bluuebunny/crossref_metadata_2025 huggingface dataset:
Regeneration of dopaminergic neurons after 6‐hydroxydopamine‐induced lesion in planarian brain
Authors: Nishimura Kaneyasu , Inoue Takeshi , Yoshimoto Kanji , Taniguchi Takashi , Kitamura Yoshihisa , Agata Kiyokazu
Published: October 2011

J. Neurochem. (2011) 10.1111/j.1471‐4159.2011.07518.x

Planarians have robust regenerative ability dependent on X‐ray‐sensitive pluripotent stem cells, called neoblasts. Here, we report that planarians can regenerate dopaminergic neurons after selective degeneration of these neurons caused by treatment with a dopaminergic neurotoxin (6‐hydroxydopamine; 6‐OHDA). This suggests that planarians have a system to sense the degeneration of dopaminergic neurons and to recruit stem cells to produce dopaminergic neurons to recover brain morphology and function. We confirmed that X‐ray‐irradiated planarians do not regenerate brain dopaminergic neurons after 6‐OHDA‐induced lesioning, suggesting that newly generated dopaminergic neurons are indeed derived from pluripotent stem cells. However, we found that the majority of regenerated dopaminergic neurons were 5‐bromo‐2′‐deoxyuridine‐negative cells. Therefore, we carefully analyzed when proliferating stem cells became committed to become dopaminergic neurons during regeneration by a combination of 5‐bromo‐2′‐deoxyuridine pulse‐chase experiments, immunostaining/in situ hybridization, and 5‐fluorouracil treatment. The results strongly suggested that G2‐phase stem cells become committed to dopaminergic neurons in the mesenchymal space around the brain, after migration from the trunk region following S‐phase. These new findings obtained from planarian regeneration provide hints about how to conduct cell‐transplantation therapy for future regenerative medicine.
Ethanol increases p190RhoGAP activity, leading to actin cytoskeleton rearrangements
Authors: Selva Javier , Egea Gustavo
Published: October 2011

J. Neurochem. (2011) 10.1111/j.1471‐4159.2011.07522.x

We previously reported that cells chronically exposed to ethanol show alterations in actin cytoskeleton organization and dynamics in primary cultures of newborn rat astrocytes, a well‐established in vitro model for foetal alcohol spectrum disorders. These alterations were attributed to a decrease in the cellular levels of active RhoA (RhoA‐GTP), which in turn was produced by an increase in the total RhoGAP activity. We here provide evidence that p190RhoGAPs are the main factors responsible for such increase. Thus, in astrocytes chronically exposed to ethanol we observe: (i) an increase in p190A‐ and p190B‐associated RhoGAP activity; (ii) a higher binding of p190A and p190B to RhoA‐GTP; (iii) a higher p120RasGAP‐p190A RhoGAP complex formation; and (iv) the recruitment of both p190RhoGAPs to the plasma membrane. The simultaneous silencing of both p190 isoforms prevents the actin rearrangements and the total RhoGAP activity increase triggered both by ethanol. Therefore, our data directly points p190RhoGAPs as ethanol‐exposure molecular targets on glial cells of the CNS.
Occupying Newcastle University: student resistance to government spending cuts in England
Authors: HOPKINS PETER , TODD LIZ , OCCUPATION NEWCASTLE
Published: October 2011

In November and December 2010, students across the UK organised and participated in protests against government spending cuts and, in particular, proposals to change how higher education is funded in England. These changes mean that universities in England can charge up to £9000 every year in tuition fees to each student as a result of their funding from the government – through the Higher Education Funding Council for England (HEFCE) – being completely withdrawn. In this commentary, we document the actions of students involved in the Newcastle Occupation and explore how they claimed space, adopted an alternative governance structure and utilised cyberspace in an attempt to foster social and political change.
In vitro evaluation of the efficacy of a veterinary dry heat fluid warmer
Authors: Chiang Vivian , Hopper Kate , Mellema Matthew S.
Published: October 2011

Objectives

To evaluate the efficacy of a veterinary dry heat fluid warmer on ambient and prewarmed crystalloid fluids and refrigerated packed red blood cells (pRBC).

Design

Prospective in vitro study.

Setting

University teaching hospital.

Animals

None.

Interventions

Ambient and prewarmed crystalloid fluids and refrigerated pRBC were delivered via a standard fluid administration set at various rates. A thermistor continuously monitored fluid outflow temperature with and without a dry heat veterinary fluid warmer (study device).

Results

The outflow temperature was significantly higher with the study device as compared to control conditions for all fluids and rates tested. The maximum outflow temperature of approximately 35°C (95°F) occurred when the study device was applied to either ambient or prewarmed crystalloid fluids at 50 mL/h. In the study device trials, the outflow temperature of ambient crystalloid fluids ranged from 35.1° to 27.3°C (95.2° to 81.1°F) as the fluid rate increased from 50 to 999 mL/h. Control trials of prewarmed crystalloids produced outflow temperatures that rapidly approached ambient temperature. Addition of the study device to prewarmed crystalloids resulted in outflow temperatures that were similar to that of the corresponding ambient crystalloid trials. Control trials of refrigerated pRBC achieved ambient temperature at rates from 10 to 500 mL/h. With the study device, pRBC were maximally warmed to an outflow temperature of 35.8°C (96.4°F) at 100 mL/h.

Conclusion

Although the study device generated statistically significant increases in outflow temperature of crystalloid fluids and pRBC, the ability of the device to decrease the metabolic cost of fluid administration is limited to specific clinical scenarios. The use of prewarmed crystalloid fluids with or without the study device offers minimal benefit over ambient temperature crystalloids. Substantial warming of pRBC occurs during administration, even without use of the study device.
VARIATION IN ANATOMICAL AND MATERIAL PROPERTIES EXPLAINS DIFFERENCES IN HYDRODYNAMIC PERFORMANCES OF FOLIOSE RED MACROALGAE (RHODOPHYTA)1
Authors: Demes Kyle W. , Carrington Emily , Gosline John , Martone Patrick T.
Published: October 2011

Over the last two decades, many studies on functional morphology have suggested that material properties of seaweed tissues may influence their fitness. Because hydrodynamic forces are likely the largest source of mortality for seaweeds in high wave energy environments, tissues with material properties that behave favorably in these environments are likely to be selected for. However, it is very difficult to disentangle the effects of materials properties on seaweed performance because size, shape, and habitat also influence mechanical and hydrodynamic performance. In this study, anatomical and material properties of 16 species of foliose red macroalgae were determined, and their effects on hydrodynamic performance were measured in laboratory experiments holding size and shape constant. We determined that increased blade thickness (primarily caused by the addition of medullary tissue) results in higher flexural stiffness (EI), which inhibits the seaweed’s ability to reconfigure in flowing water and thereby increases drag. However, this increase is concurrent with an increase in the force required to break tissue, possibly offsetting any risk of failure. Additionally, while increased nonpigmented medullary cells may pose a higher metabolic cost to the seaweed, decreased reconfiguration causes thicker tissues to expose more photosynthetic surface area incident to ambient light in flowing water, potentially ameliorating the metabolic cost of producing these cells. Material properties can result in differential performance of morphologically similar species. Future studies on ecomechanics of seaweeds in wave‐swept coastal habitats should consider the interaction of multiple trade‐offs.
Blood transfusion utilization and recipient survival at Hospital das Clinicas in São Paulo, Brazil
Authors: Goncalez Thelma T. , Sabino Ester C. , Capuani Ligia , Liu Jing , Wright David J. , Walsh Judy H. , Ferreira Joao E. , Chamone Dalton A. , Busch Michael P. , Custer Brian ,   for the NHLBI Retrovirus Epidemiology Donor Study‐II (REDS‐II) and International Component
Published: October 2011

BACKGROUND: The characteristics of blood recipients including diagnoses associated with transfusion and posttransfusion survival are unreported in Brazil. The goals of this analysis were: 1) to describe blood utilization according to clinical diagnoses and patient characteristics and 2) to determine the factors associated with survival of blood recipients.

STUDY DESIGN AND METHODS: A retrospective cross‐sectional analysis was conducted on all inpatients in 2004. Data came from three sources: The first two files consist of data about patient characteristics, clinical diagnosis, and transfusion. Analyses comparing transfused and nontransfused patients were conducted. The third file was used to determine survival recipients up to 3 years after transfusion. Logistic regression was conducted among transfused patients to examine characteristics associated with survival.

RESULTS: In 2004, a total of 30,779 patients were admitted, with 3835 (12.4%) transfused. These patients had 10,479 transfusions episodes, consisting of 39,561 transfused components: 16,748 (42%) red blood cells, 15,828 (40%) platelets (PLTs), and 6190 (16%) plasma. The median number of components transfused was three (range, 1‐656) per patient admission. Mortality during hospitalization was different for patients whose admissions included transfusion or not (24% vs. 4%). After 1 year, 56% of transfusion recipients were alive. The multivariable model of factors associated with mortality after transfusion showed that the most significant factors in descending order were hospital ward, increasing age, increasing number of components transfused, and type of components received.

CONCLUSION: Ward and transfusion are markers of underlying medical conditions and are associated with the probability of survival. PLT transfusions are common and likely reflect the types of patients treated. This comprehensive blood utilization study, the first of its kind in Brazil, can help in developing transfusion policy analyses in South America.
Envisioning Emerging Nanotechnologies: A Three‐Year Panel Study of South Carolina Citizens
Authors: Priest Susanna , Lane Thomas , Greenhalgh Ted , Hand Lindsey Jo , Kramer Victoria
Published: October 2011

This article reports results from a three‐year panel study of a nonrandom sample of 76 South Carolina citizens, recruited from a variety of walks of life, and their impressions of emerging nanotechnology. This discussion focuses on material from depth interviews conducted alongside a baseline opinion and awareness inventory at the beginning of the study, the most intensive data‐gathering phase. These results are placed in the context of data from three additional surveys conducted at about equal intervals over the three years, plus exit interviews from 21 of the 34 individuals who completed the entire study. The results give insight into popular thinking about technology but little indication of strong emerging concerns, a trajectory of amplification of those concerns, or opinion polarization over time, despite some awareness of risks and potential ethical dimensions. Nanotechnology may stand out more as an example of risk attenuation than of risk amplification, consistent with most results from national surveys.
Fluoroscopically Guided Transesophageal Echocardiogram in a Patient with Esophageal Stents
Authors: Daher Iyad N. , Queen Saulette , Banchs Jose
Published: October 2011

A 73‐year‐old man with history of coronary artery disease and bypass surgery, atrial fibrillation, and left lower lobe non–small cell lung cancer was admitted with recurrent pneumonia and was referred for transesophageal echocardiogram for suspected aortic valve endocarditis by transthoracic echocardiography. The patient had a history of radiation treatment for lung cancer 6 years ago. He had subsequently developed esophageal strictures requiring repeated dilatations, and eventually repeated esophageal stenting. Recurrent aspiration pneumonia led to the discovery of stent erosion into his trachea leading to tracheoesophageal fistula. A covered Y tracheal stent was placed to close the fistulous tract, but persistent aspiration was noted. The cross‐sectional diameter of the esophageal stents was determined to be larger than the transesophageal echocardiography (TEE) probe. TEE was performed under fluoroscopy for added safety. The esophageal stent position was confirmed with fluoroscopy before and after the procedure and the TEE probe remained inside the distal stent in the midesophageal position during the entire procedure. Small mobile vegetation was seen on the right coronary cusp and the noncoronary cusp showed a smaller vegetation. The patient tolerated the procedure well and there were no complications. Infectious disease consultation was obtained and antibiotic regimen was modified accordingly. Although there are studies addressing the safety of TEE in patients with esophageal varices, to our knowledge, there is no report of TEE being performed in patients with esophageal or tracheoesophageal stents. This case illustrates that TEE may be performed in patients with esophageal stents under careful fluoroscopic guidance. (Echocardiography 2012;29:E5‐E7)
Incremental Value of Three‐Dimensional Transesophageal Echocardiography in a Patient with Parachute Mitral Valve
Authors: Demirkol Sait , Baysan Oben , Celik Turgay , Kurt Ibrahim Halil , Kucuk Ugur , Balta Sevket
Published: October 2011

(Echocardiography 2012;29:E24‐E25)
Bivalirudin Used as Alternative Anticoagulant in Carotid Artery Stenting: A Single Center Observational Study
Authors: GEISBÜSCH PHILIPP , KATZEN BARRY T. , PEÑA CONSTANTINO , BENENATI JAMES F. , UTHOFF HEIKO
Published: October 2011

Purpose:
 To analyze and report the safety and effectiveness of bivalirudin in a large patient population undergoing carotid artery stenting (CAS).

Methods:
 Between January 2001 and November 2010 extracranial CAS was performed in 272 patients in our institution. These patients were stratified according to the anticoagulant used during the CAS procedure into 2 groups (bivalirudin n = 217 vs. unfractionated heparin [UFH] n = 55) and analyzed regarding bleeding complications and periprocedural (within 30 days) stroke and myocardial infarction (MI) rates.

Results:
 The combined end‐point of death, stroke, and MI occurred in 12 patients (4.4%) with no significant difference between the groups (bivalirudin 4.6% vs. UFH 3.6% P value 0.96). Stroke rates were 1.8% in the bivalirudin and 1.8% in the UFH group (P value 1.00), with 4/5 strokes being nondisabling. Periprocedural MI was observed in 7 patients (2.1%) with no significant differences between the groups (bivalirudin 2.7% vs. UFH 1.8%, P value 0.94). Bleeding complications occurred in 13/272 patients (4.7%) with no significant difference between the groups (bivalirudin 3.6% vs. UFH 9.0%, P value 0.15). The first activated clotting time after administration of the anticoagulants was therapeutic in 209/217 (96%) in the bivalirudin group and in 30/55 (55%) in the UFH group (P < 0.001).

Conclusions:
 In this single‐center study, bivalirudin was a safe and efficient anticoagulation strategy for CAS and could be considered a therapeutic alternative to UFH. (J Interven Cardiol 2012;25:197–202)
Spotlight Issue: Microcirculation—From a Clinical Perspective
Authors: CLOUGH GERALDINE , CRACOWSKI JEAN‐LUC
Published: October 2011

Please cite this paper as: Clough and Cracowski (2012). Spotlight Issue: Microcirculation––From a Clinical Perspective. Microcirculation 19(1), 1–4

This spotlight issue of Microcirculation contains five articles written from a clinical perspective on the role of microcirculatory abnormalities in the pathogenesis of cardiovascular disease. The reviews address issues such as the impact of modifiable (lifestyle and environmental risk factors) and non modifiable (age) on microvascular form and function; inter‐ and intra‐cell signaling pathways underlying microvascular dysfunction; microvascular assessment as a prognostic tool in clinical practice; and the potential impact of targeted therapeutic intervention on microvascular health. The articles also describe and evaluate methodological approaches to the assessment of microvascular function in organs such as the skin, retina, muscle and adipose tissue, and provide a perspective on how such approaches might be employed in future in disease risk stratification in large epidemiological studies. This timely edition of the journal Microcirculation highlights that while there is currently no identified unifying mechanism to explain the association between microvascular phenotype and susceptibility to disease, there is accumulating evidence that deficits in microvascular structure and function may be an early and important prodromal indicator and risk determinant in a wide range of chronic non‐communicable disorders, including cardiovascular and metabolic disease.
Sustained Decrease and Remarkable Increase in Red Blood Cell Velocity in Intraparenchymal Capillaries Associated With Potassium‐Induced Cortical Spreading Depression
Authors: UNEKAWA MIYUKI , TOMITA MINORU , TOMITA YUTAKA , TORIUMI HARUKI , SUZUKI NORIHIRO
Published: October 2011

Please cite this paper as: Unekawa M, Tomita M, Tomita Y, Toriumi H and Suzuki N. Sustained Decrease and Remarkable Increase in Red Blood Cell Velocity in Intraparenchymal Capillaries Associated With Potassium‐Induced Cortical Spreading Depression. Microcirculation 19: 166–174, 2012.

Objectives:  To examine changes in red blood cell (RBC) velocity in intraparenchymal capillaries of rat cerebral cortex in response to KCl‐induced cortical spreading depression (CSD).

Methods:  In isoflurane‐anesthetized rats, the velocity of fluorescently labeled RBCs flowing in capillaries in layer I was measured with a high‐speed camera laser‐scanning confocal fluorescence microscope, with simultaneous monitoring of DC potential, the electroencephalogram (EEG), partial pressure of oxygen (PO2), and cerebral blood flow (CBF).

Results:  After KCl application, a transient deflection of DC potential (i.e., CSD) repeatedly appeared concomitantly with depression of EEG, and was propagated in the distal direction. PO2 transiently decreased and CBF was slowly elevated. The frequency distribution of RBC velocity was shifted downward during CSD and was still low after the passage of CSD. When we observed RBC velocity in 38 individual capillaries, 10 capillaries exhibited slowed‐down RBC during CSD and RBC velocity remained low in 2 even after the passage of CSD. On the other hand, RBCs with moderately (<3 mm/sec) or remarkably (>3 mm/sec) increased velocities were seen in 10 and 5 capillaries, respectively.

Conclusion:  CSD‐induced excitation of neurons may sustainably decrease or greatly increase RBC velocity in capillaries.
Sintering Behavior of Nano‐ and Micro‐Sized ZnO Powder Targets for rf Magnetron Sputtering Applications
Authors: Neves Nuno , Barros Raquel , Antunes Elsa , Ferreira Isabel , Calado João , Fortunato Elvira , Martins Rodrigo
Published: October 2011

In this work, the nonisothermal sintering behavior of as‐received commercial high purity ZnO micrometric (m_ZnO), submicrometric (sm_ZnO) and nanometric (n_ZnO) powders was studied. The sintering behavior for sputtering target production was evaluated by changing the green density of samples from 62% of theoretical density (TD) to 35%. We observed that for n_ZnO powder, the maximum shrinkage rate (MSR) temperature (TMSR) was not affected by the green density, and that it was reached at lower temperatures (~710°C) compared with m_ZnO and sm_ZnO powders. For these powders, the temperature of MSR increased from 803°C to 934°C and from 719°C to 803°C as TD changed from 62% to 35% TD, respectively. Small grain size (~0.560 μm) and high density targets were obtained for n_ZnO when sintered at temperatures below the TMSR. Heating rate from 1°C to 15°C/min led to lower activation energy for n_ZnO (~201 ± 3 kJ/mol) than for the submicrometric (sm_ZnO) (~332 ± 20 kJ/mol) and micrometric (m_ZnO) (~273 ± 9 kJ/mol) powders. Using the model proposed by Bannister and Woolfrey, an n value of 0.75 was found, which was correlated with a combination of viscous flow and volume diffusion mechanisms that should control the initial stage of n_ZnO sintering. No significant differences were observed for n_ZnO powder in terms of density when the size of targets (scale‐up effect) was increased, while in the case of m_ZnO and sm_ZnO, a delay in the densification was observed, which was related to the higher sinterability of n_ZnO powder. Two inches ZnO ceramic targets with different particle sizes and final densities were used in an rf magnetron sputtering system to produce ZnO films under the same deposition conditions. Films with thickness around 100 nm and good uniformity were produced using those targets, and no variation was observed in the optical and morphological properties. However, low electrical resistivity (1.4 Ω·cm) films were obtained with n_ZnO targets, which could be explained in terms of a nonstoichiometric Zn:O composition of the started powders.
Large Piezoelectric Coefficient in (Ba1−xCax)(Ti0.96Sn0.04)O3 Lead‐Free Ceramics
Authors: Li Wei , Xu Zhijun , Chu Ruiqing , Fu Peng , Zang Guozhong
Published: October 2011

Lead‐free (Ba1−xCax)(Ti0.96Sn0.04)O3 (BCST) (x = 0–0.04) ceramics were prepared using solid‐state reaction technique. At room temperature, a polymorphic phase transition from orthorhombic phase to tetragonal phase was identified in the composition range of 0.01 ≤ x ≤ 0.03. Extremely high piezoelectric coefficient of d33 = 510 pC/N and high planar electromechanical coupling factor of kp = 48% were obtained for the BCST ceramics at x = 0.02. These results indicate that the BCSTs are promising candidates for the widely used lead‐based piezoelectric materials.
Stoichiometry Dependence of Li+ Diffusivity in LiNbO3 Crystal in Off‐Congruent, Li‐Deficient Regime
Authors: Chen Bei , Hua Ping‐Rang , Zhang De‐Long , Pun Edwin Yue‐Bun
Published: October 2011

Diffusivity at 1130°C of Li+ in LiNbO3 crystal in off‐congruent, Li‐deficient regime has been studied as a function of Li2O‐content. A diffusion‐limited Li2O‐content reduction depth profile in an X‐ or Z‐cut plate, ranging from 47.2 to 48.5 mol%, was produced by carrying out Li‐poor vapor transport equilibration (VTE) treatment on 1‐mm‐thick, initially congruent plates at 1130°C for 150 h. The profile was obtained by alternatively doing the optical polish to one crystal surface and the Li2O‐content characterization on the polished surface through the measurement on birefringence. The Boltzmann–Matano mathematical analysis was applied to the profile to obtain the Li2O‐content dependence of Li+ diffusivity. The results show that the diffusivity decreases with the decreased Li2O‐content and the decrease is by at least one order of magnitude as the Li2O‐content decreases by 1 mol% from 48.5 mol%. The diffusion shows slight anisotropy and is faster along the optical axis direction of crystal. In combination with previously reported result in the near‐stoichiometric regime, the diffusivity over the Li2O‐content range from 47 to 50 mol% is presented.
From malformations to molecular mechanisms in the male: three decades of research on endocrine disrupters
Authors: McLACHLAN JOHN A. , NEWBOLD RETHA R. , BUROW MATTHEW E. , LI SHUAN FANG
Published: October 2011

For three decades, we have known that estrogens alter the development of the mammalian reproductive system in predictable ways. In mice exposed prenatally to diethylstilbestrol (DES) or other estrogens, the male offspring exhibit structural malformations including cryptorchidism, epididymal cysts and retained Mullerian ducts. The estrogen‐associated alterations in the genital tract phenotype can be usefully considered as a model called Developmental Estrogenization Syndrome. While estrogen treatment during critical periods of morphogenesis of the male reproductive system has been associated with these changes, the mechanisms at the molecular level are still being discovered. Parallel findings on the hormones involved in Mullerian duct regression and testicular descent have helped guide research on the mechanisms of developmental estrogenization of the male. Cellular localization of molecular signals associated with key steps in genital tract development, use of mice with gene disruption, and knowledge of the mechanisms underlying persistent changes in gene expression are beginning to provide a blue print for both the physiological role and pathological effects of estrogens in reproductive tract development. Since many of the same biological principles underlie genital tract morphogenesis in mammals, one may expect some of the same changes in males of other species exposed to estrogen during the appropriate developmental periods.
Getting the problem of endocrine disruption into focus: The need for a pause for thought
Authors: ASHBY JOHN
Published: October 2011

The study of chemically‐induced endocrine disruption in mammals is a relatively new field of endeavour, and it has been assailed by an unusual level of disagreement among investigators regarding the developmental effects produced by chemicals in animals. This article discusses the several sources of uncertainty in endocrine toxicity studies, and the intrinsic variability of many of the key experimental parameters. It is concluded that current uncertainties are due to the absence of an extensive agreed control database for the developmental parameters under study, coupled to the established intrinsic variability of these parameters between strains/species of test animals and test protocols. Only when these factors are generally accepted and well studied will it be possible to design studies capable of distinguishing the possible subtle endocrine toxicity of chemicals and chance observations that cannot be independently reproduced.
Pathogenesis and epidemiology of precocious puberty. Effects of exogenous oestrogens
Authors: Partsch C.‐J. , Sippell W.G.
Published: October 2011

Precocious puberty is generally defined as the appearance of secondary sex characteristics before age 8 years in girls (or menarche before age 9 years) and before 9 years in boys. The overall incidence of sexual precocity is estimated to be 1:5000 to 1:10 000 children. The female‐to‐male ratio is ˜10:1. In addition to the psychosocial disturbances associated with precocious puberty, the premature pubertal growth spurt (with less time for prepubertal growth) and the accelerated bone maturation result in reduced adult height. Precocious puberty may be gonadotrophindependent [i.e. of central origin with premature activation of the gonadotrophin‐releasing hormone (GnRH) pulse generator] or gonadotrophin‐independent (i.e. peripheral where the GnRH pulse generator is suppressed). This can be determined by GnRH testing. The pathophysiology is the basis for different diagnostic and therapeutic strategies, i.e. in the first case a stimulated LH/FSH ratio >1 and suppressive treatment with GnRH agonists (e.g. in hypothalamic hamartoma), and in the second decreased gonadotrophins and removal or suppression of the endogenous or exogenous sex steroid source (e.g. congenital adrenal hyperplasia). While several cases of gonadotrophin‐independent precocious puberty due to oestrogen exposure via the transdermal, oral, or inhalative route have been reported, no case is known with the development of subsequent secondary central precocious puberty. Food contamination with oestrogens is theoretically possible, but would most probably be sporadic and, thus, would not lead to precocious puberty. As steroid hormones in meat production are banned in the European Union, no data on the impact of environmental oestrogenic substances on human maturation are currently available. In conclusion, the risk for children to develop precocious puberty through exposure to oestrogens (or androgens) in the environment or in food is very low. Nevertheless, studies of the effects of defined environmental oestrogenic substances on the human reproductive system and on pubertal development are warranted.
Age of puberty: Data from the United States of America
Authors: LEE PETER A. , GUO SHUMEI S. , KULIN HOWARD E.
Published: October 2011

In an attempt to determine whether the secular trend toward an earlier onset of puberty has continued over recent decades in the United States of America, published reports concerning the age of attainment of pubertal events have been reviewed. Such reports are very limited and vary in both design and inclusive ages of study subjects. Among females, two recent large cross‐sectional studies indicate that fifty percent of females in the United States attain Tanner breast stage 2 at 9.5 to 9.7 years of age. This is younger than previously thought, although adequate earlier studies of girls in the United States are not available for comparison. These two studies also indicate that about 14% of girls attain Tanner stage 2 while 8 years of age; one study extends earlier reporting that about 6% exhibit onset of breast development while 7 years of age. There is no evidence that the age of menarche or the attainment of adult (Tanner 5) breast development has decreased over the past 30 years. The data also suggest an earlier onset of Tanner stage 2 pubic hair but no change in attainment of stage 5. Among males, pubic hair may be appearing at younger ages, but data are inadequate or too inconsistent to allow firm interpretation. The lack of standardization of genital criteria of pubertal onset in the male makes any conclusions regarding secular trends impossible. In summary, earlier secular trends over recent decades related to better health, improved nutrition or socio‐economic status, or any putative influence by endocrine disrupters cannot be verified.
Causes of juvenile obesity: Clues from epidemiology
Authors: SØRENSEN THORKILD I. A.
Published: October 2011

A global epidemic of obesity is rapidly developing in children and adults, both in developed and developing countries. It is expected to create a huge public health problem in the future because of the conditions associated with obesity, both the immediate psychosocial and somatic problems and the longterm complications including glucose intolerance, type 2 diabetes, hypertension, hyperlipidaemia, and therefore an increased risk of cardiovascular diseases, increased risk of certain cancers and of gallstones, and eventually, excess mortality. It is commonly assumed that the causes of the epidemic is simple, namely both overeating and sedentary behavior, often in combination, and the preventive measures are all targeted to reverse this life style. When developed, obesity as such leads to overeating and physical inactivity for obvious reasons, but, unfortunately, it has not yet been possible to demonstrate that these behaviors precede the development of obesity. What are then the causes of obesity? Multiple family, twin and adoption studies leave no longer any doubt that obesity has a genetic predisposition that explains most if not all of the familial aggregation of obesity. Intensive search through the last 6 years has revealed some specific genes (e.g. leptin and the leptin receptor) that may cause obesity, but genetic variants that can account for the common obesity have not yet been identified. The development of obesity epidemic also shows that there in addition must be rapid environmental changes that may operate on the genetic background although clear gene‐environment interaction (synergism/antagonism) has not yet been found. We have conducted detailed analyses of very large population‐based Danish cohorts of boys in school age and young men examined as draftees, and we have have found that the obesity epidemic developed in two waves that appeared to be closely linked to birth cohorts and to be emerging already before school age: the first one during the 1940es and the second since mid 1960es. These findings strongly indicate that parallel preceding changes in the fetal or early childhood environment have played a role. To our great surprise, after having peaked among those born in the late 1980es, the prevalence of obesity in the young men is now rapidly declining again, further substantiating the role of rapidly altered environmental influences, the nature of which is unknown. Identification of the specific environmental factors may allow much more effective preventive measures to be taken in the future.
Environmental exposure to polychlorinated biphenyls (PCBs) and dioxins
Authors: BOERSMA E. R.
Published: October 2011

Polychlorinated biphenyl's (PCBs) and dioxins are environmental pollutants. Calculated on a body weight basis, prenatally as well as postnatally through breast‐feeding, large amounts are transferred from mother to the child. Formula is free of these substances. Considering their potential developmental neurotoxicity, we investigated long‐term effects of perinatal exposure to PCBs and dioxins on neurological and cognitive development. Methods. A group of 418 infants were followed from birth up to 6 years of age. Half of them were fully breast fed (BF) for at least 6 weeks. Prenatal PCB exposure was measured from cord and maternal blood. Postnatal exposure was reflected by PCB and dioxin levels in breast and formula milk and plasma PCB concentrations at 42 months of age. Both neurological and cognitive development were taken as outcome variables at 18, 42 months and at 6 years of age. At 18 and 42 months neurological condition was evaluated according to Hempel and Touwen and at 6 years of age according to Touwen. Condition was evaluated in terms of optimality. Separately, the fluency of movements was scored. Cognitive abilities were measured at 18 months by means of the Bayley Scales of Infant Development, at 42 months of age by the Kaufman Assessment Battery for Children (K‐ABC) and at 6 years of age by the McCarthy Scales. Results. At 18 months of age cognitive development was not affected by either pre‐ or postnatal exposure to the measured PCBs and dioxins. However, neurological examination showed an adverse effect of prenatal exposure to the measured pollutants on the neurological optimality score. At 42 months of age we found negative associations between prenatal PCB exposure and cognitive development. However, no effect was demonstrated of postnatal exposure to the measured pollutants. Neurological development was not affected by either pre‐ or postnatal exposure to PCBs and dioxins. At 6 years of age the preliminary results showed no evidence that cognitive and neurological development are affected by pre‐ and postnatal exposure to these pollutants. Despite a higher PCB exposure from breast milk we found at 18 months, 42 months of age, and at 6 years of age a beneficial effect of breast feeding on the quality of movements, in terms of fluency. Conclusion. These data support the evidence obtained from similar studies in the USA that prenatal exposure to PCBs may have subtle negative effects on early neurological and cognitive development of the child. Further studies are required to evaluate these findings in other parts of the world. Our studies showed consistently a beneficial effect of breast‐feeding on brain development from 18 months up to school age.
Long‐term effects on male reproduction of early exposure to common chemical contaminants in drinking water
Authors: Veeramachaneni D.N.R. , Palmer J.S. , Amann R.P.
Published: October 2011

We evaluated sequelae to early exposure of male rabbits to drinking water containing chemicals typical of ground water near hazardous waste sites. The mixture (p.p.m. at 1 x) was 7.75 arsenic, 1.75 chromium, 9.25 lead, 12.5 benzene, 3.75 chloroform, 8.5 phenol and 9.5 trichloroethylene. Dutch‐Belted does received mixture at 0 x (deionized water; control), 1 x or 3 x as drinking water from day 20 pregnancy through weaning. Exposure of individual males (7–9/treatment) continued until 15 weeks (adolescence); then, all males received deionized water. At 57–61 weeks of age, ejaculatory capability and seminal, testicular, epididymal and endocrine characteristics were evaluated. At 10 opportunities with a female teaser, all seven control males ejaculated every time, but 12 of the 17 treated males failed to express interest, achieve erection and/or ejaculate on one to five occasions; four of the 12 accomplished ejaculation with a second male teaser. Total spermatozoa/ejaculate and daily sperm production were unaffected. However, treatment caused (P < 0.03) acrosomal dysgenesis and nuclear malformations. Baseline serum concentrations of LH were lower, but with borderline significance (P = 0.05). Testosterone secretion after exogenous human chorionic gonadotrophin (P < 0.04) was low. Thus, even at 45 weeks after last exposure to drinking water pollutants, mating desire/ability, sperm quality, and Leydig cell function were subnormal.
Hormones in meat: different approaches in the EU and in the USA
Authors: STEPHANY RAINER W
Published: October 2011

The use of hormonal active growth promoters (“hormones”) in farm animals can increase the production of veal and beef significantly up to 15%. However, in the different parts of the world the regulation regarding the use of such hormones differs sharply. In the European Union there exists a total ban on such use in contrast to the United States of America where the use of some hormones is authorized under strict conditions. An overview is given of the different opposing aspects and their consequences are discussed. It has to be concluded that in some EU Member States an extented black market exists. For the USA no experimental evidence is available for such a black market. In the EU the number of ascertained different illegal “hormones” ranges between about 35 and 55. In the USA the number of legal hormones in total is six. The levels of hormone residues found in beef originating from the USA are in the fast majority of cases below the Maximum Residue Limit as recommended by the FAO/WHO Joint Expert Committee of Food Additives. No comparable experimental data are available for the EU. Finally other food commodities have to be taken into account to assess potential risks of the dietary intake of “hormones”. Eggs, example given, contribute more to the dietary intake of estradiol than beef, whether the animal is legally treated with hormones or not.
Hormone contents in peripheral tissues after correct and off‐label use of growth promoting hormones in cattle: Effect of the implant preparations Finaplix‐H®, Ralgro®, Synovex‐H®and Synovex Plus®
Authors: LANGE IRIS G. , DAXENBERGER A. , MEYER H. H. D.
Published: October 2011

Certain hormonal growth promoters are licensed in several beef producing countries outside the European Union (EU). Use in compliance with Good Veterinary Practice is mandatory. As risk assessment of hormone residues in animal tissues up to now has neglected potential off‐label use, the present study dealt with two topics: 1) multiple treatment with the implant preparations Finaplix‐H® (200 mg trenbolone acetate), Ralgro® (36 mg zeranol) and Synovex‐H® (200 mg testosterone propionate plus 20 mg estradiol benzoate) in heifers (1‐fold, 3‐fold and 10‐fold dose), and 2) non‐approved treatment of female veal calves (1‐fold dose of Synovex‐H® or Synovex Plus® with 200 mg trenbolone acetate plus 28 mg estradiol benzoate). Residues of estradiol‐17 β, estradiol‐17α, estrone and testosterone, trenbolone‐17β, trenbolone‐17α and trendione or zeranol, respectively, were measured in loin, liver, kidney and peri‐renal fat by high performance liquid chromatography/enzyme immunoassay (HPLC/EIA) after liquid‐liquid extraction and solid‐phase clean‐up. The hormone residues in the multiple‐dose experiments were dose‐dependent and partially exceeded the threshold values: in the liver in one animal after 3‐fold dose and in two animals after 10‐fold dose of Finaplix‐H®, and in the liver and kidney after 3‐fold and 10‐fold dose of Synovex‐H®. Mean hormone residues in calves were mainly below those of heifers and did not infringe threshold values.
Possible health impact of phytoestrogens and xenoestrogens in food
Authors: IBARRETA DOLORES , DAXENBERGER ANDREAS , MEYER HEINRICH H. D.
Published: October 2011

Plants produce estrogen‐like substances, denominated phytoestrogens, which are present in many human foodstuffs. The consumption of phytoestrogens has been associated with a variety of protective effects. Their relative estrogenic potency combined with their concentrations in food and human plasma indicate biological relevance. However, their biological properties differ from those of estradiol or other endogenous estrogens in humans. For instance, their possible effects on SHBG, inhibition of steroid metabolizing enzymes, anti‐proliferative and anti‐angiogenetic and other side effects have been described. Furthermore, phytoestrogens can exert estrogenic and antiestrogenic activities at the same time and their potency and metabolism have not been yet elucidated in all cases. In recent decades growing evidence has accumulated on the hormone‐like effects of synthetic chemicals that appeared in the environment. The possible impact of xenoestrogens, to which humans are also exposed through the food chain, needs to be further clarified as well. The molecular effects and control mechanisms of these substances, their pharmacokinetics, threshold levels and dose‐response differences are issues that require further research before a full assessment of their effect on humans can be drawn. Evaluating the total exposure and impact of this estrogenic effect is very challenging because of the lack of specific knowledge in some areas and the differences in the biological activity among these substances, as pinpointed in this review.
Genotoxic potential of xenobiotic growth promoters and their metabolites
Authors: METZLER MANFRED , PFEIFFER ERIKA
Published: October 2011

This paper reviews data reported in the literature as well as recent and unpublished studies from our laboratory on the metabolism and genotoxicity of the xenobiotic growth promoters 17β‐trenbolone, melengestrol acetate and zeranol. In our metabolic study, the oxidative in vitro metabolites generated by hepatic microsomes from rats, bovine and humans were analyzed by HPLC and GC/MS. 17β‐Trenbolone gave rise to at least 13 monohydroxylated products, whereas 12 mono‐ and dihydroxylated metabolites were obtained with melengestrol acetate and at least 5 with zeranol. The genotoxic potential of the parent compounds was studied using the following endpoints: induction of HPRT mutations in cultured V79 cells and of lacI mutations in E. coli; induction of micronuclei in V79 cells; and formation of DNA adducts in cultured primary rat hepatocytes. Negative results were obtained in most of these assay systems. Only the micronucleus induction was marginally positive with 17β‐trenbolone and zeranol at near‐cytotoxic concentrations. Commercial melengestrol acetate was found to contain an impurity causing apoptosis in V79 cells. The genotoxic potential of the numerous oxidative metabolites of the xenobiotic growth promoters remains to be studied.
Characterisation of the affinity of different anabolics and synthetic hormones to the human androgen receptor, human sex hormone binding globulin and to the bovine progestin receptor
Authors: BAUER E. R. S. , DAXENBERGER A. , PETRI T. , SAUERWEIN H. , MEYER H. H. D.
Published: October 2011

For the steroidal growth promoters trenbolone acetate (TBA) and melengestrol acetate (MGA) neither the complete spectrum of biological activities nor the potential endocrine disrupting activity of their excreted metabolites in the environment is fully understood. The potency of these substances in [3H]‐dihydrotestosterone ([3H]‐DHT) displacement from the recombinant human androgen receptor (rhAR) and from human sex‐hormone binding globulin (hSHBG) was evaluated. In addition, the potency for [3H]‐ORG2058 displacement from the bovine uterine progestin receptor (bPR) was tested. For comparison, different anabolics and synthetic hormones were also tested for their binding affinities. For 17β‐trenbolone (17β‐TbOH), the active compound after TBA administration, an affinity the rhAR similar to dihydrotestosterone (DHT) and a slightly higher affinity to the bPR than progesterone were demonstrated. The affinity of the two major metabolites, 17α‐trenbolone and trendione, was reduced to less than 5% of the 17β‐TbOH‐value. The affinity of these three compounds and of MGA to the hSHBG was much lower compared with DHT. MGA showed a 5.3‐fold higher affinity than progesterone to the bPR but only a weak affinity to the rhAR. The major MGA metabolites have an affinity to the bPR between 85% and 28% of the affinity of progesterone. In consequence, MGA and TBA metabolites may be hormonally active substances, which will be present in edible tissues and in manure. We conclude that detailed investigations on biodégradation, distribution and bio‐efficacy of these substances are necessary.
Exposure levels of endocrine disruptors in Nordic Countries
Authors: LARSEN JOHN CHR.
Published: October 2011

A number of different xenobiotic compounds have shown estrogenic, anti‐androgenic, or “dioxin‐like” (Ah‐receptor agonism) activities in vitro as well as adverse reproductive effects in toxicological animal studies. Although human evidence is at best weak for a few compounds, and for most compounds is absent, they have been implicated as potential endocrine disruptors affecting human male reproduction. According to their metabolic properties in mammals these compounds may be divided into two groups. Compounds such as the polychlorinated dibenzo‐p‐dioxins (PCDDs) and dibenzofurans (PCDFs), polychlorinated biphenyl (PCBs), and a number of organochlorine pesticides, i.e. DDT/DDE, HCHs, HCB, dieldrin, and toxaphenes, are highly resistant to metabolic degradation in the food chains and accumulate in the human body. Because of this property compounds belonging this group are of the greatest concern. It is not the low daily intake, but the total body burden of the pregnant woman achieved over time that is of importance. Control of emissions to the environment and restrictions in use have significantly decreased human intakes during the last 15–20 years. A number of other compounds, such as bisphenol A, certain phthalates, alkylphenols, and some pesticides in current use have also shown various effects in vitro. These compounds are readily metabolised by mammals and do not accumulate in humans and in most cases fairly high doses are required to produce reproductive effects in animal studies. Most of these compounds have been included in the Danish Food Surveillance System since the early 1980s, and their intakes have been estimated based on Danish Food Consumption Data. For PCDDs, PCDFs and dioxin‐like PCBs a recent EU SCOOP project have provided up‐dated estimates of intakes in various European countries. The presentation will discuss the significance of the human intake levels in relation to the toxicological properties of these compounds. From this exercise it seems apparent that the dioxins are among the best candidates for having produced endocrine effects in humans, in particular at the much higher exposure levels that were seen 15 or more years ago.