Hartmut M. Hanauske-Abel

Glucocorticoid Resistance Caused by Reduced Expression of the Glucocorticoid Receptor in Cells From Human Vascular Lesions

Mechanisms that control the balance between cell proliferation and death are important in the development of vascular lesions. Rat primary smooth muscle cells were 80% inhibited by low microgram doses of hydrocortisone (HC) and 50% inhibited by nanogram concentrations of transforming growth factor-beta1 (TGF-beta1), although some lines acquired resistance in late passage. However, comparable doses of HC, or TGF-beta1, failed to inhibit most human lesion-derived cell (LDC) lines. In sensitive LDC, HC (10 microg/mL) inhibited proliferation by up to 50%, with obvious apoptosis in some lines, and TGF-beta1 inhibited proliferation by more than 90%. Collagen production, as measured by [3H]proline incorporation or RIA for type III pro-collagen, was either unaffected or increased in the LDCs by HC. These divergent responses between LDC lines were partially explained by the absence of the glucocorticoid receptor (GR) and heat shock protein 90 mRNA in 10 of 12 LDC lines, but the presence of the mineralocorticoid receptor and 11beta-hydroxysteroid dehydrogenase type II. Western blot analysis confirmed the absence of the GR protein in cells lacking GR mRNA. Immunohistochemistry of human carotid lesions showed high levels of GR in the tunica media, but large areas lacking GR in the fibrous lesion. Considering the absence of the GR in most lines, the effects of HC may be elicited through the mineralocorticoid receptor. Functional resistance to the antiproliferative and antifibrotic effects of HC may contribute to excessive wound repair in atherosclerosis and restenosis.

Basement Membrane Biomarkers in Very Low Birth Weight Premature Infants

Basement membranes, critical for vital organs like the lungs, consist of two interwoven homopolymers, one assembled by type IV collagens and one by laminins. We hypothesized their serum antigens C-IV and P1, respectively, to be global measures for the maturity of these organs. In 39 very low birth weight premature neonates (means: gestational age, 25.8 weeks; birth weight, 779 g) requiring intensive care, we analyzed these biomarkers during the first two months post partum. Median C-IV and P1 exceeded adult levels by one order of magnitude. The individuals with the lowest first week C-IV values (mean: 667 ng/ml) required significantly longer neonatal intensive care unit stays than those with the highest values (mean: 2,467 ng/ml), on average 109 vs. 80 days (p = 0.008) irrespective of gestational age. Patients diagnosed with bronchopulmonary dysplasia (BPD) at 36 weeks postconceptional age, already in their first week of life displayed C-IV levels lower than in controls, suggesting a defect in pulmonary basement membrane remodeling. This is the first identification by a matrix biomarker of a BPD-antecedent state.

DEFERIPRONE, BUT NOT DEFEROXAMINE, INHIBITS BIOSYNTHESIS OF FIBRILLAR PROCOLLAGENS IN IRON-OVERLOADED THALASSEMIA PATIENTS. † 943

DEFERIPRONE, BUT NOT DEFEROXAMINE, INHIBITS BIOSYNTHESIS OF FIBRILLAR PROCOLLAGENS IN IRON-OVERLOADED THALASSEMIA PATIENTS. † 943

Objective ranking of fibrosis in standard histologic sections of human neonatal liver: applicability to alpha1-antitrypsin deficiency.

BACKGROUND The etiologic heterogeneity of fibrotic liver disease has resulted in the formulation of diverse, often disease-specific, classification systems for biopsy assessment, based on tissue morphology and staining. Their qualitative nature and observer dependency remain a concern, and no classification exists for several significant conditions--for example, alpha1-antitrypsin deficiency (alpha1-ATD). The authors propose a disease- and morphology-independent numeric ranking system to objectively quantify fibrosis in a standard histologic section, based on its content of protein amino acids. This PNC system is applied to two cases of alpha1-ATD liver fibrosis. METHODS High-performance liquid chromatography separation of the 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC)-labeled acid hydrolysate of an individual needle biopsy section, followed by the calculation of specific amino acid ratios to eliminate confounding variables. RESULTS As required by the PNC system, three numeric values were identified per tissue section, one increasing (P quotient), one decreasing (N quotient), one constant (C quotient) as fibrosis progresses, assessed by calibration against Knodell-staged samples. Generated for the alpha1-ATD sections, these three coordinates numerically referenced the degree of fibrosis in a manner that in each case was consistent with the histologic evaluation, the laboratory values, and the clinical course. CONCLUSIONS Numeric, objective referencing of the degree of fibrosis in routine liver biopsy sections, based on the PNC system, is technically possible.

DEFERIPRONE : AN IN VITRO INHIBITOR OF PROTEIN HYDROXYLASES VITAL FOR MATRIX FORMATION AND CELL PROLIFERATION † 944

DEFERIPRONE : AN IN VITRO INHIBITOR OF PROTEIN HYDROXYLASES VITAL FOR MATRIX FORMATION AND CELL PROLIFERATION † 944

Pronounced Increase of the Basement Membrane Collagen-Derived Serum Antigen C-IV after Discontinuation of Glucocorticoid Administration to Neonates

Pronounced Increase of the Basement Membrane Collagen-Derived Serum Antigen C-IV after Discontinuation of Glucocorticoid Administration to Neonates

Objective Measurement of Fibrosis: Findings in Biopsies of Pediatric Gastrointestinal Diseases

Objective Measurement of Fibrosis: Findings in Biopsies of Pediatric Gastrointestinal Diseases

A Unique Effect in Fanconi Anemia: Apparent Decrease of Only Type I Collagen Formation by Increased Amounts of Endogenous Growth Hormone

A Unique Effect in Fanconi Anemia: Apparent Decrease of Only Type I Collagen Formation by Increased Amounts of Endogenous Growth Hormone

Growth hormone and connective tissue metabolism: differential response of interstitial versus basement membrane collagens † 468

Growth hormone and connective tissue metabolism: differential response of interstitial versus basement membrane collagens † 468

Hypusine-Dependent Messenger Nucleic Acids ( hymns ): Deferiprone dislocates specific mRNAs from the polysomes. † 678

Hypusine-Dependent Messenger Nucleic Acids ( hymns ): Deferiprone dislocates specific mRNAs from the polysomes. † 678