26 patients at 3 yr, 7 at 4 yr, and 2 at 5 yr.

Aged↗
PubMed2001

Photodynamic therapy for patients with advanced non-small-cell carcinoma of the lung.

Patients with advanced non-small-cell lung carcinoma (NSCLC) have poor prognoses and experience negative sequelae of disease. Patients often suffer from dyspnea and/or hemoptysis, with overall pulmonary compromise. Patients with advanced, inoperable disease have limited options for treatment. This study summarizes our early experience and findings using photodynamic therapy (PDT) as an effective modality in the palliation of hemoptysis, dyspnea, and physical airway obstruction in cases of inoperable lung cancer. A retrospective review was conducted for the first 10 patients diagnosed with stage III/IV obstructive NSCLC who underwent PDT at our institution. Endobronchial lesions were identified by bronchoscopy. Treatments were initiated 48 hours after intravenous injection of 2 mg/kg of the photosensitizing agent porfimer sodium (Photofrin, QLT PhotoTherapeutics, Vancouver, BC). The porfimer sodium was then activated by illumination with a 630 nm wavelength light using a Coherent argon ion laser through a flexible bronchoscope. Repeated bronchoscopies were performed 1-3 days following initial PDT for evaluation and airway debridement. In 8 cases, a second treatment of PDT was administered within 72 hours of the first injection. One patient received a third treatment several months later. Three patients also received endobronchial stents after PDT. Overall, all 10 patients responded to PDT. Physical airway obstruction was reduced in all patients, with a noted improvement in bronchoscopic luminal diameter. Acute hemoptysis resolved in all 7 symptomatic patients. Median survival was 5.5 months post-PDT, while median survival postdiagnosis was 10.5 months. Three patients are alive at the time of this review at 5-21 months following therapy. Patients with unresectable late-stage NSCLC have few options for treatment. Our early experience with PDT indicates effective relief of hemoptysis, dyspnea, and airway obstruction and improves their quality of life.

Journal Article↗
PubMed2000

Pulmonary vascular pressures increase after lung volume reduction surgery in rabbits with more severe emphysema.

BACKGROUND: Emphysema is a chronic disease of the lungs with destruction of terminal alveoli and airway obstruction. Lung volume reduction surgery (LVRS) is being investigated for the treatment of emphysema. Increasing resection volumes with LVRS may lead to worsening of carbon monoxide diffusing capacity (Dlco) despite improvement in compliance and flow. We hypothesized that the pulmonary circulation-related parameters, pulmonary artery pressure (PAP) and diffusing capacity (Dlco), may be used as indicators of the maximally tolerated LVRS resection volume. METHODS: Emphysema was induced in 55 rabbits by endotracheal nebulization, with either single 15,000-unit (mild emphysema) or three 11,000-unit (moderate emphysema) doses of elastase. At Week 6, bilateral LVRS was performed via median sternotomy with an endoscopic stapler. Single-breath Dlco, static compliance, and PAP were measured prior to emphysema induction, preoperatively, and 1 week following LVRS. Animals were divided into the following groups: Group I (mild emphysema, <3 g resected), group II (mild emphysema, >3 g resected), group III (moderate emphysema, <3 g resected), group IV (moderate emphysema, >3 g resected). RESULTS: All animals having LVRS had immediate postoperative increase in pulmonary vascular resistance (PVR) following lung resection. Mean PAP, however, remained elevated when measured 1 week after LVRS (sacrifice) in animals with moderate emphysema. This is in contrast to animals with mild emphysema, in which follow-up PAPs approached preoperative baseline. CONCLUSION: These finding suggests that sustained increased PVR, denoted by elevated PAP, is more likely to occur after LVRS in animals with more severe emphysema and larger volume resection. The spirometric and compliance benefits of greater resection volumes have to be weighed against the compromise in pulmonary vasculature in the effort to determine the ideal resection volume for various degrees of emphysema.

Animals↗
PubMed2000

Characterization of the anticonvulsant and neuroprotectant BIIR 561 CL in vitro: effects on native and recombinant alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors.

BIIR 561 CL is a novel blocker of AMPA receptors and voltage-dependent sodium channels. In this study we further describe the effects of BIIR 561 CL on AMPA receptor-mediated membrane currents in rodent neurons, as well as in cells expressing recombinant human GluR1/2 receptors in more detail. BIIR 561 CL suppressed responses to kainate in neuronal cultures from rat cortex with an IC50 of 9.8 microM. Similar effects were observed using acutely dissociated neurons from the CA1 region of rat hippocampus (IC50 = 9.5 microM). Inhibition of kainate responses by BIIR 561 CL was prevented by preapplication of GYKI 53655, suggesting that both non-competitive inhibitors bind to a common site of the receptor. The effect of 10 microM BIIR 561 CL on kainate-induced currents was dependent on extracellular pH, with more pronounced block (84.1%) under acidic conditions (pHextern=6.4), compared to only 30.1% at a pHextern of 8.4. Thus, it can be hypothesized that BIIR 561 CL inhibits AMPA receptors in ischaemic brain regions more effectively than in healthy tissue. BIIR 561 CL inhibited responses to 1 mM glutamate in cells expressing recombinant human GluR1/2 receptors with similar potency, as compared to kainate responses in rat neurons (IC50=17.3 microM). The reference compound NBQX had an IC50 of 25.2 nM. None of the two compounds affected the glutamate-induced receptor desensitization at any tested concentration. The block by BIIR 561 CL was not use-dependent and had fast on- and off-kinetics (tauon=6.8 s; tauoff=1.3 s in hGluR1/2 receptors with 30 microM BIIR 561 CL). Thus, BIIR 561 CL can be anticipated to have a promising profile for the treatment of neurological disorders like brain ischaemia and head trauma.

Animals↗
PubMed2000

Improved patient outcome after surgical treatment for loculated empyema.

BACKGROUND: Empyemas complicate the hospital course of many patients. Advanced stages of empyema often require surgical intervention. METHODS: A retrospective review of 70 adult patients with empyema, hospitalized between the years of 1992 and 1997, was performed. Data on age, length of stay, comorbidities, diagnostic studies, and treatment was obtained. We compared patient outcome from patients with loculated empyemas who had surgical treatment and those who were managed nonsurgically. RESULTS: Seventy patient records were reviewed, 37 of which were of patients with loculated empyemas. Parapneumonic empyemas comprised 60% of all cases. Chest radiographs, computed tomography scan, and thoracentesis were the most common studies performed in both groups. Thirty-three patients with the radiographic finding of a loculated empyema were treated with either surgical decortication or tube thoracostomy. CONCLUSION: Empyemas at various stages of development require different forms of therapy; advanced empyemas treated early with decortication have a shorter duration of treatment, lower incidence of recurrence and fewer complications.

Adult↗
PubMed2000

Relationship between amount of lung resected and outcome after lung volume reduction surgery.

BACKGROUND: Lung volume reduction surgery (LVRS) is being actively investigated for palliative treatment of severe emphysema. Considerable focus is directed toward patient selection and outcomes of LVRS. However, there is little information available regarding surgical methods to guide optimal extent of resection. We hypothesized that acute improvement and long-term survival after bilateral staple LVRS would be related to the extent of tissue resected. METHODS: The relationship between acute improvement in forced expiratory volume in 1 second and forced vital capacity was examined as a function of the total grams of lung tissue resected in 237 patients who underwent bilateral staple LVRS by a single group of surgeons. Overall survival was assessed based on extent of resection by quartiles of tissue weight resected using Kaplan-Meier survival methods. RESULTS: Improvement in forced expiratory volume in 1 second and forced vital capacity correlated with extent of tissue resected (p < 0.01), although there was considerable variability to individual response (r = 0.3). In contrast, there was no apparent relationship between the amount of tissue resected and overall postoperative survival (p = 0.7). CONCLUSIONS: There is a correlation between the amount of tissue resected and improvement in forced expiratory volume in 1 second and forced vital capacity after bilateral staple LVRS, with generally greater postoperative improvement after larger volume resections. However, there does not appear to be greater long-term survival with larger volume resections despite greater improvement in spirometry. This study suggests that factors other than improvement in spirometric variables may govern optimal LVRS resection volumes and long-term outcome. Future studies will clearly be needed in this important area of LVRS emphysema research.

Adult↗