Identification of sites responsible for the potentiating effect of niflumic acid on ClC-Ka kidney chloride channels.

BACKGROUND AND PURPOSE: ClC-K kidney Cl(-) channels are important for renal and inner ear transepithelial Cl(-) transport, and are potentially interesting pharmacological targets. They are modulated by niflumic acid (NFA), a non-steroidal anti-inflammatory drug, in a biphasic way: NFA activates ClC-Ka at low concentrations, but blocks the channel above approximately 1 mM. We attempted to identify the amino acids involved in the activation of ClC-Ka by NFA. EXPERIMENTAL APPROACH: We used site-directed mutagenesis and two-electrode voltage clamp analysis of wild-type and mutant channels expressed in Xenopus oocytes. Guided by the crystal structure of a bacterial CLC homolog, we screened 97 ClC-Ka mutations for alterations of NFA effects. KEY RESULTS: Mutations of five residues significantly reduced the potentiating effect of NFA. Two of these (G167A and F213A) drastically altered general gating properties and are unlikely to be involved in NFA binding. The three remaining mutants (L155A, G345S and A349E) severely impaired or abolished NFA potentiation. CONCLUSIONS AND IMPLICATIONS: The three key residues identified (L155, G345, A349) are localized in two different protein regions that, based on the crystal structure of bacterial CLC homologs, are expected to be exposed to the extracellular side of the channel, relatively close to each other, and are thus good candidates for being part of the potentiating NFA binding site. Alternatively, the protein region identified mediates conformational changes following NFA binding. Our results are an important step towards the development of ClC-Ka activators for treating Bartter syndrome types III and IV with residual channel activity.

Prevalence of sexual dysfunction in a cohort of middle-aged women: influences of menopause and hormone replacement therapy.

In order to determine the prevalence of sexual dysfunction (SD) and related risk factors in a cohort of middle-aged women the Laumann's test (DSM-IV) was passed to 534 healthy women between 40 and 64 years old (mean: 52.4+/-5.7) attending the Southern Metropolitan Health Service in Santiago de Chile. Of all the women, 82.8% were peri- or postmenopausal, 23% had received hormone replacement therapy (HRT) and 79.2% were sexually active. Among those who were sexually active a total of 51.3% presented SD. The prevalence of SD increased with age (from 22.2% in the 40-44-year age group to 66% in the 60-64-year age group). HRT users and healthy women presented a lower risk of SD (OR: 0.1 CI: 0.0-0.1 and OR: 0.6 CI: 0.3-0.9, respectively). The risk increased after the menopause (OR: 3.3 CI: 1.6-6.9) and with age older than 49 years (OR: 3.4 CI: 1.8-6.4), hysterectomy (OR: 3.7 CI: 1.3-10.6) and when male partners presented erectile dysfunction (OR: 3.2 CI: 1.2-8.6). In conclusion sexual dysfunction affects more than 51% of middle-aged women who are sexually active and increases with age. Ovarian function and HRT significantly influence sexual activity.

Mortality and morbidity from intra-aortic balloon pumps. Risk analysis.

BACKGROUND: The purpose of this study, was to assess the incidence of and predictors for mortality and morbidity in patients who required postoperative intra-aortic balloon pump (IABP) support. METHODS: We have retrospectively estimated 116 patients and data were statistically analyzed, and significant variables were evaluated with multivariate analysis. RESULTS: Mortality rate was 57.8% (67 patients). Nineteen patients (16.3%) had major vascular complications: 12 patients (10.3%) limb ischemia, 1 patient (0.9%) aortic dissection, 6 patients (5.2%) mesenteric infarction. Thirty patients (25.8%) had minor vascular complication: 23 patients (19.8%) bleeding from insertion site, 7 (6%) patients infection of insertion site. Limb ischemia was resolved by IABP removal (10 patients), thrombectomy (2 patients). No patient required limb amputation. Sixty patients (51.7%) had renal insufficiency, of which 40 patients needed dialysis. Fifteen patients (10.3%) had neurological complications, 13 patients (11.2%) thrombocytopenia and 5 patients (4.3%) sepsis. CONCLUSIONS: The incidence of IABP insertion in our institution was 1.5%. Mortality rate is similar to mortality of other studies in which the IABP has been inserted in the postoperative period. We have found that timing of IABP insertion, thrombocytopenia, presence of peripheral vascular disease and the redo intervention are independent predictors of mortality. We also found that female sex, diabetes, history of cigarette smoking and preoperative use of antiplatelet drugs are independent predictors of limb ischemia. The following factors are instead independent predictors of renal insufficiency: postoperative ejection fraction lower than 40% and non use of dobutamine in the postoperative period.

Quality of life after the menopause: a population study.

OBJECTIVE: To assess the impact of menopause and some sociodemographic variables on quality of life (QoL). MATERIALS AND METHODS: Four hundred and eighty-one women aged 40-59 years attending the Southern Metropolitan Health Service in Santiago de Chile were studied using the Specific Quality of Life Questionnaire for Menopause from Toronto University. RESULTS: Univariate analysis showed that menopausal women have worse QoL scores than women conserving cycles in the four areas of the questionnaire: They show a 10.6-fold higher risk for suffering vasomotor disorders affecting QoL, a 3.5-fold higher risk for psychosocial impairment, a 5.7-fold higher risk for physical disorders, and a 3.2-fold higher risk for sexual disorders (P < 0.0001). Regarding the influence of social markers (age, marital status, school years, work, number of children and sexual activity), housewives were found to have higher, worse, scores than working women in all test components (vasomotor, 3.11+/-1.90 versus 2.57+/-1.71, P < 0.003; psychosocial, 3.44+/-1.59 versus 2.92+/-1.45, P < 0.0007; physical, 3.45+/-1.36 versus 2.96+/-1.20, P < 0.0001; sexual, 3.63+/-2.23 versus 2.49+/-1.95, P < 0.0001). However, logistic regression demonstrated that the only variable found to cause a significant impairment in QoL was menopause. CONCLUSION: Menopause causes a decrease in quality of life, which is independent from age and other sociodemographic variables.

[Patterns of sexual behavior in Chilean women]. / Patrones de conducta sexual en mujeres chilenas.

BACKGROUND: Sexuality has an individual connotation, is influenced by biological, environmental and cultural factors and is present throughout all life. AM: To assess the sexual behavior of a group of Chilean women. SUBJECTS AND METHODS: A specially devised inquiry was applied to 301 women, aged 20 to 70 years old, that consulted in a medical service. RESULTS: Seventy seven percent of women were sexually active. These figures ranged from 80% of women aged 40-44 years old to 40% of women over 60. Sixty percent of women living together, 53.7% of single women, 65.6% of divorced women, 94.2% of married women and 100% of widows were sexually active. Women aged 25 to 29 years old had a mean of 8.4 relations per month compared with 3.3 relations among women older than 55. The frequency of sexual intercourse was higher in women living together and lower in widows. The mean age at the first intercourse was 20.6 +/- 4.5 years. Ninety three percent had experienced sexual desire and the percentage of satisfactory sexual relations does not change with age. Less educated women had a lower frequency of orgasms. CONCLUSIONS: Age and legal status of women are related to their sexual behavior and less educated women have a less satisfactory sexual life.

Cis/carboplatin + vinorelbine +/- radiotherapy in stage III and IV non small cell lung carcinoma.

The aim of this study was the retrospective evaluation of the effectiveness of cis/carboplatin + vinorelbine +/- radiotherapy in 118 patients with advanced non small cell lung carcinoma (NSCLC). To evaluate the response, pts were divided into three groups: a) Stage III pts. who received both chemotherapy and radiotherapy treatment (RC + RP = 43.75%, median survival 16.25 months); b) Stage III pts. who underwent only CT because RT was contraindicated (RC + RP = 21.95%, median survival 12.7 months); c) Stage II pts treated with CT alone (RC + RP = 20%, median survival = 12.1 months). Toxicity was mild. The results of the present study, both in terms of response rate and survival, confirm the effectiveness of the combination cis/carboplatin + vinorelbine +/- radiotherapy as palliative treatment of advanced NSCLC.

[Effects of estrogen supplementation on psychological variables in climacteric women]. / Estrógenos en climaterio femenino: efecto sobre variables psicológicas.

BACKGROUND: The beneficial effects of estrogen supplementation in climacteric women are clear. However, their psychological effects are not well documented. AIM: To study the effects of estrogen supplementation on psychological variables in climacteric women. SUBJECTS AND METHODS: Forty postmenopausal women were divided in two groups to receive a daily dose of 2 mg oestradiol valerate and 2.5 mg medroxyprogesterone acetate or an identical placebo during six months. Initially and at the end of the treatment period, they were subjected to a psychiatric interview and the Graffar, Hamilton and Eysenk personality tests were applied. Also, an Analysis of Verbal Behavior was used, that results in hope and hopeless scores. RESULTS: There were no differences in the initial assessment between the two treatment groups. In women receiving hormonal supplementation, the Hamilton score decreased from 11.2 to 4.9 (p < 0.002) and in women receiving placebo from 8.1 to 5.3 (NS). No other significant changes in psychological tests were observed. CONCLUSIONS: Hormonal supplementation decreases the Hamilton depression score in postmenopausal women.

Effect of octreotide on neuroenolase levels in patients with small cell lung cancer.

AIMS AND BACKGROUND: The somatostatin analog octreotide has an antiproliferative effect on small cell lung cancer lines in vitro and in experimental xenograft transplantation systems in vivo. Thus it is worth investigating octreotide activity in the clinical setting. METHODS: We studied the effect of octreotide (200 micrograms three times a day subcutaneously for seven days) on serum levels of the tumor marker neuroenolase in 13 patients with small cell lung cancer. RESULTS: A decrease in neuroenolase levels was observed at day 7 during octreotide treatment, with a mean +/- SD of 32.6 +/- 42.0 ng/ml compared to basal values of 44.4 +/- 57.7 ng/ml and to washout values of 50.3 +/- 65.7 ng/ml (P < 0.03). CONCLUSIONS: Our results indicate that octreotide is effective in reducing neuroenolase levels in small cell lung cancer patients. These data suggest a possible role for octreotide in the treatment of this kind of tumor.

[Knowledge and beliefs of the effect of menopause and estrogenic therapy on health. Study in women attending the Barros Luco-Trudeau Hospital]. / Conocimientos y creencias del efecto de la menopausia y de la terapia estrogénica sobre la salud. Estudio en mujeres beneficiarias del Hospital Barros Luco-Trudeau.

The benefits of hormonal replacement therapy are widely known. In spite of this, the proportion of women under treatment is low. The study aims to evaluate the amount of knowledge that patients have, about menopause, and how it influences compliance with therapy. In our study, 494 women attending the outpatient's clinic of Hospital Barros Luco-Trudeau were interviewed; 93.5% considered that menopause has adverse effects upon health; 87.9% believes that it produces emotional disturbances; 55.1% bone-related and 40.9% cardiac problems. Sixty six point eight percent of the consulted women know that there is a treatment for menopause. Half of the women interviewed had consulted the physician specifically for this reason; however, only one third are or were under treatment. Obesity, hirsutism and cancer are considered to be the main secondary effects to treatment. Patients who have not received hormone therapy have a much lower degree of knowledge about menopause than the treated ones, and amongst the latter, those who abandon treatment have less information than the ones that remain under treatment. As a conclusion, we may say that our patients have information about menopause and also that they attend to the physician's office for this reason. The knowledge about the matter and related beliefs influence both adherence to and compliance with therapy.

[Double-blind method of the effect of menopause symptoms, lipid profile, and endometrial thickness of continuous therapy with estradiol valerate and medroxyprogesterone acetate]. / Estudio doble ciego del effecto sobre la sintomatología menopáusica, el perfil lipídico y el grosor endometrial de una terapia continua de valerato de estradiol más acetato de medroxiprogesterona.

Continuous combined therapy (CCT) using estrogens and progestagens has appeared as an alternative to avoid vaginal bleeding, which is characteristic of sequential hormone therapy, and the main reason for the stopping treatment. Irregular vaginal bleeding can occur at the beginning of treatment, but it has been observed that after a few months patients are in amenorrhea. Fifty postmenopausal women were studied in order to evaluate the clinical outcome. Half of them were treated with a product containing 2 mg estradiol valerate and 2.5 mg medroxiprogesterone acetate, while the other half received a placebo. Menopause symptomatology was recorded as described by Blatt-Kupperman, depression was evaluated with the use of Hamilton's test, lipid profile by enzymatic methods and endometrial thickness by transvaginal ultrasonography. Patients were evaluated at the beginning, third and sixth month of the study, following a double blind methodology. Symptomatology diminished both in patients under CCT and using placebo, although improvement was significantly greater in patient under CCT. Thus in the hormone treated group the Blatt-Kupperman score fell from 12.1 to 6.4 and 3.2 in the third and sixth month respectively, while in the group receiving placebo the score fell from 11.5 to 6.3 in the third month and raised to 7.4 in the sixth month. Hamilton's test showed a significant improvement of depression only in patients under hormone therapy. Nineteen out of twenty five women using CCT had vaginal bleeding, showing no changes in the endometrial thickness during the study. Finally, HDL-cholesterol was raised in 14.5% while LDL-cholesterol was lowered in 18.7% (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Concurrent carboplatin (CBDCA), vindesine (VDS) and radiotherapy in stage III non small cell lung cancer (NSCLC).

AIMS: Aim of the study was to test, in a cooperative and prospective trial, the effectiveness and feasibility of a chemoradio-therapy program in stage III non small cell lung cancer (NSCLC). METHODS: The schedule consisted in carboplatin (CBDCA) 150 mg/m2/iv on days 1, 3, 5 and vindesine VDS 2.5 mg/m2/iv on days 1, 8, 15, 22 every 4 weeks for 2 cycles followed by radiotherapy 60 Gy with CBDCA 50 mg/m2 weekly as radioenhancer. The same schedule was proposed as neoadjuvant treatment in 10/47 patients (stage III A) and as exclusive treatment in 37/47 (stage III B) admitted patients. RESULTS: In the neoadjuvant subgroup partial remission was obtained in 5/10 patients, and 3 of them underwent surgery with consequent CR. In the stage III B subgroup, 2 complete remissions were obtained (survival 14 and 9+ months). Toxicity was mild. CONCLUSIONS: Our results confirm the feasibility of the schedule in stage III NSCLC.

Fluconazole vs amphotericin B: "in vitro" comparative evaluation of the minimal inhibitory concentration (MIC) against yeasts isolated from AIDS patients.

Fluconazole, a novel triazole antifungal drug, holds promise as a significant advance in the management of human fungal diseases. This new drug can be both orally and parenterally administered and is reported to be less toxic than other antifungal agents. The Authors studied the in vitro susceptibility of yeasts isolated from AIDS patients to this antimycotic drug, in order to evaluate if fluconazole's MICs were comparable to those of amphotericin B. A sample of 200 yeast strains (100 C.albicans, 20 C.parapsilosis, 20 C.tropicalis, 8 C.guilliermondii, 6 C.krusei, 6 C.pseudotropicalis, 24 T.glabrata and 16 Cr.neoformans) was tested. The results show an average MIC for amphotericin B (MIC90: 3.12 micrograms/ml) ten-fold lower than for fluconazole (MIC90: 100 micrograms/ml). However, C.albicans and Cr.neoformans presented the same MIC value (3.12 micrograms/ml) both for fluconazole and for amphotericin B, suggesting that fluconazole could represent a valid alternative to amphotericin B in the treatment of fungal infections caused by these two agents.

Itraconazole vs amphotericin B: in vitro comparative evaluation of the minimal inhibitory concentration (MIC) against clinically isolated yeasts.

Itraconazole is a triazole compound which, following several clinical trials, has begun to be used for therapy of mycotic infections. This new drug, with a broad-spectrum antifungal activity, can be orally administered. The Authors studied the in vitro susceptibility to amphotericin B and itraconazole of the following clinical isolates of pathogenic yeasts: 100 Candida albicans, 20 C. tropicalis, 20 C. parapsilosis, 8 C. guilliermondii, 6 C. pseudotropicalis, 24 Torulopsis glabrata and 16 Cryptococcus neoformans. Serial two-fold dilution, from 100 micrograms/ml to 0.04 micrograms/ml, of each drug were prepared in Yeast Nitrogen Base + Glucose 5%, after dissolving the itraconazole in dimethylsulfoxide (DMSO) and amphotericin B in 5% glucose solution. Amphotericin B (MIC90: 3.12 micrograms/ml) was found to have an average in vitro MIC six-fold lower than itraconazole (MIC90: 25 micrograms/ml). Thus, even though itraconazole is active, amphotericin B remains one of the most effective of the antifungal drugs.

Routine application of the evaluation of yeasts susceptibility to the main antimycotic drugs.

We evaluated the susceptibility of 618 strains of yeasts belonging to the genus Candida, isolated from various biological specimens. Amphotericin B, Nystatin, Fluorocytosine, Clotrimazole, Miconazole, Econazole and Ketoconazole were tested with the Kirby-Bauer method, modified according to Drouhet and Dupont. The polyenes Amphotericin B and Nystatin and the antimetabolyte Fluorocytosine were the most effective drugs, while the imidazole derivatives (Clotrimazole, Miconazole, Econazole and Ketoconazole) generally showed a lower activity. We emphasize the importance of routine evaluation of the susceptibility of isolated yeasts to the main antimycotic drugs.

Vitamin A and female lung cancer: a case-control study on plasma and diet.

Plasma and dietary levels of retinol and beta-carotene were evaluated in a consecutive series of 47 females with histologically proven primary lung cancer and 159 nonneoplastic hospital controls. The dietary questionnaire included 69 different items: special care was given to foods rich in vitamin A and seasonal foods (e.g., vegetables and fruits), whereas serum analysis was focused on retinol and beta-carotene. Age-adjusted mean values for cases and controls were, respectively, 458.3 vs. 551.3 mg for plasma retinol, 276.1 vs. 390.1 mg for plasma carotene; 598.1 vs 820.6 mg for daily retinol, and 628.0 vs. 882.5 mg for dietary carotene. The odds ratios for low vs. high tertile, adjusted for age, smoking, retinol or carotene, cholesterol, and triglycerides by multivariate analysis were, respectively, 1.13 for plasma retinol, 5.04 for plasma carotene, 3.27 for dietary retinol, and 2.93 for dietary carotene. For all the examined items, there was a trend of increased risk for the second and third tertile, and statistical significance was reached for plasma beta-carotene (p less than 0.05). The hypothesis that a higher risk of lung cancer is related to a low vitamin A consumption is supported by these data.

Event-related slow potential (ERSP) correlates of thyroid gland function level.

This study shows an association between thyroid gland function level and event-related slow brain potential (ERSP) parameters (peak amplitude and area under the curve), obtained during "classical" and "operant" reaction-time paradigms. A significant positive correlation between ERSP parameters and 24-hr I131 uptake and a negative nonsignificant one between them and ankle jerk reflex were found. Organismic factors related to thyroid function had greater influence upon ERSP amplitude and area than situational ones, for no significant effect of task was evidenced and no interaction between them was found under the conditions employed. Hyper- and hypothyroids showed also a tendency to present longer reaction times than euthyroids. These results are discussed within the framework of the arousal-distraction coupling hypothesis as proposed by Tecce and Cole (1976) and compared to those previously obtained in high-neuroticism anxiety-prone indivuduals. Although these and hyperthyroids do show indications of similar behavioral manifestations (excessive reactive arousal), both groups are considered to differ regarding empirical referennts of anticipatory arousal (ERSP parameters). A major difference seems to be the absence of a "ceiling effect" in hyperthyroids. This hypothetical phenomenon can be expected on the basis of the inverted U-shaped relation between ERSP amplitude and arousal level. A stronger "distraction" effect associated with increased arousal in anxiety neurotics is postulated and tentatively attributed to covert verbalizations of worry and feelings added to increased awareness of autonomic input. The contention is advanced that similar behavioral manifestations could be distinguishable at the physiological level employed and this might add further insights to diagnostic typologies (e.g., "psychosomatic" vs. "psychoneurotic" patients).