Exaggerated impact of ATP-sensitive K(+) channels on afferent arteriolar diameter in diabetes mellitus

Experiments were performed to determine the involvement of ATP-sensitive K(+) channels (K(ATP) channels) in the renal afferent arteriolar dilation that occurs during the hyperfiltration stage of insulin-dependent diabetes mellitus (IDDM). IDDM was induced in rats by streptozotocin (STZ) injection, and adequate insulin was provided to maintain moderate hyperglycemia. Sham rats received vehicle treatments. Two weeks later, afferent arteriolar function was assessed using the in vitro blood-perfused juxtamedullary nephron technique. Baseline afferent arteriolar lumen diameter was greater in STZ rats (25.9 +/- 1.1 microm) than in sham rats (20.8 +/- 1.0 microm). Glibenclamide (3 to 300 microM) had virtually no effect on afferent arterioles from sham rats; however, this K(ATP) antagonist caused concentration-dependent afferent arteriolar constriction in kidneys from STZ-treated rats, restoring lumen diameter to 20.6 +/- 1.7 microm (P > 0.05 versus sham baseline). In both groups of rats, pinacidil (a cyanoguanidine K(ATP) agonist; 0.3 to 300 microM) evoked concentration-dependent afferent arteriolar dilation, indicating the functional expression of K(ATP) channels; however, lumen diameter was increased by 73% in STZ kidneys but only by 48% in sham kidneys. The gliben-clamide-sensitive afferent arteriolar dilator response to 1 microM PCO-400 (a benzopyran K(ATP) agonist) was also accentuated in STZ kidneys. These observations suggest that increases in both the functional availability and basal activation of K(ATP) channels promote afferent arteriolar vasodilation during the early stage of IDDM, changes that likely contribute to the etiology of diabetic hyperfiltration.     

Psychological job demands as a risk factor for common cold in a Dutch working population

OBJECTIVE: We investigated the effect of Psychological Job Demands (PJD) on the occurrence of the clinical symptoms of common cold. METHODS: Subjects, participating in a large prospective cohort study on psychological determinants of fatigue at work, were asked to fill in a questionnaire on the occurrence of common cold during the previous four months. High PJD were considered as a potential risk factor. Other factors such as age, gender, and having young children were considered as potential confounders. RESULTS: In logistic regression analysis, the adjusted odds ratio (OR) for having a recent cold in subjects reporting high PJD vs. those reporting low PJD was 1.20 (95% confidence interval (CI), 1.08-1.33). A higher risk emerged among those with young children (OR, 1.70; 95% CI, 1.47-1.96), those having a history of asthma (OR, 1.69; 95% CI, 1.28-2.22), or being under the age of 40 (OR, 1.28; 95% CI, 1.14-1.43) and among smokers (OR, 1.23; 95% CI, 1.09-1.38). CONCLUSION: The results support an association between PJD and common cold. In spite of the almost inevitable shortcoming of a large cohort study using questionnaires, this study gave us the opportunity to study the relationship between common cold and work-related factors in a nonexperimental setting with participants observed in a natural environment with all the normal everyday hassles.     

Bladder cancer in the textile industry

OBJECTIVES: This study examined the occupations and industries at high risk for bladder cancer in an area where the textile industry is plentiful and the incidence of the disease is very high. METHODS: A case-referent study concerning 218 incident bladder cancer cases diagnosed during 1993-1995 in the county of Vallès Occidental, Barcelona, was carried out. A reference group (N=344) was selected from municipal lists matched to the cases by age, gender, and area of residence. All the subjects were personally interviewed, and a complete occupational history was abstracted together with other sociodemographic and life-style factors. All odds ratios (OR) and 95% confidence intervals (95% CI) were adjusted for age, gender, and smoking. RESULTS: No overall excess risk was found forever having worked in the textile industry (OR 1.13, 95% CI 0.79-1.63) nor for specific sectors of this industry (ie cotton, wool, silk). An excess risk was observed for spinners and winders employed for more than 20 years (OR 3.28, 95% CI 1.08-9.97) and for machine setters employed between 1960 and 1974 (OR 4.26, 95% CI 1.09-16.7). CONCLUSIONS: The results of this study do not support the findings of some earlier studies for an increased bladder cancer risk in the textile industry. However, some elevated risks were observed among the workers with the highest exposures.     

ARHI is the center of allelic deletion on chromosome 1p31 in ovarian and breast cancers

In our previous work, we had characterized ARHI as an imprinted putative tumor-suppressor gene in ovarian and breast cancers. ARHI is expressed in primary breast and ovarian cell lines but largely absent from the corresponding malignant tumors. Moreover, the non-imprinted functional allele is typically deleted in malignant cells. Since ARHI had been mapped to 1p31, a common deletion site in breast and ovarian cancer and male germ-cell tumors, in this study, we set out to define precisely the physical location of ARHI at 1p31 and to determine if this location lies within the smallest common region of deletion in breast and ovarian cancers. To this end, we first carried out radiation hybrid mapping of ARHI and surrounding markers, followed by a high-resolution study of loss of heterozygosity at 1p31 in 49 ovarian and breast cancers. Combining a radiation hybrid map and a physical map of the region encompassing ARHI, 3 discrete regions of minimal deletion were found at 1p31 in breast and ovarian cancers. ARHI is the most common deletion region at 1p31. Two other less common regions of deletion were found centromeric to this gene. One of them centered on D1S207 and the other one included and was proximal to D1S488. We also confirmed the preferential loss of non-imprinted functional allele in 7 of 9 tumor specimens. These data support the possibility that ARHI is a tumor-suppressor gene and suggest that additional tumor-suppressor genes may lie proximal to ARHI at 1p31. The data obtained from our study should aid in the identification and characterization of genes in this novel imprinted region.     

Stability of monoHER in an aqueous formulation for i.v. administration

MonoHER is a semisynthetic flavonoid used successfully in modulating the cardiotoxic effect of doxorubicin but not its antitumor activity. The oral bioavailability of monoHER is <1%. Therefore, it should be prepared as an i.v. formulation for use in clinical trials. The solubility of monoHER in water is highly pH dependent. At pH相似文献   

Expression of major histocompatibility antigens and nature of inflammatory cellular infiltrate in ovarian neoplasms

Expression of histocompatibility antigens and the intensity of inflammatory cellular infiltrate were evaluated in frozen tissue sections from 70 human ovarian tumors and six normal ovaries using monoclonal antibodies and an avidin-biotin immunoperoxidase technique. In the normal human ovary, surface epithelial cells, mature granulosa cells and lutein cells reacted with anti-HLA-A, B, C (HLA) and beta₂-microglobulin antibodies but not with anti-la (la-like, HLA-DR). Stromal cells and granulosa cells of the primordial follicles did not react with any of the antibodies. Among the neoplasms examined, all benign epithelial tumors, 86% of borderline an 81% of malignant epithelial tumors reacted with anti-HLA and/or beta₂-microglobulin antibodies. HLA-negative epithelial tumors were of serous or endometrioid types. Although la was not found in normal ovarian surface epithelium, the antigen could be detected in 44% of benign, and 43% of borderline and malignant epithelial ovarian tumors. Mono-nuclear cellular infiltrate was generally scarce in ovarian tumors and consisted mainly of T cells. Malignant epithelial tumors contained significantly more T cells than did benign tumors. More T cells were observed in HLA-positive ovarian tumors than in HLA-negative neoplasms, but the difference did not achieve statistical significance. No correlation could be found between la expression and the intensity of T-cell infiltrate. Significantly more T8 and Leu-3a-positive cells were found in the tumor stroma than amongst neoplastic cells. HNK-I-positive natural killer cells, OK-MI-positive macrophages and BI-positive B lymphocytes were rarely encountered either in the tumor stroma or between adjacent tumor cells.     

Spectral interaction of orphenadrine and its metabolites with oxidized and reduced hepatic microsomal cytochrome P-450 in the rat

Product inhibition has been suggested to be a determinant in orphenadrine pharmacokinetics. Two possibilities for the mechanism of product inhibition in orphenadrine metabolism are explored in this study. Orphenadrine and its metabolites may compete for cytochrome P-450 catalytic binding sites. Therefore the interaction of orphenadrine and some of its metabolites with hepatic microsomal ferricytochrome P-450 of the rat was investigated. The spectral dissociation constant for the type I (substrate) interaction of orphenadrine and its metabolites displayed no relationship with the lipophilicity of the compounds. Orphenadrine is only partially displaced from its cytochrome P-450 binding sites by its respective metabolites. For this mechanism to be significant in vivo. the metabolites need to reach concentrations near cytochrome P-450 similar to that of orphenadrine. This is not known yet. The significance of this mechanism for the product inhibition phenomenon is therefore uncertain. In this study it is also established that during both in vitro as well as in vivo metabolism of orphenadrine, a metabolic intermediate is formed, which binds irreversibly to ferrous-cytochrome P-450 (MI complex). In vitro, both the rate and extent of the MI complex formation with orphenadrine and metabolites as precursor, decreased in the order N-hydroxytofenacine >; tofenacine > orphenadrine > bisnororphenadrine. The metabolite orphenadrine-N-oxide did not produce an MI complex, in vitro. Furthermore. in vitro, it was shown that the N-demethylation of tofenacine paralleled the concomitant MI complex formation. Together, the data suggest that the first N-demethylation step of orphenadrine occurs via α-carbon oxidation, whereas the second N-demethylation step mainly comes about via N-oxidation. Both metabolic pathways eventually lead to the MI complex forming species. These two parallel pathways also account for the complicated substrate dependency and concentration dependency in MI complex formation. Finally, the formation of the nitroxide radical (the ultimate ligand for MI complexation) has been shown to be susceptible to inhibition by its precursors.The occurrence of MI complex formation resulting in metabolic inactive cytochrome P-450 is probably the main mechanism for the product inhibition phenomenon in orphenadrine metabolism.     

Relaxant effects of estradiol through non-genomic pathways in male and female pig bladder smooth muscle

The precise effect of low estrogen levels on urinary bladder contractility remains controversial. The present study was designed to analyze the effect of 17beta-estradiol in bladder smooth muscle contractility and the involvement of specific estrogen receptor stimulation in this effect. Castrated male and female pig detrusor strips were mounted for tension recording in an organ bath, superfused with Krebs solution at 37 degrees C and stimulated electrically and pharmacologically. In order to verify the acute effect of 17beta-estradiol on muscle contractility, the strips were incubated with different concentrations of the hormone. Muscle contractions were induced by potassium chloride, acetylcholine chloride and electrical field stimulation. The involvement of the estrogen receptor in the effects of 17beta-estradiol was assessed by incubation of some strips with the selective estrogen receptor antagonist ICI 182.780 before estradiol was applied. Estradiol at a dose of 30 micromol/l elicited a lower amplitude of contractions induced by EFS, Ach and KCl in female as well as in castrated male pig bladder smooth muscle strips. The effects of 17beta-estradiol were stronger in contractions induced by potassium chloride than those induced by other forms of stimulation. Pre-treatment with the pure estrogen receptor antagonist had no effect on 17beta-estradiol-induced inhibition of muscle contractility. These observations suggest that 17beta-estradiol induces lower amplitude of contraction of female as well as castrated male pig detrusor which is not mediated by the classic estrogen receptor. Furthermore, we can conclude that estradiol has a stronger inhibitory effect on the depolarization of muscle cell membrane compared to a muscarinic receptor-induced contraction.