Biomedical subjects

Michael Tamm

Publications and source records attributed to Michael Tamm.

68 records · Page 4Linked to original sources

PubMed2003

An individualized, adjustable maintenance regimen of budesonide/formoterol provides effective asthma symptom control at a lower overall dose than fixed dosing.

PRINCIPLES: Current asthma management employing inhaled corticosteroids (ICS) and longacting b2-agonists (LABA) aims to rapidly achieve and then maintain overall asthma control including symptoms with minimal medication. This study compared self-guided adjustable maintenance dosing with budesonide/formoterol in a single inhaler with fixed dosing. METHODS: In an open-label, parallel-group, multicentre study, 127 asthmatic patients, well controlled on ICS and LABA, were treated with budesonide/formoterol (Symbicort) Turbuhaler) 200/6 mg (equivalent to 160/4.5 mg delivered dose) 2 inhalations bid for 4 weeks, and were then randomised to budesonide/formoterol adjustable dosing (n = 69) (guided self-adjustment of dose: 1 inhalation bid or 2 inhalations at night with interim step ups to 2 inhalations bid and if not sufficient up to 4 inhalations bid for 14 days) or fixed dosing (2 inhalations bid) (n = 58) for 12 weeks. RESULTS: Patients used adjustable dosing effectively; >50% used a decreased maintenance dose on >50% of the days. Seventy-two percent (50/69) from the adjustable-dosing group reduced their maintenance dose within the first 2 treatment weeks. Thirteen adjustable-dose patients (18.8%) never reduced their dose and 4 (5.8%) stepped up their dose. Symptom severity (NHLBI severity grade) decreased in both groups; however, the decrease was only statistically significant (p = 0.004) in the adjustable-dosing group. Treatment failures occurred in 17% and 24% of patients (adjustable and fixed dosing, respectively p = 0.35). Nocturnal awakenings (0.057 vs. 0.067/night, p = 0.006) and rescue medication use (0.15 vs. 0.23 inhalations/day, p <0.0001) were significantly less frequent with adjustable dosing, and the average daily medication dose was significantly reduced (3.0 vs. 3.9, p <0.0001) compared with fixed dosing. Lung function measurements (FEV1 and PEF) were not significantly different between groups during the study. There were no asthma-related hospital admissions. CONCLUSION: Asthma patients on adjustable maintenance dosing with budesonide/ formoterol maintained control of symptoms using significantly less medication overall than fixed dosing. Thus, adjustable maintenance dosing achieved guideline goals of effective asthma control at an appropriately low maintenance dose. However, larger studies on adjustable maintenance dosing are needed.

Adolescent↗

PubMed2003

Hypoxia modulates the effects of transforming growth factor-beta isoforms on matrix-formation by primary human lung fibroblasts.

Chronic hypoxia is implicated in lung fibrosis, which is characterized by enhanced deposition of extracellular matrix (ECM) molecules. Transforming growth factor-beta (TGF-beta) plays a key role in fibroblast homeostasis and is involved in disease states characterized by excessive fibrosis, such as pulmonary fibrosis. In this study, we investigated if hypoxia modulates the effects of TGF-beta on the expression of gelatinases: matrix metalloproteinase (MMP)-2 and MMP-9, interstitial collagenases: MMP-1 and MMP-13, tissue inhibitors of MMP (TIMP), collagen type I and interleukin-6 (IL-6). Primary human lung fibroblasts, established from tissue biopsies, were cultivated under normoxia or hypoxia in the presence of TGF-beta1, TGF-beta2 or TGF-beta3. Gelatinases were assessed by gelatin zymography and collagenases, TIMP, collagen type I and IL-6 by ELISA. Under normoxia fibroblasts secreted MMP-2, collagenases, TIMP, collagen type I and IL-6. TGF-betas significantly decreased MMP-1 and increased TIMP-1, IL-6 and collagen type I. Hypoxia significantly enhanced MMP-2, and collagenases. Compared to normoxia, the combination of TGF-beta and hypoxia reduced MMP-1, and further amplified the level of TIMP, IL-6, and collagen type I. Thus, in human lung fibroblasts hypoxia significantly increases the TGF-betas-induced secretion of collagen type I and may be associated to the accumulation of ECM observed in lung fibrosis.

Collagen Type I↗

PubMed2003

Ultraflex stents for the management of airway complications in lung transplant recipients.

OBJECTIVE: We present our experience with the use of the Ultraflex (nitinol) stents in the management of airway complications in lung transplant (LT) recipients. METHODOLOGY: Nine LT recipients underwent insertion of uncovered Ultraflex stents. Mean change in FEV1, duration to formation of granulation tissue and follow-up post-stent insertion were compared with results obtained in LT recipients who had undergone Gianturco stent (n = 10) and Wallstent insertion (n = 16). RESULTS: Mean improvement in FEV1 after insertion of Gianturco, Wallstent and Ultraflex stents was 670 +/- 591 mL, 613 +/- 221 mL and 522 +/- 391 mL, respectively. No patient with an Ultraflex stent developed mucus plugging or stenosis at stent extremity at a follow up of 263 +/- 278 days. The mean and median duration to stenosis at stent extremity for patients with Gianturco stents was 102 +/- 85 days and 73 days, respectively, compared with 132 +/- 87 days and 142 days, respectively, for patients with Wallstents. Stricture formation in the middle of the Ultraflex stent occurred bilaterally, at the level of anastomosis in one patient in whom stent placement was undertaken in the presence of inflammation. Stent migration in one patient was related to undersizing of the stent diameter relative to the airway diameter. A larger diameter relative stent was subsequently inserted successfully. CONCLUSION: Ultraflex stents appear to have fewer long-term complications when used in the management of airway complications following LT.

Adult↗

PubMed2003

Chlamydia pneumoniae activates epithelial cell proliferation via NF-kappaB and the glucocorticoid receptor.

Chlamydia pneumoniae is an obligate intracellular eubacterium and a common cause of acute and chronic respiratory tract infections. This study was designed to show the effect of C. pneumoniae on transcription factor activation in epithelial cells. The activation of transcription factors by C. pneumoniae was determined in human epithelial cell lines (HL and Calu3) by electrophoretic DNA mobility shift assay, Western blotting, and luciferase reporter gene assay. The activation of transcription factors was further confirmed by immunostaining of C. pneumoniae-infected HL cells and mock-infected controls. The effect of transcription factors on C. pneumoniae-induced host cell proliferation was assessed by [(3)H]thymidine incorporation and direct cell counting in the presence and absence of antisense oligonucleotides targeting transcription factors or the glucocorticoid receptor (GR) antagonist RU486. The activation of the GR, CCAAT-enhancer binding protein (C/EBP), and NF-kappaB was induced within 1 to 6 h by C. pneumoniae. While the interleukin-6 promoter was not activated by C. pneumoniae, the GR-driven p21((Waf1/Cip1)) promoter was increased 2.5- to 3-fold over controls 24 h after infection. C. pneumoniae dose-dependently increased the DNA synthesis of the host cells 2.5- to 2.9-fold, which was partly inhibited either by RU486 or by NF-kappaB antisense oligonucleotides. Furthermore, we provide evidence that heat-inactivated C. pneumoniae does not cause a significant increase in cell proliferation. Our results demonstrate that C. pneumoniae activates C/EBP-beta, NF-kappaB, and the GR in infected cells. However, only NF-kappaB and the GR were involved in C. pneumoniae-induced proliferation of epithelial cells.

Base Sequence↗

PubMed2003

Radiofrequency heat ablation for lung tumors: potential applications.

Radiofrequency ablation (RFA) is an image guided percutaneous procedure using thermal energy that is used to treat malignant lesions in various organs including liver, breast and lungs. It has also been used bronchoscopically to treat endobronchial tumors. Current passing through tissue from the active electrode leads to ion agitation, which is converted by means of friction into heat leading to irreparable cellular damage and coagulation necrosis. The potential benefits include decreased cost and morbidity, treating patients who are not surgical candidates due to age, co-morbidity or extent of disease and the possibility of performing the procedure on an outpatient basis. The aim is usually to reduce tumor size. Whether it can be used with a curative intent in well localized primary tumors remains to be determined by well designed studies. However, caution should be exercised because selective tumor resection is not the gold standard to treat potentially resectable lung malignancies that are treated with lobectomy. Obviously, lung volume reduction surgery combined with tumor resection has challenged this approach. RFA might be the treatment of choice for multiple lung metastases that are usually approached surgically for long-term remission. A specific indication may also be bilateral pulmonary metastases. Other potential applications might be tumor size reduction by a non-surgical procedure followed by adjuvant chemotherapy. Currently, these thoughts remain only speculations, until proven by clinical trials with medium to long-term follow up. Furthermore, the risk of this procedure for pulmonary application has to be better defined.

Catheter Ablation↗

PubMed2002

Interaction between glucocorticoids and beta2 agonists on bronchial airway smooth muscle cells through synchronised cellular signalling.

BACKGROUND: Increased airway smooth muscle bulk is a pathological feature of asthma. Asthma is well controlled by the combined inhalation of glucocorticoids and beta2-adrenoceptor agonists. The basic molecular mechanism of the interaction of the two drugs on proliferation of airway smooth muscle cells is yet to be identified. Our aim was to elucidate how glucocorticoids and beta2 agonists affect the growth of human bronchial airway smooth muscle cells. METHODS: We assessed the effect of formoterol and budesonide on the activation and function of transcription factors by immunohistochemistry, western blotting, DNA mobility shift assay, and a luciferase reporter gene assay. The effect of the drugs and the involvement of specific transcription factors on cell proliferation was ascertained by direct cell count and confirmed by thymidine incorporation. FINDINGS: Both classes of drugs (10(-8) mol/L) activated C/EBP-alpha and the glucocorticoid receptor with different kinetic profiles, and inhibited proliferation. The combination of lower doses of drugs (10(-12) to 10(-9) mol/L) resulted in a synchronised activation of the transcription factors and an enhanced antiproliferative effect. The action of the drugs alone or in combination on transcription-factor activity and proliferation was suppressed by either depletion of C/EBP-alpha or in the presence of a glucocorticoid-receptor blocker. INTERPRETATION: Our findings could provide one explanation for the interaction of beta2 agonists and glucocorticoids at a molecular level, and indicate that the concentration of inhaled glucocorticoids can be reduced when combined with beta2 agonists, minimising the side-effects of the drugs.

Adrenergic beta-Agonists↗

PubMed2002

A fluorescence in situ hybridization-based assay for improved detection of lung cancer cells in bronchial washing specimens.

BACKGROUND: Interphase fluorescence in situ hybridization (FISH) is a powerful tool for detecting chromosome and locus-specific changes in tumor cells. We developed a FISH-based assay to detect genetic changes in bronchial washing specimens of lung carcinoma patients. METHODS: The assay uses a mixture of fluorescently labeled probes to the centromeric region of chromosome 1 and to the 5p15, 8q24 (site of the c-myc gene), and 7p12 (site of the EGFR gene) loci to assess cells in bronchial washing specimens for chromosomal abnormalities indicative of lung carcinoma. The FISH assay was performed on 74 specimens that had been assessed previously for evidence of malignancy by routine cytology with Pap staining. RESULTS: Forty-eight patients had histologically confirmed lung carcinoma and 26 patients had a clinical diagnosis that was negative for lung carcinoma. FISH analysis was performed without knowledge of the patient's clinical information. The finding of six or more epithelial cells with gains of two or more chromosome regions was considered a positive FISH result (i.e., evidence of malignancy). The sensitivity of FISH for the detection of lung carcinoma was 82% in this set of specimens compared with a 54% sensitivity by design for cytology (FISH vs. cytology, P = 0.007). FISH detected 15 of 18 specimens that were falsely negative by cytology. The specificities of FISH and cytology were 82% and 100%, respectively, and were not significantly different (P = 0.993). CONCLUSIONS: The data indicate a potential utility of the FISH assay as an adjunct to bronchial washing cytology in routine clinical practice.

Adenocarcinoma↗

PubMed2002

Resolution of native lung pneumothorax by insertion of a nitinol stent for bronchostenosis in the transplanted lung.

Following single lung transplantation, the native lung remains a potential source of morbidity from spontaneous pneumothorax, hyperinflation, bacterial and fungal infection and malignancy. The case of a single lung transplant recipient for idiopathic pulmonary fibrosis who developed a recurrent, non-resolving, spontaneous multiloculated pneumothorax in the native lung following thoracoscopic talc pleurodesis is reported. The pneumothorax ultimately resolved following insertion of a nitinol stent for coexisting bronchostenosis in the transplanted lung. In a single lung transplantation recipient in whom a native lung pneumothorax reoccurs or persists despite appropriate initial management, it may be useful to undertake bronchoscopy to exclude the possibility of bronchostenosis in the transplanted lung.

Adult↗

PubMed2002

Array-based diagnostic gene-expression score for atopy and asthma.

Whether gene expression is useful in discriminating different atopic phenotypes is unclear. The aim of the study was to evaluate a gene-expression score for the diagnosis of atopy and asthma and to assess disease activity as a guide for therapeutic decisions. Purified mRNA from PBMCs of 18 atopic asthmatic subjects, 8 atopic nonasthmatic subjects, and 14 healthy control subjects was hybridized to cDNA membranes. A composite atopy gene expression (CAGE) score was determined by using 10 genes dysregulated in atopic individuals according to a specific algorithm. The CAGE score was better than total IgE in differentiating atopic from nonatopic subjects (sensitivity, 96%; specificity, 92%). Correlation between the CAGE score and total IgE (P <.001) was found, and there was a trend for correlation with asthma severity (P =.051). The CAGE score was able to quantify phenotype-specific alteration in gene expression of atopic individuals. The CAGE score might be used as a diagnostic tool or to monitor the effects and side effects of therapy.

Adolescent↗

PubMed2002

Hypoxia differentially enhances the effects of transforming growth factor-beta isoforms on the synthesis and secretion of glycosaminoglycans by human lung fibroblasts.

Interstitial lung diseases associated with hypoxia, such as lung fibrosis, are characterized by enhanced production of transforming growth factor-beta (TGF-beta) and increased deposition of extracellular matrix (ECM) molecules, including glycosaminoglycans (GAGs). In this study, we investigated the effect of hypoxia (3% O(2)) on TGF-beta-induced GAG synthesis by primary human pulmonary fibroblasts, established from lung biopsies. Total GAG synthesis was assessed by the incorporation of [(3)H]glucosamine into GAGs associated with the cell layer (cells and ECM) or secreted in the medium. GAGs were isolated and purified by gel filtration, fractionated by electrophoresis on cellulose acetate membranes, and characterized using GAG-degrading enzymes. GAG molecules identified in the cell layer and the medium were: hyaluronic acid, and chondroitin, dermatan, and heparan sulfates. All TGF-beta isoforms time dependently induced [(3)H]glucosamine incorporation into GAGs of the cell layer or the medium. Characterization of individual GAG molecules indicated that this was attributed to dermatan and heparan sulfates in the cell layer and to hyaluronic acid and chondroitin and dermatan sulfates in the medium. Hypoxia enhanced the effect of all TGF-beta isoforms, particularly that of TGF-beta3, on the secretion of hyaluronic acid and chondroitin and dermatan sulfates. In the cell layer, hypoxia stimulated only the effect of TGF-beta2-induced [(3)H]glucosamine incorporation into GAGs. Our data indicate that hypoxia differentially enhances the effect of TGF-beta isoforms on the secretion and deposition of GAGs and may hasten ECM remodeling associated with the pathogenesis of lung fibrosis.

Cell Culture Techniques↗

PubMed2002

Prediction of functional reserves after lung resection: comparison between quantitative computed tomography, scintigraphy, and anatomy.

BACKGROUND AND OBJECTIVES: We prospectively compared five techniques to estimate predicted postoperative function (ppo F) after lung resection: recently proposed quantitative CT scans (CT), perfusion scans (Q), and three anatomical formulae based on the number of segments (S), functional segments (FS), and subsegments (SS) to be removed. METHODS: Four parameters were assessed: FEV(1), FVC, DL(CO) and VO(2max), measured preoperatively and 6 months postoperatively in 44 patients undergoing pulmonary resection, comparing their ppo value to the postoperatively measured value. RESULTS: The correlations (r) obtained with the five methods were for CT: FEV(1) = 0.91, FVC = 0.86, DL(CO) = 0.84, VO(2max) = 0.77; for Q: 0.92, 0.90, 0.85, 0.85; for S: 0.88, 0.86, 0.84, 0.75; for FS: 0.88, 0.85, 0.85, 0.75, and for SS: 0.88, 0.86, 0.85, 0.75, respectively. The mean difference between ppo values and postoperatively measured values was smallest for Q estimates and largest for anatomical estimates using S. Stratification of the extent of resection into lobectomy (n = 30) + wedge resections (n = 4) versus pneumonectomy (n = 10) resulted in persistently high correlations for Q and CT estimates, whereas all anatomical correlations were lower after pneumonectomy. CONCLUSIONS: We conclude that both Q- and CT-based predictions of postoperative cardiopulmonary function are useful irrespective of the extent of resection, but Q-based results were the most accurate. Anatomically based calculations of ppo F using FS or SS should be reserved for resections not exceeding one lobe.

Aged↗

PubMed2002

Identification of a novel IL-6 isoform binding to the endogenous IL-6 receptor.

Interleukin (IL)-6 is a multifunctional cytokine showing a wide variety of biologic functions on various tissues. Extracellular IL-6 signals through heterohexameric complex formation with IL-6 receptor-alpha (IL-6Ralpha) and IL-6 receptor-beta (IL-6Rbeta). In analogy to cytokines IL-2 and IL-4, we investigated the expression of IL-6 splice variants in lung tissue and cultivated fibroblasts. In human lung specimens, four different IL-6 transcripts were characterized as follows: native IL-6; IL-6 missing either exon 2 (IL-6Delta2), exon 4 (IL-6Delta4), or missing both; and exons 2 and 4 (IL-6Delta2,4). Only native IL-6 and IL-6Delta4 encoded for proteins of ~ 26 and 17 kD, respectively. Although the overall structure and most functional sites of the IL-6Delta4 protein were predicted to be maintained, IL-6Delta4 was found to lack two amino acids necessary for IL-6/IL-6 homodimerization as well as two of the six amino acids required for interaction with IL-6Rbeta. Receptor mobility shift assays confirmed that the new isoform formed a stable complex with IL-6Ralpha; however, no interaction with IL-6Rbeta was observed. Thus, IL-6Delta4 is likely to compete with native IL-6 for IL-6Ralpha binding but fails to transmit IL-6Rbeta-mediated signaling.

Alternative Splicing↗

PubMedDate not supplied

Hemodynamic effects of endobronchial application of ornipressin versus terlipressin.

BACKGROUND: Ornipressin and terlipressin, two ADH-derivates, are instilled endobronchially for bronchoscopy- related bleeding without sufficient evidence of efficacy, nor safety. OBJECTIVES: To compare the immediate hemodynamic effects of ornipressin and terlipressin used for procedure-related bleeding during flexible bronchoscopy. METHODS: This retrospective study included patients referred for flexible bronchoscopy who needed administration of ornipressin (15 patients) or terlipressin (15 patients) for procedure-related bleeding. Endobronchial ornipressin (5 IU) or terlipressin (0.5 mg) was administered through the bronchoscope when bleeding persisted for 2 min of continuous suction, or when bleeding was considered increasing in time or major. Hemodynamic data were collected before, during and after administration of either drug. RESULTS: Biopsy-associated hemoptysis requiring medical treatment occurred in 110 (4.2%) of 2,592 bronchoscopies. After administration of ornipressin, no significant change in heart rate or blood pressure was observed. Following terlipressin instillation, heart rate increased from 93 +/- 17 to 101 +/- 22 b.p.m. (p = 0.03), and blood pressure decreased from 107 +/- 14 to 101 +/- 17 mm Hg (p = 0.04). Oxygen saturation under supplemental nasal oxygen was not different in both groups. None of the 110 patients died from bronchoscopy-related hemoptysis or needed further intervention to stop bleeding or prolonged monitoring because of hemodynamic instability. CONCLUSIONS: In contrast to ornipressin, administration of terlipressin is associated with significant changes in heart rate and blood pressure. However, these changes are of minor clinical importance, and terlipressin can be safely given for bronchoscopy-associated bleeding.

Adult↗

PubMedDate not supplied

Sedative drug requirements during flexible bronchoscopy.

BACKGROUND: There is a paucity of data comparing doses of sedative medication during bronchoscopy in immunosuppressed and non-immunosuppressed patients. OBJECTIVES: The aim of this study was to define the sedative medication doses used in specific patient groups during bronchoscopy. METHODS: Bronchoscopy was performed under local anesthesia, sedation with intermittent boluses of intravenous midazolam and intravenous hydrocodone 5 mg. Two hundred and thirty-nine consecutive bronchoalveolar lavage procedures were included. Procedures in non-immunosuppressed patients were classified as controls (n = 91). Procedures in immunosuppressed patients who received midazolam consisted of stem cell transplant (34), solid organ transplant (25), chemotherapy (33), HIV with drug abuse (10), HIV (5), prednisone (17) and immunosuppression for other diseases (12). Intravenous propofol was administered during 12 procedures due to inability to achieve optimal sedation with midazolam in a previous bronchoscopy (stem cell transplant recipient 1, lung transplant for cystic fibrosis 5) and during the same bronchoscopy due to inadequate sedation with a high dose of midazolam--renal transplant recipient 1, drug abuse (HIV 1, renal transplant recipient 1), bronchoscopy combined with gastroscopy (2) and a hypoxemic patient (1). The mean dose of propofol administered was 2.8 +/- 1.3 mg/kg. RESULTS: Midazolam requirement was significantly higher in patients with stem cell transplantation (0.09 +/- 0.05 mg/kg) compared with controls (0.06 +/- 0.03 mg/kg; p = 0.0002). In the HIV patients with drug abuse (0.12 +/- 0.10 mg/kg), there was a tendency for the need of a higher dose of midazolam compared with the control group (p = 0.0754). CONCLUSION: Stem cell transplant recipients and selected HIV patients with drug abuse need higher doses of midazolam for bronchoscopy.

Bronchoalveolar Lavage↗