Combined converting enzyme inhibition and angiotensin receptor blockade reduce proteinuria greater than converting enzyme inhibition alone: insights into mechanism.

Patients with various renal diseases receiving an angiotensin-converting enzyme inhibitor (CEI) were enrolled in a protocol to determine whether adding an angiotensin type 1 receptor blocker (ARB) reduces urinary protein excretion (UPE). All patients had significant proteinuria (range 517-8,562 mg/24 h) despite administration of CEI for at least 4 weeks. Following baseline measurements, losartan (50 mg/d) was started and testing was repeated at 1 month. Compared with CEI alone, combined CEI plus ARB reduced UPE by 45 +/- 8% (p < 0.005). Compared with CEI alone, CEI + ARB lowered UPE in each patient independent of baseline protein excretion or renal diagnosis. Reduction in proteinuria occurred independent of changes in mean arterial blood pressure (MAP), suggesting that the mechanism involved local changes in glomerular dynamics. If renal angiotensin II (ANG II) formation occurred despite CEI, the ANG II formed would suppress plasma renin activity (PRA), and adding an ARB would cause PRA to rise. In 7 of 10 subjects, addition of ARB to CEI increased PRA (p < 0.03) suggesting that intrarenal ANG II formation occurred in CEI-treated subjects. As a second marker of ANG II tissue activity, we measured the effects adding ARB on plasma aldosterone (ALDO). In 9 of 10 subjects, ALDO was acutely lowered (p < 0.009) suggesting that ANG II levels were incompletely blocked by CEI. We conclude that: combined CEI and ARB reduces UPE greater than CEI alone; reduction in proteinuria is independent of changes in MAP or renal diagnosis; and the additive effects of CEI and ARB are due at least in part to greater inhibition ofANG II action at the tissue level in the kidneys and adrenal glomerulosa.

Stimulation of reactive oxygen species production by an antidepressant visible light source.

BACKGROUND: The mechanism by which visible light stimulates chronobiological phase-shifting or antidepressant effects in humans is unknown. METHODS: Normal human NIH/3T3 nonpigmented fibroblasts were irradiated with a visible light source (SunRay) used in the treatment of winter seasonal depression. Electron spin resonance was assessed before and after 10 min of illumination at 2 mW/cm(2) (illuminance of 3700 lux), with and without the presence of 5 microL of 0.0214 mg/mL vitamin C. RESULTS: The fibroblasts showed evidence of production of reactive oxygen species after 10 min of irradiation. CONCLUSIONS: These in vitro data establish that an antidepressant source of visible light is capable of inducing the production of reactive oxygen species in skin. Such species may participate in signal transduction pathways leading to mood changes.

Defense mechanisms, negative emotions, and psychopathology in adolescent inpatients.

Ego defense mechanisms were compared in adolescent psychiatric inpatients and healthy adolescents to determine their relationship to specific diagnoses and to negative emotions. Seventy-one patients with schizophrenia, 28 with major depressive disorder, and 24 with obsessive-compulsive disorder (OCD) and 87 normal adolescents were assessed for defense mechanisms by the Life Style Index (LSI) and Ego Defense Scale (EDS). The Beck Depression Inventory (BDI), State-Trait Anxiety Inventory (STAI), and Multidimensional Anger Inventory (MAI) were used to assess depression, anxiety, and anger. Several defenses distinguished all psychiatric patients from controls, and a few defenses characterized different patient groups, especially those with OCD. Projection (on the LSI), displacement, and regression correlated significantly with anger; displacement, reaction formation, and undoing on the EDS correlated with anxiety, and denial was negatively correlated with depression. These findings have some relevance for the evaluation of Plutchik's psychoevolutionary theory of emotions and for the further empirical study of defenses in psychopathology.

Green fluorescent protein photobleaching: a model for protein damage by endogenous and exogenous singlet oxygen.

Characterization of protein damage during photosensitization of chlorin e6-treated cells was performed using the green fluorescent protein (GFP). The GFP-chromophore damage caused by singlet oxygen was studied in COS 7 kidney cells and E. coli bacteria following light irradiation. Electron spin resonance (ESR) revealed the generation of endogenous singlet oxygen (1O2) by photoactivated GFP, an effect similar to that produced by the exogenous photosensitizer chlorin e6. A light dose-dependent photobleaching effect of GFP was pronounced at low pH or upon photosensitization with chlorin e6. However, the 1O2 quenchers beta-carotene and sodium azide minimized GFP photo-bleaching. Gel electrophoresis of photosensitized GFP followed by fluorescence multi-pixel spectral imaging revealed the binding of chlorin e6 to GFP, affecting the photobleaching efficacy. Fluorescence multi-pixel spectral imaging of GFP-transfected COS 7 cells demonstrated the presence of GFP in the cytoplasm and nucleus, while chlorin e6 was found to be concentrated in the perinuclear vesicles. Exposure of the cells to light induced GFP photobleaching in the close vicinity of chlorin e6 vesicles. We conclude that photoactivated GFP generates endogenous 1O2, inducing chromophore damage, which can be enhanced by the cooperation of exogenous chlorin e6.

Advanced nasopharyngeal carcinoma in the young: The Northern Israel Oncology Center experience, 1973-1991.

Between 1973 and 1991, 10 patients with locally advanced [stages III and IV] nasopharyngeal carcinoma were treated at the Northern Israel Oncology Center. All patients were treated with wide-field irradiation to the primary tumor, including the base of skull, neck, and supraclavicular region. After 1984, 6 patients also received cisplatin/5FU-based chemotherapy prior to radiotherapy and 1 patient received it after radiotherapy. All the patients who received chemotherapy are alive with no evidence of disease, for a mean disease-free survival of 96 months (range, 77 to 108 months), and no serious therapy-related late side-effects have been noted, except in one patient. We conclude that adjuvant chemotherapy may be effective in improving outcome, but only randomized prospective studies can evaluate its exact role.

Update on nasopharyngeal carcinoma in northern Israel.

PURPOSE: Because Israel is one of the world's intermediate risk areas for nasopharyngeal carcinoma (NPC), we continue to analyze retrospectively all referred cases. PATIENTS AND METHODS: We previously reported our work with 49 NPC patients, and we now extend our analysis to include an additional 26 patients. All our 75 patients were treated between 1968 and 1991 at the Northern Israel Oncology Center in Haifa. They were typical in the preponderance of male sex (74%), Mediterranean origin (80%) and late stage presentation (91%). All patients received a combination of photon and electron radiotherapy to the tumor site, base of skull and neck, with an average dose to the nasopharynx of 6095 cGy. Nearly 40% of the patients received combined modality treatment (CMT), i.e., cisplatin-based chemotherapy prior to radiotherapy. RESULTS: There was an overall complete response (CR) of 88%, with 44% of the patients experiencing recurrence. Serious complications occurred in 5%. We found a 5-year survival rate of 48% and a 10-year survival rate of 44%, with some indication that CMT was advantageous to later-stage patients with non-keratinizing histologies, but not to earlier stages nor to those with keratinizing squamous cell carcinoma (SCC). Pediatric patients had better survival rates. CONCLUSIONS: 1. The somewhat better survival performance of Arabs and Sephardic Jews may reflect their greater tendency to have the non-keratinizing histological variants (lymphoepithelioma and undifferentiated carcinoma). 2. Ethnicity was consistently prognostic, both as risk and survival factors. 3. The role of CMT in advanced non-keratinizing NPC should be explored in future randomized trials.

Effects of differentiation-inducing agents on purine nucleotide metabolism in an ovarian cancer cell line.

The effects of the differentiation-inducing agents sodium butyrate (NaOBt), dimethylsulfoxide (DMSO) and mycophenolic acid (MA), on purine nucleotide metabolism, was studied in an ovarian carcinoma cell line (GZL-8). Exposure to these agents inhibited cell proliferation, but did not affect cell viability. Three hours following exposure, NaOBt and DMSO moderately decelerated purine synthesis de novo, but MA accelerated it three-fold, this being associated with a two-fold increase in the excretion of hypoxanthine and xanthine into the incubation medium. NaOBt and DMSO did not affect the cellular nucleotide content, but MA caused a 73% decrease in GTP content and about a 50% increase in the cellular content of UTP. The following alterations in cellular enzyme activity were observed 72 h following exposure: NaOBt decreased the activity of hypoxanthine-guanine phosphoribosyltransferase and increased the activity of IMP and of AMP 5'-nucleotidases, DMSO increased the activity of IMP 5'-nucleotidase, and MA increased the activity of the two nucleotidases. The results suggest that, in the carcinoma cell line studied, the differentiation process induced by NaOBt and DMSO may be associated with a general shift in the direction of purine metabolism from anabolism to catabolism, whereas that induced by MA is associated with a specific decrease in the production of GTP.

Effect of light on calcium transport in bull sperm cells.

The effect of light on calcium transport was studied. Bull sperm cells were irradiated with an He-Ne (630 mm) laser and a 780 nm diode laser at various energy doses, and 45Ca2+ uptake was measured by the filtration technique. It was found that there is an accelerated Ca2+ transport in the irradiated cells, which means that laser light can stimulate Ca2+ exchange through the cell membrane. This may cause transient changes in the cytoplasmic Ca2+ concentration which, in spermatozoa, has a regulatory role in control of motility and acrosome reaction, and in other cells can trigger mitosis.