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Biomedical subjects

M Brenner

Publications and source records attributed to M Brenner.

At least 91 records · Page 5Linked to original sources
PubMed1998

Stimulation of tyrosine phosphorylation of a brain protein by hibernation.

Mammalian hibernation is a state of natural tolerance to severely decreased brain blood flow. As protein tyrosine phosphorylation is believed to be involved in the development of resistance to potentially cell-damaging insults, we used immunoblotting for the phosphotyrosine moiety to analyze extracts from various tissues of hibernating and nonhibernating ground squirrels. A single, hibernation-specific phosphoprotein was detected in the brain, but not in any other tissue tested. This protein, designated pp98 to reflect its apparent molecular weight, is distributed throughout the brain, and is associated with the cellular membrane fraction. The presence of the protein is tightly linked to the hibernation state; it is not present in contemporaneously assayed animals that are exposed to the same cold temperature as the hibernators, is present for the duration of a hibernation bout (tested from 1 to 14 days), and disappears within 1 hour of arousal from hibernation. The close association of pp98 with the hibernation state, its presence in cellular membranes, and the known properties of membrane phosphotyrosine proteins suggest that it may transduce a signal for adaptation to the limited availability of oxygen and glucose and low cellular temperature that characterizes hibernation in the ground squirrel.

Animals↗
PubMed1998

Chronic relapsing experimental autoimmune encephalomyelitis: effects of insulin-like growth factor-I treatment on clinical deficits, lesion severity, glial responses, and blood brain barrier defects.

Chronic relapsing experimental autoimmune encephalomyelitis (crEAE), a model for multiple sclerosis, was used to test 2 regimens of insulin-like growth factor-I (IGF-I) treatment. We induced crEAE by injecting 3x10(7) myelin basic protein-(MBP) sensitized lymph node cells into adult female SJL/J mice. Fifty-one mice, divided randomly into 4 groups, were used in the first trial. Two groups received IGF-I (a gift of Cephalon, Inc.) 0.6 mg/kg/d subcutaneously from day 7 to day 16 and the other two groups received placebo injections. IGF-I treatment reduced clinical deficits during the first attack and during 2 subsequent relapses. Image analysis of immunostained and histological sections showed that IGF-I treatment reduced BBB defects and both the numbers and sizes of inflammatory, demyelinating, and demyelinated lesions. Twelve mice that had recovered from their first attack were used in our second trial to evaluate possible adverse effects of prolonged treatment with a higher dose of IGF-I. Six received 1.2 mg/kg/d for 6 weeks (days 19-63). No adverse effects of IGF-I treatment were identified. The eyes, hearts, livers, and kidneys of IGF-I-treated mice were normal histologically and their spleens also appeared normal except for mild to moderate microscopic increases in lymphopoesis. Our results suggest that prolonged IGF-I treatment is well tolerated and that the anti-inflammatory effects of IGF-I have a major role in reducing clinical deficits and lesion severity in crEAE. These effects, if present in multiple sclerosis, may benefit patients with this disease.

Animals↗
PubMed1998

Rate of FEV1 change following lung volume reduction surgery.

INTRODUCTION: Lung volume reduction surgery (LVRS) improves pulmonary function and dyspnea symptoms acutely in selected patients with heterogeneous emphysema. Limited data are available regarding long-term function following LVRS. We analyzed short-term (<6 months) and long-term rate of change of pulmonary function in 376 patients who underwent unilateral or bilateral LVRS using thoracoscopic or median sternotomy, staple, laser, or combined techniques. We hypothesized that the long-term rate of deterioration in lung function would be dependent on the surgical procedure used and would be greatest in those with the largest short-term postoperative improvement. METHODS: Pulmonary function was assessed preoperatively and at repeated intervals following LVRS. The change in pulmonary function over time was assessed for each patient by determining the individual change in FEV1 using linear regression analysis short and long term. Overall rate of change in pulmonary function was calculated for the composite group of patients and subgrouped by operative procedure. RESULTS: Lung function appears to improve in the first few months following LVRS in most patients, maximizing at approximately 3 to 6 months and declining thereafter. The short-term incremental improvement following staple procedures is superior to improvements following laser procedures or unilateral surgery: FEV1 increase (mean+/-SD) of 0.39+/-0.03 L for bilateral staple, 0.25+/-0.03 L for unilateral staple, 0.10+/-0.03 L for unilateral laser, and 0.22+/-0.1 L for mixed unilateral staple/laser procedures. However, the long-term rate of decline in FEV1 was greatest for bilateral staple LVRS procedures as well: 0.255+/-0.057 L/yr for bilateral staple, 0.107+/-0.068 L/yr for unilateral staple, 0.074+/-0.034 L/yr for unilateral laser, and 0.209+/-0.12 L/yr for mixed staple laser procedures. There was a general correlation between the magnitude of short-term incremental improvement and the rate of deterioration in FEV1 (r=0.292, p=0.003). CONCLUSIONS: While bilateral staple LVRS procedures lead to greater short-term improvement in FEV1, the more rapid rate of FEV1 decline in these patients and the general association between greater short-term incremental improvement and higher rates of deterioration raise questions regarding optimal long-term procedures. Further studies will be needed to answer these important questions.

Aged↗
PubMed1998

Serial lung function and elastic recoil 2 years after lung volume reduction surgery for emphysema.

STUDY OBJECTIVE: To evaluate serial lung function studies, including elastic recoil, in patients with severe emphysema who undergo lung volume reduction surgery (LVRS). To determine mechanism(s) responsible for changes in airflow limitation. METHODS: We studied 12 (10 male) patients aged 68+/-9 years (mean+/-SD) 6 to 12 months prior to and at 6-month intervals for 2 years after thoracoscopic bilateral LVRS for emphysema. RESULTS: At 2 years post-LVRS, relief of dyspnea remained improved in 10 of 12 patients, and partial or full-time oxygen dependency was eliminated in 2 of 7 patients. There was significant reduction in total lung capacity (TLC) compared with pre-LVRS baseline, 7.8+/-0.6 L (mean+/-SEM) (133+/-5% predicted) vs 8.6+/-0.6 L (144+/-5% predicted) (p=0.003); functional residual capacity, 5.6+/-0.5 L (157+/-9% predicted) vs 6.7+/-0.5 L (185+/-10% predicted) (p=0.001); and residual volume, 4.9+/-0.5 L (210+/-16% predicted) vs 6.0+/-0.5 L (260+/-13% predicted) (p=0.000). Increases were noted in FEV1, 0.88+/-0.08 L (37+/-6% predicted) vs 0.72+/-0.05 L (29+/-3% predicted) (p=0.02); diffusing capacity, 8.5+/-1.0 mL/min/mm Hg (43+/-3% predicted) vs 4.2+/-0.7 mL/min/mm Hg (18+/-3% predicted) (p=0.001); static lung elastic recoil pressure at TLC (Pstat), 13.7+/-0.5 cm H2O vs 11.3+/-0.6 cm H2O (p=0.008); and maximum oxygen consumption, 8.7+/-0.8 mL/min/kg vs 6.9+/-1.5 mL/min/kg (p=0.03). Increase in FEV1 correlated with the increase in TLC Pstat/TLC (r=0.75, p=0.03), but not with any baseline parameter. CONCLUSION: Two years post-LVRS, there is variable clinical and physiologic improvement that does not correlate with any baseline parameter. Increased lung elastic recoil appears to be the primary mechanism for improved airflow limitation.

Aged↗
PubMed1998

Fatal encephalopathy with astrocyte inclusions in GFAP transgenic mice.

Increased expression of glial fibrillary acidic protein (GFAP) is a hallmark of gliosis, the astrocytic hypertrophy that occurs during a wide variety of diseases of the central nervous system. To determine whether this increase in GFAP expression per se alters astrocyte function, we generated transgenic mice that carry copies of the human GFAP gene driven by its own promoter. Astrocytes of these mice are hypertrophic, up-regulate small heat-shock proteins, and contain inclusion bodies identical histologically and antigenically to the Rosenthal fibers of Alexander's disease. Mice in the highest expressing lines die by the second postnatal week. The results support the notion that Alexander's disease is a disorder of astrocytes, and provide an animal model for studying the causes and consequences of inclusion body disease.

Animals↗
PubMed1998

Insight on emphysema--the first 300 cases of surgical treatment.

Our experience with lung volume reduction surgery for emphysema now encompasses more than 300 cases, including several prospective trials. We have a 3.5% operative mortality rate and, with aggressive use of Heimlich valves over the past 6 months, an average hospital length of stay of 8 days. Proper patient selection is essential and can be based primarily on results of pulmonary function tests (PFTs), ventilation/perfusion (V/Q) scans, and computed tomography (CT) scans. We have found that bilateral is more effective than unilateral staple lung volume reduction surgery, which is in turn better than unilateral laser surgery. In patients with bilateral upper lobe disease, average FEV1 (forced expiratory volume in a 1-second interval) improvement is 82%; overall, it is 61% (range -33 to 217%). We conclude that lung volume reduction surgery can be performed safely with acceptable mortality and excellent clinical results in properly selected, motivated patients.

Aged↗
PubMed1998

An early comparison between endoscopic ultrasound-guided fine-needle aspiration and mediastinoscopy for diagnosis of mediastinal malignancy.

Precise mediastinal lymph node staging is essential in non-small cell lung cancer for proper evaluation and treatment. In addition to CT, mediastinoscopy is routinely used for staging and diagnosis of mediastinal malignancy. Recently, endoscopic ultrasound (EUS) combined with fine-needle aspiration (FNA) biopsy has been used to evaluate mediastinal disease. The purpose of this study was to assess and compare mediastinoscopy with EUS/FNA in the evaluation of mediastinal masses. From August 1995 to July 1997, 21 patients with suspected mediastinal malignancy underwent cervical mediastinoscopy with biopsy. During this same period, seven patients with suspected mediastinal malignancy were evaluated using EUS/FNA. All patients were retrospectively studied. Both mediastinoscopy and EUS/FNA were highly sensitive in diagnosing mediastinal malignancy (100% and 86%, respectively). Specificity and positive predictive value were 100 per cent for both procedures. Mediastinoscopy and EUS/FNA are highly accurate methods of staging mediastinal malignancy. Mediastinoscopy provides better access to the upper and anterior mediastinum, whereas EUS/FNA can safely be used to biopsy subcarinal and posterior mediastinal masses. Mediastinoscopy and EUS/FNA target different areas of the mediastinum and may be complimentary in the evaluation of mediastinal malignancy and staging of bronchogenic carcinoma.

Adenocarcinoma↗
PubMed1997

CD40 ligand induces an antileukemia immune response in vivo.

Leukemia cells may express tumor specific antigens in association with Class I and II major histocompatability complex (MHC) molecules. However, lack of expression of conventional costimulator molecules means that these cells tend to induce specific T-cell anergy rather than activation. CD40 ligand (CD40L) is a costimulator molecule that directly activates T cells and may promote antigen presentation by CD40-expressing cells, which include professional antigen presenting cells and B-acute lymphoblastic leukemia (ALL) cells from many patients. We determined whether transgenic expression of CD40L could enhance an antileukemia immune response using a CD40+ murine lymphoblastic (A20) leukemia and a CD40- myeloblastic (WEHI-3) leukemia in a tumor treatment model. Injection of otherwise nonimmunogenic A20 cells in the presence of CD40L induced an immune response active against preexisting A20 tumor at a distant site. Moreover, concomitant local secretion of transgenic interleukin-2 (IL-2) further amplified the antileukemic response induced and increased protection against preexisting tumor. In ex vivo studies, CD40 activation of A20 cells enhances the antigen presenting potential of A20 cells by upregulating expression of B7.1 (CD80), Class I and II MHC molecules, and increases expression of fas antigens. The importance of CD40 activation to the resulting antitumor response is further emphasized by the failure of transgenic CD40L to protect against the CD40- WEHI myeloblastic leukemia. Depletion studies showed the protective effects against A20 cells to be mediated by a combination of CD4+ and CD8+ T lymphocytes and by natural killer (NK) cells. These results suggest a means by which CD40+ leukemia cells may be rendered immunogenic in vivo.

Animals↗
PubMed1997

A novel herpes vector for the high-efficiency transduction of normal and malignant human hematopoietic cells.

Herpes simplex viruses (HSVs) would offer numerous advantages as vectors for gene transfer, but as yet they have not proved capable of transducing hematopoietic cells. Using a genetically inactivated form of HSV that is restricted to a single cycle of replication (disabled single-cycle virus, [DISC-HSV]), we have transduced normal human hematopoietic progenitor cells and primary leukemia blasts with efficiencies ranging from 80% to 100%, in the absence of growth factors or stromal support. Toxicity was low, with 70% to 100% of cells surviving the transduction process. Peak expression of transferred genes occurred at 24 to 48 hours after transduction with the DISC-HSV vector, declining to near background levels by 14 days. Despite this limitation, sufficient protein is produced by the inserted gene to permit consideration of the vector for applications in which transient expression is adequate. One example is the transfer of immunostimulatory genes, to generate leukemia immunogens. Thus, murine A20 leukemia cells transduced with a DISC-HSV vector encoding granulocyte-macrophage colony-stimulating factor were able to stimulate a potent antitumor response in mice, even against pre-existing leukemia. The exceptional transducing ability of the DISC-HSV vector should therefore facilitate genetic manipulation of normal and malignant human hematopoietic cells for biological and clinical investigation.

Animals↗
PubMed1997

Patient selection criteria for lung volume reduction surgery.

OBJECTIVE: Our intent was to refine the patient selection criteria for lung volume reduction surgery because various centers have different criteria and not all patients benefit from the procedure. METHODS: Patient information, x-ray results, arterial blood gases, and plethysmographic pulmonary function tests in 154 consecutive patients who underwent bilateral thoracoscopic staple lung volume reduction surgery were compared with clinical outcome (change in forced expiratory volume in 1 second and dyspnea scale) with t tests and analysis of variance. RESULTS: Three hundred thirty-three of 487 (69%) patients evaluated for lung volume reduction surgery were rejected for lack of heterogeneous emphysema (n = 212), medical contraindications (n = 88), hypercapnia (n = 20), uncontrolled anxiety or depression (n = 10), or pulmonary hypertension (n = 1). Two patients died during the evaluation process. When tested by analysis of variance, there was no difference in clinical outcome associated with preoperative forced expiratory volume in 1 second, residual volume, total lung capacity, single-breath diffusing, and arterial oxygen or carbon dioxide tension. All patients selected for the operation had a heterogeneous pattern of emphysema. The upper lobe heterogeneous pattern of emphysema on chest computed tomography and lung perfusion scan was strongly associated with improved outcome with a mean (95% confidence interval) improvement in forced expiratory volume in 1 second of 73.2% (63.3 to 83.1) for the upper lobe compared with a mean (95% confidence interval) improvement of 37.9% (22.9 to 53.0) for the lower lobe or diffuse pattern of emphysema. CONCLUSION: The most important selection criteria for lung volume reduction surgery is the presence of a bilateral upper lobe heterogeneous pattern of emphysema on chest computed tomography and lung perfusion scan. After patients have been selected on the basis of a heterogeneous pattern of emphysema, clinical factors and physiology are not associated with clinical outcome well enough to further refine patient selection criteria. These results do not support the arbitrary patient selection criteria for lung volume reduction surgery reported in the literature.

Age Factors↗
PubMed1997

Comparison of Ho:YAG versus Nd:YAG thoracoscopic laser treatment of pulmonary bullae in a rabbit model.

OBJECTIVE: To determine the relative efficacy and morbidity of Ho:YAG versus Nd:YAG laser treatment of bullous lung disease in an animal model. SUMMARY BACKGROUND DATA: Laser coagulation procedures for treatment of emphysematous pulmonary bullae and heterogeneous emphysema continue to evolve. The role of lasers in lung volume reduction surgery remains controversial due to issues of relative efficacy and morbidity. The Nd:YAG laser is most commonly used for these procedures. We hypothesized that the shallower penetration of the Ho:YAG laser may be better suited for laser bullae coagulation and emphysema lung volume reduction with increased efficacy and reduced lung injury. METHODS: Thirty New Zealand White rabbits (15 normal rabbits; 15 with bullous lung disease) were evaluated with Ho:YAG compared to Nd:YAG laser exposures. Bullae were coagulated by either Ho:YAG or Nd:YAG treatment. In all animals (bullous-induced and normals), unaffected lung tissue in the upper lobes and contralateral lungs were treated with 5 spot exposures of Nd:YAG and Ho:YAG, each to assess depth of lung injury. Animals were sacrificed at Days 0, 7, and 21 and their lungs were examined histologically. RESULTS: Ho:YAG and Nd:YAG exposures caused equivalent lung injury to normal lung tissue. In the acute phase, parenchymal necrosis depth was similar for both Ho:YAG and Nd:YAG (850 +/- 273 microns vs. 900 +/- 270 microns respectively, p = 0.7). By Day 7, lung necrosis depth was 925 +/- 133 microns Ho:YAG vs. 1225 +/- 235 microns Nd:YAG (p = 0.33), and lung fibrosis depth was 300 +/- 134 microns Ho:YAG vs. 558 +/- 127 microns Nd:YAG (p = 0.11). By Day 21, pulmonary parenchymal necrosis was not seen. Pleural fibrosis depth was maximal at Day 21, reaching 250 +/- 102 microns for Ho:YAG vs. 300 +/- 156 microns Nd:YAG (P = 0.88). Pleural necrosis depth was 67 +/- 42 microns Ho:YAG vs 48 +/- 34 microns Nd:YAG (p = 0.42) on Day 7 and resolved by Day 21. During surgical coagulation procedures, the Ho:YAG laser was dramatically more efficient in coagulating bullae. The Ho:YAG laser required less exposure at equivalent power and resulted in immediate desiccation of bullae, in sharp contrast to the Nd:YAG laser. CONCLUSIONS: Because the Ho:YAG was more effective and did not result in more acute lung injury than the standard Nd:YAG laser in this study, Ho:YAG lasers may have improved potential for laser treatment of bullae or lung volume reduction surgery (LVRS) compared to Nd:YAG lasers.

Animals↗
PubMed1997

Bone mineral density changes during lactation: maternal, dietary, and biochemical correlates.

The objectives of this study were to characterize the effects of lactation and weaning on maternal bone mineral density (BMD) and on biochemical markers of bone turnover, and to determine the effects of dietary intake, milk output, and other maternal factors on changes in BMD. Twenty-six fully lactating and eight nonlactating women were followed longitudinally through 7 mo postpartum; the lactating women were followed through postweaning. Maternal dietary and supplement intake data, infant milk intake measurements, blood and urine samples, and midradius and L2-L4 vertebral BMD measurements were obtained 0.5, 3, 5, and 7 mo postpartum. Biochemical analyses included measurements of calciotropic hormones, 24-h urinary excretion of calcium, markers of bone formation and resorption, estradiol, and prolactin. Estimated maternal demands for calcium excretion in milk were met by a combination of high calcium intake (from diet and supplements, 1500 +/- 460 mg/d at 0.5 mo for lactating women) and a decline of approximately 4% in vertebral BMD between 0.5 and 3 mo postpartum. Postweaning BMD (n = 15) at this site approximated initial values. Two factors were positively associated with vertebral BMD, estradiol (P < 0.001) and calcium intake (P = 0.03), whereas two factors were negatively associated, parity (P = 0.03) and protein intake (P = 0.01). In these well-nourished women, the results suggest that the extent of bone loss associated with lactation and its recovery postweaning are negatively influenced by parity. The results also suggest that the bone loss may be attenuated by a generous dietary ratio of calcium to protein.

Absorptiometry, Photon↗
PubMed1997

Global forebrain ischemia results in differential cellular expression of interleukin-1beta (IL-1beta) and its receptor at mRNA and protein level.

The mRNA expression of the proinflammatory cytokine interleukin-1beta (IL-1beta) has been shown to be induced in neural elements during ischemia. It is not clear which cells generate the IL-1beta mRNA and eventually synthesize IL-1 protein and which cells respond to this signaling by producing IL-1 receptors during ischemia. To clarify this question, rats were subjected to global ischemia by bilateral carotid occlusion and hypotension for 20 minutes, followed by reperfusion for 2 hours (n = 7), 8 hours (n = 7), or 24 hours (n = 7). Cryostat sections were hybridized using antisense oligonucleotide probes (30 dimer). Multiple cell markers were used in immunohistochemical staining to identify the cells expressing IL-1beta and IL-1R protein. The sham animals (n = 5) showed no or only a weak expression of IL-1R or IL-1beta mRNA. The number of IL-1beta mRNA-expressing cells was significantly increased by 2 hours of reperfusion in several brain areas including cortex (12-fold compared with sham) and caudate-putamen (14-fold), and was maximally increased in most hippocampal regions by 8 hours of reperfusion (mean +/- SD of positive cells/field versus sham equivalent being 37.9 +/- 12.3 versus 4.0 +/- 3.3; 30.6 +/- 9.0 versus 3.1 +/- 2.3; 41.3 +/- 17.5 versus 2.9 +/- 1.9; in CA1; CA2; CA3/CA4 regions of the hippocampus, respectively). IL-1beta mRNA signal was also intensified in the white matter areas. Changes in IL-1R mRNA were seen in the hippocampus (after 2 hours CA1: 16-fold; CA2: 17-fold; DG: 24-fold increase; and CA3/CA4: 10-fold increase after 8 hours), and the expression was prolonged especially in CA1 and CA2 regions up to 24 hours of reperfusion. The major cellular source of IL-1beta protein was glia (astrocytes, oligodendrocytes, microglia, and scattered perivascular macrophages/monocytes), while neurons and sporadic microvascular endothelia showed IL-1R immunoreactivity. The data suggest that neurons in discrete areas vulnerable for selective neuronal death, and possibly the vascular endothelium, are target cells for ischemia-induced glial IL-1beta production.

Animals↗
PubMed1997

Objective predictors of response for staple versus laser emphysematous lung reduction.

Recently described surgical approaches to the treatment of emphysema, including buttressed stapled volume reduction and laser coagulation, are associated with variable clinical outcomes. We examined objective preoperative factors as predictors of response to treatment in patients enrolled in a randomized trial of staple versus laser volume-reduction surgery in order to help define patient selection criteria for these procedures. Seventy-two patients with severe symptomatic emphysema without bullae were entered into the protocol (39 staple, 33 laser). Preoperative objective variables (pulmonary function tests, smoking history, demographics, and graded chest computed tomographic [CT] scans) were evaluated as predictors of response to treatment (defined as a change in FEV1) at 3- to 6-mo follow-up, using linear and multivariate regression analysis. Follow-up pulmonary function was obtained on 90% of the 68 patients surviving at 6 mo. Overall improvement was significant only for staple-treated patients, and improved outcome correlated with greater smoking history and younger age for staple-treated patients. When physiologic variables were analyzed, greater smoking history, lower DL(CO), and younger age predicted improved outcome for laser-treated patients. Preoperative FEV1 and gas-exchange variables did not predict outcome in staple-treated patients. When CT scan grading was included in multivariate regression analysis, hyperinflation (increased thoracic gas volume) was the primary predictor of response for laser-treated patients. These findings suggest that younger patients with evidence of advanced emphysematous lung disease and hyperinflation are optimal candidates for lung-volume-reduction surgery, particularly by staple-reduction techniques. Additional studies with long-term follow-up, bilateral procedures, and assessment of other outcome measures must be performed to further define operative criteria for lung-volume-reduction surgery for emphysema.

Age Factors↗
PubMed1997

Dyspnea response following bilateral thoracoscopic staple lung volume reduction surgery.

PURPOSE: Lung volume reduction surgery (LVRS) has shown promise for treating patients with severe emphysema in recent clinical trials. However, response following surgery is difficult to assess due to frequent discrepancies between subjective and objective outcomes. We evaluated the relationship between improvement in dyspnea and pulmonary function response in 145 consecutive patients with inhomogeneous emphysema enrolled in a bilateral thoracoscopic lung volume reduction protocol in order to assess predictors of improved dyspnea outcome and correlation of subjective and objective improvement measures. MATERIALS AND METHODS: Baseline complete pulmonary function testing, spirometry, gas exchange, plethysmography, gas dilution lung volumes, along with resting dyspnea index determinations were performed preoperatively, and repeated short term (mean, 33 days; n=129) and long term (>6 months; mean, 276 days; n=84) following surgery. RESULTS: Improvement in FEV1 percent predicted was significantly associated with improvement in dyspnea scores, though considerable variability exists (r=0.04, p<0.01, short term; r=0.4, p=0.1, long term). In this preselected patient group, those with the extreme degrees of hyperinflation may have less improvement in dyspnea following LVRS than those with milder preoperative hyperinflation. Greater improvement in dyspnea short term and long term was seen in patients with lower presenting residual volume/total lung capacity ratios (r=0.4, p=0.02, short term; r=0.4, p<0.05, long term). CONCLUSIONS: Bilateral thoracoscopic staple LVRS results in significant objective and subjective improvement in patients with severe emphysema and hyperinflation. There was considerable variability between improvement in dyspnea and improvement in spirometry, and preoperative predictors of response may differ between these outcome variables. Further studies are needed to define the long-term implications of these findings.

Aged↗
PubMed1996

Conditional ablation of cerebellar astrocytes in postnatal transgenic mice.

Astrocytes have been proposed to have multiple roles in the development and maintenance of the vertebrate CNS. To facilitate documentation of these roles, we designed a transgene to enable their ablation at selectable times. The transgene consists of the coding region for the herpes simplex virus-thymidine kinase (HSV-TK) under the control of the human glial fibrillary acidic protein gene promoter. The HSV-TK is innocuous but converts the antiherpetic agent ganciclovir (GCV) to a toxic product that interferes with DNA replication in proliferating cells. In a developmental study, transgenic mice were treated with GCV during the first postnatal week, with evaluation at P19. Treated mice displayed severe ataxia. Histological examination revealed disrupted astrocyte development, particularly in the cerebellum, with marked secondary effects on other cell types. Cerebellar defects included a loss in the numbers of astrocytes and an overall reduction in cerebellar size and disruption of the normally well defined cellular layers. Radial glia were disordered, Purkinje cells were ectopically distributed and displayed abnormal dendritic trees, and granule cells were markedly depleted. These effects were more severe in animals treated on postnatal day 1 versus treatment at day 5. A major factor causing granule cell death was excitotoxicity attributable to activation of NMDA receptors. These results suggest a critical role for astrocytes in cerebellar development.

Animals↗