Smoking is known to affect microcirculatory function in a middle-aged population. However, the effects of smoking on myocardial perfusion in young smokers have not been studied. Myocardial perfusion ...was measured in 15 smokers (24 +/- 2 years) and 15 nonsmokers (24 +/- 3 years) using positron emission tomography. Myocardial perfusion was measured at rest, during cold stress and during dipyridamole. Resting myocardial blood flow was similar in the two groups. The well-described correlation between rate-pressure product and myocardial blood flow was present only in the nonsmokers (r(2) = 0.61, p < 0.001). Myocardial blood flow corrected for the rate-pressure product declined during cold by 20% in the smokers 1.11 +/- 0.28 vs. 0.92 +/- 0.20 ml x g(-1) x min(-1) (p = 0.012), but remained unchanged in nonsmokers 1.11 +/- 0.25 vs. 1.09 +/- 0.30 ml x g(-1) x min(-1) (p = NS). Dipyridamole-induced hyperemia was similar in the two groups 2.23 +/- 0.78 vs. 2.42 +/- 0.65 ml x g(-1) x min(-1) (p = NS). In conclusion, smoking induces abnormalities in myocardial microcirculatory regulation in young otherwise healthy smokers. The coronary flow reserve, however, is not significantly altered.
Malignant mesothelioma is a rare malignancy with a median survival, ranging from 4 to 18 months in untreated patients. In a phase II study of patients with mesothelioma, the efficacy and toxicity of ...ifosfamide and mesna was evaluated. Twenty-nine previously untreated patients, with histologically proven and unresectable mesothelioma, entered the study. Three patients were later excluded from the study due to revision of the diagnoses. The patients had to have bidimensionally measurable disease by CT scans and a WHO performance status ≤3. Eligible patients received ifosfamide 3000 mg/m
2 per day for 3 days as a 1-h infusion and mesna 1800 mg/m
2 per day for 3 days every third week. Dose modifications were made according to the degree of hematologic, neurologic and renal toxicity. Response to treatment was evaluated in accordance with WHO criteria. The median age of patients was 59 years (range 39–68), 18 patients (69%) had a history of asbestos exposure and the median of treatment cycles was four (range 1–10). No complete responses were observed. One patient obtained a partial response after five cycles with a duration of response of 25 months. Nine patients (35%) had stable disease, while 13 (54%) progressed. The median survival for all patients was 10 months. The toxicity of the treatment was considerable. Thirteen patients (50%) had grade 4 leucopenia, ten patients (38%) had grade 3 or 4 reversible neurotoxicity and ten patients (38%) had grade 3 or 4 nausea and vomiting. Eleven patients (42%) went off the study due to the toxicity of the treatment. In conclusion, ifosfamide did not show any substantial activity of relevance in malignant mesothelioma at the dose level investigated, in spite of considerable toxicity.
To examine the importance of cytomegalovirus (CMV) in bronchoalveolar lavage (BAL) fluid of patients with HIV-associated Pneumocystis carinii pneumonia (PCP) treated with adjunctive corticosteroids ...(CS).
Analysis of clinical data during a 5-year period.
Department of infectious diseases where clinical and paraclinical data on patients suspected of having PCP have been sampled prospectively.
148 consecutive patients with a first episode of PCP in a 5-year period.
Vital status 3 months after diagnosis of PCP.
Patients with PCP treated with adjunctive CS who had CMV cultured from BAL fluid had a two times higher mortality within 3 months from bronchoscopy than others (p=0.08). This difference could not be explained by differences in CD4 count, Po2 or PCO2 at time of bronchoscopy.
With the accepted usage of adjunctive CS in severe PCP, the role of CMV as a pulmonary copathogen may have changed. Active CMV infection may be an important cause of failing treatment of severe PCP in those treated with adjunctive CS.
(CHEST 1995; 108:411-14)
B lymphocytes are responsible for antigen uptake and presentation, as well as antibody production. These reactions require close cell-to-cell contact between B lymphocytes and monocytes. In this ...study we demonstrate that interleukin 8 (IL-8), γ-immune protein 10 (γIP-10) and tumour necrosis factor α (TNF-α) all induce a significant chemokinetic response of human B lymphocytes. Among the cytokines tested, rIL-8 was the strongest B lymphocyte migratory factor with a migratory index (MI) of 2.03±0.32, (P<0.002), followed by rTNF-α (MI=1.89±0.17,P<0.001) and rγIP-10 (MI=1.63±0.17,P<0.001). We did not observe B lymphocyte migration towards rIL-1α, rIL-2, rIL-4, rIL-10, interferon γ (rINF-γ) or transforming growth factor β (rTGF-β). Furthermore, we report that human B lymphocytes have a constitutive IL-8 mRNA expression and protein secretion in vitro. Resting as well as stimulated B lymphocytes secrete on average 1.5 ng IL-8/ml medium/24 h (2×106B lymphocytes). Our data indicate a possible mechanism by which B lymphocytes make contact with other cells, during immuno-inflammatory processes.
MHC class II positive T cells found in areas of inflammation are believed to play an important pathogenetic role in autoimmunity. In experimental models , class II molecules have been shown to ...regulate adhesion between human T cells. It is, however, not known in detail how class II molecules are functionally linked to adhesion molecules. Some data suggest that beta2 integrin (CD11a/CD18) molecules play a role in class-II-induced homotypic adhesion in B cells, monocytes, and virus-transformed or neoplastic cell lines. We have previously obtained evidence that adhesion molecules other than beta2 integrins might play a role in class-II-mediated adhesion in T cells. To study further class-II-mediated adhesion in T cells, we have taken advantage of (allo)antigen-specific beta2-integrin-negative, CD4-positive T cell lines obtained from a leukocyte adhesion deficiency patient. We show that class II ligation induces homotypic adhesion in both beta2-integrin-positive and negative, CD4-positive T cell lines. Anti-CD18 monoclonal antibody (mAb) weakly inhibited the adhesion response in beta2-integrin-positive T cells and had no effect on beta2-integrin-negative T cells. In contrast, an anti-CD58 (LFA-3) mAb almost completely inhibited the adhesion response in beta2-integrin-negative T cells. Antibodies against the CD58 ligand, CD2, partly inhibited the adhesion response in beta2-integrin-negative T cells whereas antibodies against other adhesion molecules did not. The adhesion response in beta2-integrin-positive T cells was partly inhibited by antibodies against CD58 and CD2. Taken together, these data provide the first evidence that CD58 molecules are involved in class-II-induced homotypic adhesion between T cells.
beta2 integrin molecules are involved in a multitude of cellular events, including adhesion, migration, and cellular activation. Here, we studied the influence of beta2 integrins on interleukin-2 ...(IL-2)-mediated signal transduction in human CD4(+) T cell lines obtained from healthy donors and a leukocyte adhesion deficiency (LAD) patient. We show that IL-2 induces tyrosine phosphorylation of a 125-kDa protein and homotypic adhesion in beta2 integrin (CD18)-positive but not in beta2-integrin-negative T cells. EDTA, an inhibitor of integrin adhesion, blocks IL-2-induced tyrosine phosphorylation of the 125-kDa protein but not other proteins in beta2-integrin-positive T cells. Likewise, a beta2 integrin (CD18) antibody selectively inhibits induction of the 125-kDa phosphotyrosine protein, whereas cytokine-mediated tyrosine phosphorylation of other proteins is largely unaffected. Immunoprecipitation experiments indicate that the IL-2-induced 125-kDa phosphotyrosine protein is the focal adhesion kinase-related protein B (fakB). Thus, IL-2 induces strong tyrosine phosphorylation of fakB in beta2-integrin-positive but not in beta2-integrin-negative T cells, and CD18 mAb selectively blocks IL-2-induced fakB-tyrosine phosphorylation in beta2-integrin-positive T cells. In parallel experiments, IL-2 does not induce or augment tyrosine phosphorylation of p125(FAK). In conclusion, our data indicate that IL-2 induces beta2-integrin-dependent signal transduction events involving the tyrosine kinase substrate fakB.
In the present study we have analysed the expression of insulin-like growth factor II (IGF-II) in the human rhabdomyosarcoma cell line IN157.IN157 cells express high levels of three IGF-II mRNAs of ...6.0 kb, 4.8 kb and 4.2 kb. In contrast, normal skeletal muscle expresses a negligible amount of IGF-II mRNA. Two forms of IGF-II with molecular masses of 7.5 kDa and 10 kDa, corresponding to the mature IGF-II and IGF-II with a C-terminal extension of 21 amino acids (IGF-IIE21), were secreted into the culture medium at amounts of 17 ng/ml (2.3 nM) and 15 ng/ml (1.5 nM), respectively. IN157 cells also produce IGF binding protein-2. The bioactivity of recombinant IGF-IIE21 was compared with human IGF-I and IGF-II. IGF-I, IGF-II and IGF-IIE21 bound with high affinity to human IGF-I receptors (Kd approximately 1 nM), whereas the human IGF-II/mannose 6-phosphate (IGF-II/Man 6-P) receptor bound IGF-II and IGF-IIE21 with Kd values of 0.5 nM and 2 nM, respectively, and IGF-I with about 500 times lower affinity. IGF-II and IGF-IIE21 stimulated DNA synthesis via the IGF-I receptor, whereas the IGF-II/Man 6-P receptor mediated their rapid internalization and inactivation. During culture of IN157 cells about 50% of their IGF-I receptors were occupied by endogenous IGF-II. We conclude that IN157 cells express high levels of bioactive 10 kDa IGF-II and 7.5 kDa IGF-II that may stimulate the proliferation of rhabdomyosarcomas by interaction with IGF-I receptors on the cells.
Background: Imerslund-Graesbeck Syndrome (IGS) is a rare genetic disorder characterised by juvenile megaloblastic anaemia. IGS is caused by mutations in either of the genes encoding the intestinal ...intrinsic factor-vitamin B sub(12) receptor complex, cubam. The cubam receptor proteins cubilin and amnionless are both expressed in the small intestine as well as the proximal tubules of the kidney and exhibit an interdependent relationship for post-translational processing and trafficking. In the proximal tubules cubilin is involved in the reabsorption of several filtered plasma proteins including vitamin carriers and lipoproteins. Consistent with this, low-molecular-weight proteinuria has been observed in most patients with IGS. The aim of this study was to characterise novel disease-causing mutations and correlate novel and previously reported mutations with the presence of low-molecular-weight proteinuria. Methods: Genetic screening was performed by direct sequencing of the CUBN and AMN genes and novel identified mutations were characterised by in silico and/or in vitro investigations. Urinary protein excretion was analysed by immunoblotting and high-resolution gel electrophoresis of collected urines from patients and healthy controls to determine renal phenotype. Results: Genetic characterisation of nine IGS patients identified two novel AMN frameshift mutations alongside a frequently reported AMN splice site mutation and two CUBN missense mutations; one novel and one previously reported in Finnish patients. The novel AMN mutations were predicted to result in functionally null AMN alleles with no cell-surface expression of cubilin. Also, the novel CUBN missense mutation was predicted to affect structural integrity of the IF-B sub(12) binding site of cubilin and hereby most likely cubilin cell-surface expression. Analysis of urinary protein excretion in the patients and 20 healthy controls revealed increased urinary excretion of cubilin ligands including apolipoprotein A-I, transferrin, vitamin D-binding protein, and albumin. This was, however, only observed in patients where plasma membrane expression of cubilin was predicted to be perturbed. Conclusions: In the present study, mutational characterisation of nine IGS patients coupled with analyses of urinary protein excretion provide additional evidence for a correlation between mutation type and presence of the characteristic low-molecular-weight proteinuria.
The paired box and homeodomain containing transcription factors Pax4 and Pax6 are known to be essential for development of the pancreatic endocrine cells. In this report we demonstrate that stable ...expression of Pax4 in a rat glucagon-producing cell line inhibits the endogenously expressed glucagon gene completely. Furthermore, Pax4 represses Pax6 independent transcription of the insulin promoter, suggesting that Pax4 can actively repress transcription in addition to acting by competition with the transcriptional activator Pax6.
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