Glucocorticoids can promote androgen-independent growth of prostate cancer cells through a mutated androgen receptor.

The androgen receptor (AR) is involved in the development, growth and progression of prostate cancer (CaP). CaP often progresses from an androgen-dependent to an androgen-independent tumor, making androgen ablation therapy ineffective. However, the mechanisms for the development of androgen-independent CaP are unclear. More than 80% of clinically androgen-independent prostate tumors show high levels of AR expression. In some CaPs, AR levels are increased because of gene amplification and/or overexpression, whereas in others, the AR is mutated. Nonetheless, the involvement of the AR in the transition of CaP to androgen-independent growth and the subsequent failure of endocrine therapy are not fully understood. Here we show that in CaP cells from a patient who failed androgen ablation therapy, a doubly mutated AR functioned as a high-affinity cortisol/cortisone receptor (ARccr). Cortisol, the main circulating glucocorticoid, and its metabolite, cortisone, both equally stimulate the growth of these CaP cells and increase the secretion of prostate-specific antigen in the absence of androgens. The physiological concentrations of free cortisol and total cortisone in men greatly exceed the binding affinity of the ARccr and would activate the receptor, promoting CaP cell proliferation. Our data demonstrate a previously unknown mechanism for the androgen-independent growth of advanced CaP. Understanding this mechanism and recognizing the presence of glucocorticoid-responsive AR mutants are important for the development of new forms of therapy for the treatment of this subset of CaP.

Prevalence of anemia among pregnant women and adolescent girls in 16 districts of India.

BACKGROUND: Nutritional anemia is one of India's major public health problems. The prevalence of anemia ranges from 33% to 89% among pregnant women and is more than 60% among adolescent girls. Under the anemia prevention and control program of the Government of India, iron and folic acid tablets are distributed to pregnant women, but no such program exists for adolescent girls. OBJECTIVE: To assess the status of anemia among pregnant women and adolescent girls from 16 districts of 11 states of India. METHODS: A two-stage random sampling method was used to select 30 clusters on the basis of probability proportional to size. Anemia was diagnosed by estimating the hemoglobin concentration in the blood with the use of the indirect cyanmethemoglobin method. RESULTS: The survey data showed that 84.9% of pregnant women (n = 6,923) were anemic (hemoglobin < 110 g/L); 13.1% had severe anemia (hemoglobin < 70 g/L), and 60.1% had moderate anemia (hemoglobin > or = 70 to 100 g/L). Among adolescent girls (n = 4,337)from 16 districts, the overall prevalence of anemia (defined as hemoglobin < 120 g/L) was 90.1%, with 7.1% having severe anemia (hemoglobin < 70 g/L). CONCLUSIONS: Any intervention strategy for this population must address not only the problem of iron deficiency, but also deficiencies of other micronutrients, such as B12 and folic acid and other possible causal factors.

Absorption of nicotine induces oxidative stress among bidi workers.

Chronic exposure to tobacco dust causes nasal inhalation and cutaneous absorption of tobacco alkaloids especially nicotine, therefore the considerable evidences showed that workers employed in bidi industries are at risk of cancer, lung diseases and other many health related common problems. Many references revealed that tobacco dust exposure induces mutations, damage to DNA etc. which are supposed to be the consequences of free radical generation. In present study attempt have been made to evaluate the status of oxidants and antioxidants and their relation with nicotine. 90 bidi workers were screened for serum lipid peroxide (MDA) and serum nitric oxide (NO*) as oxidant and erythrocytic-Superoxide Dismutase (RBC-SOD), Vitamin-C as antioxidant. Total antioxidant capacity (TAC) and urinary cotinine were also measured. These bidi workers were further divided in 3 groups, Group 1, 11 and III exposed to tobacco dust for about 10 to 14 yrs, 15 to 19 yrs and 20 to 24 yrs of exposure respectively. Highly significant excretion of Urinary cotinine was found in all groups of bidi workers as compared with control (p < 0.001). The levels of MDA, and NO* were found to be significantly elevated in all the three groups with progression of exposure, than the control (p < 0.001), where as the levels of RBC-SOD, Vitamin-C and TAC were significantly decreased in all the three groups as compared with controls (p < 0.001). From our findings it is evident that nicotine absorption might contribute to the disturbed oxidant and antioxidant balance leading to oxidative stress.

1alpha,25-Dihydroxyvitamin D3 down-regulates estrogen receptor abundance and suppresses estrogen actions in MCF-7 human breast cancer cells.

1alpha,25-Dihydroxyvitamin D3 [1,25(OH)2D3], the active metabolite of vitamin D, is a potent inhibitor of breast cancer cell growth. Because the estrogen receptor (ER) plays a key role in breast cancer progression, we have studied the effects of 1,25(OH)2D3 on the regulation of ER in the estrogen-responsive MCF-7 human breast cancer cell line, which is known to predominantly express ERalpha. 1,25(OH)2D3 causes significant inhibition of MCF-7 cell growth, and it also decreases the growth-stimulatory effect of 17beta-estradiol (E2). Treatment of MCF-7 cells with 1,25(OH)2D3 reduces ER levels in a dose-dependent manner, as shown by ligand binding assays and Western blot analysis. The 1,25(OH)2D3 analogues EB-1089, KH-1060, Ro 27-0574, and Ro 23-7553 are more potent than 1,25(OH)2D3 in both their antiproliferative actions as well as ER down-regulation. There is a striking correlation (R2 = 0.98) between the growth-inhibitory actions of 1,25(OH)2D3 or analogues and their ability to down-regulate ER levels. Treatment with 1,25(OH)2D3 shows that the reduction in ER is accompanied by a significant decrease in the steady-state levels of ER mRNA. The decrease in ER mRNA is not abolished by the protein synthesis inhibitor cycloheximide. Inhibition of mRNA synthesis with actinomycin D reveals no significant differences between ER mRNA half-life in control and 1,25(OH)2D3-treated cells. Nuclear run-on experiments demonstrate significant decreases in ER gene transcription at the end of 17 h of treatment with 1,25(OH)2D3. These findings indicate that 1,25(OH)2D3 exerts a direct negative effect on ER gene transcription. Coincident with the decrease in ER levels there is an attenuation of E2-mediated bioresponses after 1,25(OH)2D3 treatment. Induction of progesterone receptor by E2 is suppressed by 1,25(OH)2D3, and the E2-mediated increase in breast cancer susceptibility gene (BRCA1) protein is reduced by 1,25(OH)2D3 treatment. Overall, these results suggest that the antiproliferative effects of 1,25(OH)2D3 and its analogues on MCF-7 cells could partially be mediated through their action to down-regulate ER levels and thereby attenuate estrogenic bioresponses, including breast cancer cell growth.

Effect of variations in dietary fat and carbohydrate intake on postprandial lipemia in patients with noninsulin dependent diabetes mellitus.

The effect of dietary composition on concentrations of postprandial lipoproteins was studied in eight sulfonylurea-treated patients with noninsulin dependent diabetes mellitus. Two diets were consumed by each patient for 2 weeks in random order, one contained (as percent of total calories) 15% protein, 40% fat, and 45% carbohydrate (CHO), whereas the other consisted of 15% protein, 25% fat, and 60% CHO. At the end of each dietary period, patients were given Vitamin A (60,000 U/m2) with their noon meal, and the concentration of triglyceride (TG) and retinyl esters in plasma and two lipoprotein fractions (Sf > 400 and Sf 20-400) determined over the next 12 h. The results indicated that both postprandial TG and retinyl ester concentrations were higher in plasma (Sf > 400, and Sf 20-400 lipoproteins), when patients ate the 25% fat/60% CHO diet. Thus, replacing saturated fat with CHO accentuates the magnitude of postprandial lipemia. Since TG-rich lipoproteins may be atherogenic, appropriate dietary advice for patients with type 2 diabetes may deserve reappraisal.

Differences in postprandial lipemia between patients with normal glucose tolerance and noninsulin-dependent diabetes mellitus.

In this paper we have compared the postprandial increase in triglyceride (TG) rich lipoproteins of intestinal origin in 10 patients with noninsulin-dependent diabetes mellitus (NIDDM) and 10 subjects with normal glucose tolerance. The two groups were matched for age, sex distribution, body mass index, and plasma TG concentration. Breakfast was consumed at 0800 h and lunch at 1200 h, at which time vitamin A was also administered. Blood was sampled frequently from 1200 h to 2400 h, and measurements made of glucose, insulin, and TG concentrations. Furthermore, the retinyl palmitate (RP) content of plasma, the Sf > 400 lipoprotein fraction, and the Sf 20-400 lipoprotein fraction was also determined, and differences compared by two-way analysis of variance. Fasting and postprandial (from 1200 h to 2400 h) TG concentrations in the plasma and the two lipoprotein fractions were not significantly different in normal subjects and patients with NIDDM. In addition, the postprandial RP concentration of the two groups was not different in the chylomicron containing Sf > 400 lipoprotein fraction. However, the postprandial Sf 20-400 RP concentration was significantly higher (P < 0.001) in patients with NIDDM, estimated as hourly values over time, peak value, or total integrated response area. Significant correlation coefficients (r = 0.60-0.75, P < 0.08 < 0.02) were seen in patients with NIDDM between the total integrated insulin response and both the TG and RP responses in the Sf > 400 and Sf 20-400 fractions. In addition, fasting high density lipoprotein-cholesterol concentration in patients with NIDDM was significantly correlated with the postprandial TG response in the Sf > 400 (r = -0.64, P < 0.05) and the Sf 20-400 (r = -0.68, P < 0.05) lipoprotein fractions. In summary, the postprandial RP concentration in the Sf 20-400 lipoprotein fraction was higher than normal in patients with NIDDM. In addition, associations have been defined in patients with NIDDM between postprandial insulin response, fasting TG and high density lipoprotein-cholesterol concentrations, and magnitude of postprandial increase in TG-rich lipoproteins of intestinal origin.

A new enzyme-linked immunosorbant assay for the measurement of human vitamin D receptor.

The hormonal actions of 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] are mediated by its cognate receptor protein, the vitamin D receptor (VDR). Despite the growing importance of the VDR system as a modulator of cell growth and differentiation, convenient assays for quantitative measurement of VDR are not readily available, and [(3)H]1,25(OH)(2)D(3) ligand binding assays remain the standard method. In this paper, we present data to validate and characterize the usefulness of a new VDR enzyme-linked immunosorbant assay (ELISA) kit developed for the measurement of VDR in biological samples. In this assay, samples are added to microtitration wells coated with anti-VDR antibody and incubated with a second anti-VDR antibody that is biotinylated. The antibody receptor complex is then detected with streptavidin-labeled horseradish peroxidase followed by incubation with a chromogenic substrate, tetramethylbenzidine. The assay was found to be sensitive and accurate for measurements of VDR and compared favorably with the conventional radioligand binding assay (RBA). The interassay variation ranged from 5% to 25% and the intraassay variation was less than 5%. The ELISA presents several advantages over existing methodology, including the use of nonradioactive detection systems, lower protein and sample volume requirements, as well as convenience and speed. The assay can be completed in as short a time as 3 h, avoiding overnight incubations. Data are also presented to demonstrate the ability of the ELISA to detect both occupied and unoccupied VDR, making it a valuable research tool in settings where 1,25(OH)(2)D(3) is present. However, the ELISA, as currently formulated, is only useful for the detection of human VDR.

Estradiol inhibits glucocorticoid receptor expression and induces glucocorticoid resistance in MCF-7 human breast cancer cells.

Our study has shown that treatment of MCF-7 human breast cancer cells with 17-beta estradiol (E(2)) produced significant decreases in glucocorticoid receptor (GR) concentrations and GR mRNA levels. E(2) pre-treatment of MCF-7 cells stably transfected with the GR responsive pMTV-CAT reporter (MCF-7-MTV cells), caused significant attenuation of dexamethasone (DEX)-induced chloramphenicol acetyl transferase (CAT). In MCF-7 cells transiently transfected with [(GRE)(3)-Luc] reporter plasmid, E(2) pre-treatment significantly suppressed DEX-induced luciferase, which was abolished by the estrogen receptor antagonist ICI 182,780. We examined the effect of chronic E(2) treatment as well as E(2) withdrawal on GR function and abundance. MCF-7-MTV cells were treated with vehicle (control) or E(2) for up to 16 days. A third group received E(2) for 5 days followed by E(2) withdrawal from day 6 to 16. Chronic E(2) treatment almost totally abrogated DEX-induced CAT and reduced GR to very low levels. Interestingly, in the group subjected to E(2) withdrawal, neither the DEX response nor GR abundance recovered and reached control values suggesting that the estrogen mediated suppression is long lasting and could not be easily reversed. The E(2) induced resistance to glucocorticoid action may be of potential clinical significance in a number of settings including breast cancer, neuroendocrine response to stress and osteoporosis and could possibly contribute to the differences in glucocorticoid responsiveness among patients.

Urge incontinence.

This article discusses the management of patients presenting with urge incontinence as the main symptom. The etiological factors, though not understood completely, are grouped into logical subsets and discussed. The incidence and the implications of urge incontinence on the quality of life of patients is considered. A summary of available treatment methods is presented in an algorithm.

Human immunodeficiency virus (HIV)-related risk-taking behaviors in women attending inner-city prenatal clinics in the mid-west.

OBJECTIVE: Federal guidelines recommend the provision of human immunodeficiency virus education to all attendees of prenatal clinics. The current study was conducted to assess risk-taking behaviors among urban women voluntarily pursuing prenatal care. DESIGN AND SETTING: African American women attending urban prenatal clinics in Cleveland, Ohio were subjected to an extensive interview before receiving an experimental AIDS education curriculum. The interview sought detailed information regarding demographics, lifetime and recent sexual activity, condom use, and lifetime and recent illicit drug use. RESULTS: A total of 1017 women were interviewed; of those women, approximately 73% were single. The majority had a monthly income of less than $500. A total of 66% had only one partner in the past year, and almost 90% had < or = 1 partner in the past 6 months. A total of 98% identified a main partner. Nearly all subjects were at least fairly certain that this partner did not use intravenous drugs, and 71% were at least fairly certain that he was monogamous. Only 19% used condoms most or all the time. Intravenous drug use among study subjects was very infrequent. CONCLUSION: These data indicate that inner-city Cleveland women seeking prenatal care are largely monogamous around the time of their gestation, and that a history of intravenous drug use is infrequent. They suggest that prenatal counseling in urban clinics will need to address women who largely are engaged in single-partner relationships at the time of the intervention.

Rates and appropriateness of antimicrobial prescribing at an academic children's hospital, 2007-2010.

OBJECTIVE AND DESIGN: Antimicrobial use in hospitalized children has not been well described. To identify targets for antimicrobial stewardship interventions, we retrospectively examined pediatric utilization rates for 48 antimicrobials from 2007 to 2010 as well as appropriateness of vancomycin and cefepime use in 2010. PATIENTS AND SETTING: All children hospitalized between 2007 and 2010 at the Mayo Clinic Children's Hospital, a 120-bed facility within a larger adult hospital in Rochester, Minnesota. METHODS: We calculated antimicrobial utilization rates in days of therapy per 1,000 patient-days. Details of vancomycin and cefepime use in 2010 were abstracted by chart review. Two pediatric infectious disease physicians independently assessed appropriateness of antibiotic use. RESULTS: From 2007 to 2010, 9,880 of 17,242 (57%) hospitalized children received 1 or more antimicrobials. Antimicrobials (days of therapy per 1,000 patient-days) used most frequently in 2010 were cefazolin (97.8), vancomycin (97.1), fluconazole (76.4), piperacillin-tazobactam (70.7), and cefepime (67.6). Utilization rates increased significantly from 2007 to 2010 for 10 antimicrobials, including vancomycin, fluconazole, piperacillin-tazobactam, cefepime, trimethoprim-sulfamethoxazole, caspofungin, and cefotaxime. In 2010, inappropriate use of vancomycin and cefepime was greater in the pediatric intensive care unit than ward (vancomycin: 17.8% vs 6.4%, P = .001; cefepime: 9.2% vs 3.9%, P = .142) and on surgical versus medical services (vancomycin: 20.5% vs 8.0%, P = .001; cefepime: 19.4% vs 3.4%, P ≤ .001). The most common reason for inappropriate antibiotic use was failure to discontinue or de-escalate therapy. CONCLUSIONS: In our children's hospital, use of 10 antimicrobials increased during the study period. Inappropriate use of vancomycin and cefepime was greatest on the critical care and surgical services, largely as a result of failure to de-escalate therapy, suggesting targets for future antimicrobial stewardship interventions.

The pitfalls of protocols - a case of postpartum splenic artery aneurysm rupture.

The authors present a case of splenic artery aneurysm rupture, which neatly illustrates some of the problems of modern medical practice and the potential detriment of blind adherence to protocol driven care, without adequate reflection on the whole clinical picture and possible alternative diagnoses.

Synchronous resections of intra-abdominal pathologies during radical nephrectomy. A case-linked cohort study evaluation of outcomes.

OBJECTIVES: We report the outcomes of radical nephrectomy with synchronous surgical resection of intra-abdominal pathologies to guide practice. PATIENTS AND METHODS: The data of patients requiring radical nephrectomy and surgical resection of a synchronous intra-abdominal pathology over a period of 12 years was extracted on pre-designed data extraction sheets from the case notes and included: age, sex, nature of second intra-abdominal pathology, intra-operative and postoperative details including complications, recurrence rate and survival on follow-up. RESULTS: Two hundred and ninety patients underwent radical nephrectomy for non-metastatic renal cell carcinoma between January 1995 and January 2007. Amongst these, 30 patients (12%) had an additional surgical resection of a second intra-abdominal pathology at the time of radical nephrectomy. Fifteen underwent radical nephrectomy and surgical resection of a second intra-abdominal non-urological malignancy: colonic tumour - 8, rectal tumour - 3, oesophageal tumour - 2 and gastric tumour - 2. Fifteen patients underwent radical nephrectomy and surgical resection of a synchronous benign intra-abdominal pathology: gall bladder - 8, spleen - 3, uterine fibroid - 1, abdominal aortic aneurysm - 1, colonic polyp - 1 and suspected tumour infiltration of colon - 1. There was a higher morbidity (40%) of radical nephrectomy with synchronous resection of an additional intra-abdominal pathology as compared to radical nephrectomy alone group (25%); however it not was statistically significant (P-value 0.275). CONCLUSION: It is feasible to offer simultaneous resection of synchronous intra-abdominal pathologies with renal cell carcinoma patients undergoing radical nephrectomy, albeit, at a higher morbidity.