Perinatal exposure to the fungicide prochloraz feminizes the male rat offspring.

Prochloraz is a commonly used fungicide that has shown multiple mechanisms of action in vitro. It antagonizes the androgen and the estrogen receptors, agonizes the Ah receptor, and inhibits aromatase activity. In vivo prochloraz acts antiandrogenically in the Hershberger assay by reducing weights of reproductive organs, affecting androgen-regulated gene expressions, and increasing luteinizing hormone (LH) levels. The purpose of this study was to investigate reproductive toxic effects after exposure during gestation and lactation to prochloraz alone and a mixture of five pesticides (deltamethrin, methiocarb, prochloraz, simazine, and tribenuron-methyl). Prochloraz (30 mg/kg/day) or the mixture (20 mg/kg/day) was dosed to pregnant Wistar dams from gestational day (GD) 7 until postnatal day (PND) 16. Some dams were taken for cesarean section at GD 21, and others were allowed to give birth. Results showed that prochloraz and the mixture significantly reduced plasma and testicular testosterone levels in GD 21 male fetuses, whereas testicular progesterone was increased. Gestational length was increased by prochloraz. Chemical analysis of the rat breast milk showed that prochloraz was transferred to the milk. In males a significant increase of nipple retention was found, and the bulbourethral gland weight was decreased, whereas other reproductive organs were unaffected. In addition cytochrome P450 (CYP)1A activities in livers were induced by prochloraz, possibly as a result of Ah receptor activation. Behavioral studies showed that the activity level and sweet preference of adult males were significantly increased. Overall these results strongly indicate that prochloraz feminizes the male offspring after perinatal exposure, and that these effects are due, at least in part, to diminished fetal steroidogenesis.     

Comparison of the ECST, CC, and NASCET grading methods and ultrasound for assessing carotid stenosis

We compared three angiographic methods for grading of carotid stenosis and examined the correlation between angiographic and ultrasound findings. Two observers independently measured 111 carotid stenoses on arteriographic films of 84 patients. The stenoses were graded according to the European Carotid Surgery Trial (ECST), North American Symptomatic Carotid Endarterectomy Trial (NASCET), and Common Carotid (CC) methods. The results obtained by these methods were compared, and the interobserver reproducibility of the measurements was calculated. In addition, all angiographic results were compared to ultrasound findings obtained before angiography. Measurements using the CC method were the most reproducible and those using the NASCET method the least. The NASCET method underestimated the degree of stenosis compared to the other methods. The ECST and CC methods yielded almost identical results (97% agreement). Ultrasound provided an accuracy of 94% compared to ECST and CC methods and 84% compared to the NASCET method. Interobserver reproducibility of angiographic quantification of carotid stenoses was best for the CC and ECST methods and least for the NASCET method. Ultrasound demonstrated better accuracy than the ECST and CC methods. Received: 7 April 1999/Received in revised form: 5 October 1999/Accepted: 11 April 2000     

Overexpression of the cytochrome p450 activator hpr6 (heme-1 domain protein/human progesterone receptor) in tumors.

OBJECTIVE: Hpr6 (heme-1 domain protein/human progesterone receptor) is one of a family of proteins that are implicated in progesterone metabolism, resistance to genotoxic agents and steroid biosynthesis. Because these processes are frequently misregulated in tumors, we have examined the expression of Hpr6 in a group of clinical tumor samples and cancer cell lines. METHODS: Hpr6 expression was analyzed by Western blot in extracts from breast, cervix, colon and thyroid cell lines and in nonmalignant and adjacent tumor tissue from breast, colon and thyroid. Hpr6 localization was determined by immunofluorescence. RESULTS: Hpr6 expression is significantly elevated in breast tumors in comparison with matched nonmalignant tissue and demonstrated limited overexpression in colon and thyroid tumors. Hpr6 is strongly expressed in a panel of tumor cell lines originating from breast, thyroid and colon. Hpr6 localizes to the perinuclear region of the cell, consistent with a role in cell detoxification, signaling and/or sterol synthesis. CONCLUSIONS: Hpr6 homologues regulate cytochrome P450 proteins implicated in hormone, steroid and xenobiotic chemical metabolism. These are the first studies linking Hpr6 expression to cancer progression and cellular survival. Our results suggest that Hpr6 is an important marker for cancer progression and a potential anticancer therapeutic target.     

Stem cell therapy with skeletal myoblasts accelerates neointima formation in a mouse model of vein graft disease

Although still a matter of controversial discussion, skeletal myoblasts are one of the options for stem cell transplantation improving cardiac function after myocardial infarction, exhibiting several advantages including the availability, the ability of self-renewal and differentiation, and the lack of ethical and immunological problems. The aim of this study was to investigate the impact of stem cell therapy with skeletal myoblasts on experimental venous bypass grafts in a mouse model of vein graft disease.Forty C57BL/6J mice underwent bypass grafting interposing a venous bypass graft of the donor mouse into the carotid artery of the recipient mouse.Twenty mice received periadventitially treatment with 1 million fluorescence labeled skeletal myoblasts suspended in culture medium (treatment group), the other twenty mice received only culture medium without myoblasts (control group).Two weeks after bypass surgery, the vein grafts of all 40 mice were harvested, stained and histologically investigated under light and immunofluorescence microscope.Against our expectations, skeletal myoblasts stayed in place and were still located in the adventitia after bypass grafting. Additionally, vein grafts of the myoblast group revealed a 2fold increased neoneointima formation, a decreased media thickness, a slightly increased neovascularization, a higher percentage of reendothelialization and also a slightly higher percentage of PDGFR ɑ, PDGFR ß, MMP-7 and MMP-9 positive cells, suggesting a paracrine mechanism responsible for accelerated neointima formation.In conclusion, the results of our study do not support the use of skeletal myoblast for the treatment of vein graft disease after coronary artery bypass surgery.     

Extended cortical activations during evaluating successive pain stimuli

Comparing pain is done in daily life and involves short-term memorizing and attention focusing. This event-related functional magnetic resonance imaging study investigated the short-term brain activations associated with the comparison of pain stimuli using a delayed discrimination paradigm. Fourteen healthy young volunteers compared two successive pain stimuli administered at a 10 s interval to the same location at the nasal mucosa. Fourteen age- and sex-matched subjects received similar pain stimuli without performing the comparison task. With the comparison task, the activations associated with the second pain stimulus were significantly greater than with the first stimulus in the anterior insular cortex and the primary somatosensory area. This was observed on the background of a generally increased stimulus-associated brain activation in the presence of the comparison task that included regions of the pain matrix (insular cortex, primary and secondary somatosensory area, midcingulate cortex, supplemental motor area) and regions associated with attention, decision making, working memory and body recognition (frontal and temporal gyri, inferior parietal lobule, precuneus, lingual cortices). This data provides a cerebral correlate for the role of pain as a biological alerting system that gains the subject''s attention and then dominates most other perceptions and activities involving pain-specific and non-pain-specific brain regions.     

A note on calculating asymptotic confidence intervals for the adjusted risk difference and number needed to treat in the Cox regression model

Recently, Laubender and Bender (Stat. Med. 2010; 29: 851–859) applied the average risk difference (RD) approach to estimate adjusted RD and corresponding number needed to treat measures in the Cox proportional hazards model. We calculated standard errors and confidence intervals by using bootstrap techniques. In this paper, we develop asymptotic variance estimates of the adjusted RD measures and corresponding asymptotic confidence intervals within the counting process theory and evaluated them in a simulation study. We illustrate the use of the asymptotic confidence intervals by means of data of the Düsseldorf Obesity Mortality Study. Copyright © 2013 John Wiley & Sons, Ltd.     

Pulmonary Atresia with Ventricular Septal Defect and Multifocal Pulmonary Blood Supply: Does an Intensive Interventional Approach Improve the Outcome?

Introduction. Pulmonary atresia with ventricular septal defect (VSD) continues to be associated with significant morbidity and mortality, with significant institutional variation in therapeutic strategies. This study reports a single center experience utilizing an intensive transcatheter approach to promote pulmonary vascular growth. Methods. A retrospective analysis of 20 patients undergoing surgical and transcatheter treatment for pulmonary atresia with VSD between 2002 and 2010. Results. The median age at initial surgical palliation was 6.3 months (8 days to 2.5 years). Eleven patients (group 1) underwent initial surgical palliation without VSD closure and nine patients (group 2) underwent an initial complete repair with fenestrated or complete VSD closure. Group 1 had a smaller Nakata index (54 mm²/m² vs. 134 mm²/m², P= .04) and a smaller absolute native pulmonary artery diameter (2.7 mm vs. 4.5 mm, P= .01) than group 2. Intraoperative angiography was performed in 10 cases to evaluate if early transcatheter intervention was warranted. The median follow‐up during the study period was 2.3 years (1.6 months to 8.3 years). Of the 16 patients who survived the initial early postoperative period, 15 patients (94%) went on to receive surgical (n = 11) and/or interventional (n = 25) catheterization procedures. There was improvement in the mean Nakata index from the initial presurgical evaluation to the most recent catheterization data (38.4 mm²/m² vs. 169.7 mm²/m², P≤ .05). To date, two of 11 (18%) patients in group 1 ultimately underwent surgical VSD closure. Overall mortality was six of 20 (30%) with four deaths in group 1 and two deaths in group 2. There were no procedural deaths. Conclusions. Combining surgical unifocalization procedures with subsequent early and intensive catheter‐based pulmonary artery rehabilitation may improve vascular growth, ultimately rendering many patients suitable for fenestrated VSD closure. Risk stratification, including intraoperative exit angiography, is essential to determine the need for early transcatheter interventions.