Regulation of hepatocyte activator inhibitor-1 expression by androgen and oncogenic transformation in the prostate

Hepatocyte activator inhibitor-1 (HAI-1) is a transmembrane serine protease inhibitor that regulates the conversion of latent to active hepatocyte growth factor (HGF). Studies supporting a role for the HGF pathway in prostate carcinogenesis prompted an analysis of HAI-1 expression in the prostate. Here we analyze the regulation of HAI-1 expression by androgen, oncogenic transformation, and cancer progression. Immunohistochemical analysis revealed that HAI-1 expression was restricted to prostate epithelium, where staining occurred primarily in basal and atrophic luminal epithelial cells. Compared to normal glands, HAI-1 expression was significantly increased in localized prostate cancer and was present in most prostate cancer metastases. HAI-1 protein expression levels were sensitive to androgen in normal epithelium but not in cancer. Although androgen did not increase HAI-1 protein expression levels in LNCaP cells, it decreased HAI-1 surface expression, consistent with previous data from our group (Martin DB, Gifford DR, Wright ME, Keller A, Yi E, Goodlett DR, Aebersold R, Nelson PS: Quantitative proteomic analysis of proteins released by neoplastic prostate epithelium. Cancer Res 2004, 64:347-355). HAI-1 overexpression in cancer was predictive of prostate-specific antigen recurrence (relative risk, 1.24). These results suggest that HAI-1 regulates the HGF Met axis on prostate epithelial cells and influences HGF mediated tumor invasion and metastasis.     

Heterogeneous expression of CD59 on human Purkinje cells

The expression of CD59 and other complement regulators was studied in human cerebellum from 14 individuals with no cerebellar pathology, from one patient with multiple sclerosis (MS) and from two patients with paraneoplastic cerebellar degeneration (PCD). CD59 was present on the Purkinje cells at various levels in eight of the 14 cases with no cerebellar pathology. CD59 was also present on the Purkinje cells of the patient with MS, but not on the scarce remaining Purkinje cells of the two patients with PCD. Other complement regulators (CD35, CD46 and CD55) were not expressed on the Purkinje cells, whereas CD59, CD46 and CD55 were present on the molecular, granulosa and endothelial cells. The results suggest that Purkinje cells not expressing CD59 could be especially prone to complement-mediated damage.     

A monoclonal antibody that recognizes the alpha chain of HLA-DR antigens

A monoclonal antibody, HC2.1, has been generated that specifically reacts with both the denatured and the in vitro translated alpha chain of the DR antigen. Although HC2.1 antibody reacted with the alpha chain of protein immunoprecipitated by two DR-specific monoclonal antibodies, L227 and LB3.1, it did not react with the alpha chain of the DQ1 antigen immunoprecipitated by the monoclonal antibody, Genox 3.53. The isoelectric focusing pattern of the alpha chain precipitated by HC2.1 antibody was invariant across a range of DR specificities within a panel of lymphoblastoid cells. The alpha chain of DR antigen from a B cell line was purified by HC2.1-Sepharose immunoaffinity chromatography and limited amino acid sequence analysis was carried out with Staphylococcus aureus SV8 protease fragments purified by high-pressure liquid chromatography. The sequence analysis confirmed that the antigen reactive with HD2.1 antibody is encoded by the DR alpha chain gene.     

重度肥胖患者胃肠分流术后低氧血症机制的分析

目的　研究重度肥胖对胃肠分流术后动脉血氧分压的影响。方法　对 6 1例进行胃肠分流术的重度肥胖患者及 5 5例择期腹部手术的正常体重患者进行术前肺功能、术前及术后 1～ 5d的血气分析检测。结果　肥胖组术后1～ 5d、对照组术后 1～ 2d的动脉血氧分压较术前显著下降 (P <0 .0 5 ) ;肥胖组术后 1～ 2d动脉血氧分压与其最大分钟通气量及腰臀比显著相关 (P <0 .0 0 0 1)。结论　重度肥胖者较正常体重患者在腹部手术后发生低氧血症的程度较严重且持续时间长。     

Biomarkers for exposure to ambient air pollution--comparison of carcinogen-DNA adduct levels with other exposure markers and markers for oxidative stress

Human exposure to genotoxic compounds present in ambient air has been studied using selected biomarkers in nonsmoking Danish bus drivers and postal workers. A large interindividual variation in biomarker levels was observed. Significantly higher levels of bulky carcinogen-DNA adducts (75.42 adducts/10(8) nucleotides) and of 2-amino-apidic semialdehyde (AAS) in plasma proteins (56.7 pmol/mg protein) were observed in bus drivers working in the central part of Copenhagen, Denmark. In contrast, significantly higher levels of AAS in hemoglobin (55.8 pmol/mg protein), malondialdehyde in plasma (0. 96 nmol/ml plasma), and polycyclic aromatic hydrocarbon (PAH)-albumin adduct (3.38 fmol/ microg albumin) were observed in the suburban group. The biomarker levels in postal workers were similar to the levels in suburban bus drivers. In the combined group of bus drivers and postal workers, negative correlations were observed between bulky carcinogen-DNA adduct and PAH-albumin levels (p = 0.005), and between DNA adduct and [gamma]-glutamyl semialdehyde (GGS) in hemoglobin (p = 0.11). Highly significant correlations were found between PAH-albumin adducts and AAS in plasma (p = 0.001) and GGS in hemoglobin (p = 0.001). Significant correlations were also observed between urinary 8-oxo-7, 8-dihydro-2'-deoxyguanosine and AAS in plasma (p = 0.001) and PAH-albumin adducts (p = 0.002). The influence of the glutatione S-transferase (GST) M1 deletion on the correlation between the biomarkers was studied in the combined group. A significant negative correlation was only observed between bulky carcinogen-DNA adducts and PAH-albumin adducts (p = 0.02) and between DNA adduct and urinary mutagenic activity (p = 0.02) in the GSTM1 null group, but not in the workers who were homozygotes or heterozygotes for GSTM1. Our results indicate that some of the selected biomarkers can be used to distinguish between high and low exposure to environmental genotoxins.     

Obstructive nephropathy in the pig

Summary Kidney growth was investigated in 30-kg pigs after 72 h of unilateral ureteral obstruction. The data were compared to control kidneys from normal non-operated pigs at same weight. Kidney wet weight was determined. Cortex and medulla were separated, and from both regions RNA, DNA, protein and kidney tissue insulin-like growth factor I was determined. Unilateral obstruction caused a doubling of the wet hydronephrotic kidney weight and an ipsilateral 76% increase in total kidney protein content. RNA increased by 45% in the cortex and 76% in the medulla. Kidney protein in the contralateral cortex increased by 23% and RNA by 42%. In the hydronephrotic kidney DNA was reduced by 13% in the cortex and by 21% in the medulla. Contralaterally, DNA was the same as in the controls. Mean kidney insulin-like growth factor I increased sevenfold in the ipsilateral medulla but in the cortex it was the same as in the controls. Serum insulin-like growth factor I concentration was 1.7 ±1.1 g/l in the hydronephrotic animals and 1.2±0.8 g/l in controls. At this stage of obstruction, our data demonstrate (1) hydronephrotic growth that is most probably hyperplastic in the medulla, associated with an increase in medullary insulin-like growth factor I, (2) hyperplastic growth in the cortex, and (3) contralateral kidney growth that is mainly hypertrophic after 72 h of contralateral ureteral obstruction.     

Effect of short-term hyperventilation on cerebral blood flow autoregulation in patients with acute bacterial meningitis

BACKGROUND AND PURPOSE: Cerebral blood flow (CBF) autoregulation is impaired in patients with acute bacterial meningitis: this may be caused by cerebral arteriolar dilatation. We tested the hypothesis that CBF autoregulation is recovered by acute mechanical hyperventilation in 9 adult patients with acute bacterial meningitis. METHODS: Norepinephrine was infused to increase mean arterial pressure (MAP) 30 mm Hg from baseline. Relative changes in CBF were concomitantly recorded by transcranial Doppler ultrasonography of the middle cerebral artery, measuring mean flow velocity (V(mean)), and by measurement of arterial to jugular oxygen content difference (a-v DO(2)). The slope of the regression line between MAP and V(mean) was calculated. Measurements were performed during normoventilation and repeated after 30 minutes of mechanical hyperventilation. RESULTS: At normoventilation (median PaCO(2) 4.4 kPa, range 3.5 to 4.9), MAP was increased from 68 mm Hg (60 to 101) to 109 mm Hg (95 to 126). V(mean) increased with MAP from 48 cm/s (30 to 61) to 65 cm/s(33 to 86) (P<0.01), and a-v DO(2) decreased from 2.2 mmol/L (1.0 to 2.7) to 1.4 mmol/L (0.8 to 1.8) (P<0.05). During hyperventilation (PaCO(2) 3.5 kPa, range 3.3 to 4.1), MAP was increased from 76 mm Hg (58 to 92) to 109 mm Hg (95 to 121). V(mean) increased from 45 cm/s (29 to 55) to 53 cm/s (33 to 78) (P<0.01), and a-v DO(2) decreased from 2.5 mmol/L (1.8 to 3.0) to 1.8 mmol/L (1.2 to 2.4) (P<0.05). Four patients recovered autoregulation completely during hyperventilation. The slope of the autoregulation curve decreased during hyperventilation compared with normoventilation (P<0.05). CONCLUSIONS: CBF autoregulation is partially recovered during short-term mechanical hyperventilation in patients with acute bacterial meningitis, indicating that cerebral arteriolar dilation in part accounts for the regulatory impairment of CBF in these patients.     

Apoliprotein E and multiple sclerosis: impact of the epsilon-4 allele on susceptibility, clinical type and progression rate

The purpose of this study was to investigate the relation between APOE genotype and Multiple Sclerosis (MS) in a genetically homogeneous population. We examined 240 patients consulting the MS-clinic during a period of 3 years (1996 - 1999). The mean age of the patients was 41.7 years (range 19 - 80 Y, SD 10.0 Y). As a measure of the progression rate (PR) the last registered Expanded Disability Status Scale (EDSS) score was divided by the time span (years) from disease onset until the latest assessment. The APOE genotype was determined from saliva and/or blood samples using PCR-techniques. The prevalence of different APOE genotypes was compared with the allele-distribution in a population of 361 persons from a Danish cross-sectional population study. The frequency of APOE-epsilon 4/epsilon 4 homozygotes was significantly higher in the MS-group as compared to controls (P<0.05, odds ratio: 2.3), whereas the frequency distribution of other genotypes did not differ significantly. The rate of progression was significantly faster in the APOE-epsilon 4/epsilon 4 homozygotes compared to other genotypes in the MS group (P<0.05). This study suggests that the APOE-epsilon 4/epsilon 4 homozygotes have an increased risk of developing MS. MS patients with the APOE-epsilon 4/epsilon 4 allele may also have an increased rate of disease progression. Multiple Sclerosis (2000) 6 226 - 230