bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of estradiol and its metabolites in meat
Authors: MAUME D. , DECEUNINCK Y. , POUPONNEAU K. , PARIS A. , LE BIZEC B. , ANDRÉ F.
Published: October 2011

Most studies related to research on steroids in main edible tissues (muscle, liver or kidney) have focused on measurement of parent or major metabolite residues. In order to evaluate the estradiol content in bovine edible tissues, a multi‐step extraction procedure was developed in conjunction with parallel metabolism studies of [14C]‐17β‐estradiol in cattle (1–2). Various classes of free estradiol and conjugates were separated: estradiol −17β and −17α, estradiol‐ 17‐fatty acid esters, estradiol 17‐glycoside, estradiol 3‐glucuronide, estradiol‐17‐glycoside and 3‐ glucuronide (diconjugates) were separated. No sulphates conjugated forms have been found at the detection level of the method. The quantification was realized by calibration with deuterated 17β −estradiol −d3 standard and was validated at the ng · kg−1(ppt) level. Muscle, liver, kidney and fat samples from control or Revalor S® single (licensed implantation) or multi‐implanted steers have been assayed.

The results show a wide variation between animals, but both the highest value and the mean of total estradiol content in each group proportionally increase from untreated to multi‐implanted animals. In accordance with international rules, a calculation of the daily food supply of estradiol by such edible tissues in comparison with the acceptable daily intake was performed.
Trends in the incidence of cryptorchidism and hypospadias, and methodological limitations of registry‐based data
Authors: Toppari J. , Kaleva M. , Virtanen H.E.
Published: October 2011

Cryptorchidism and hypospadias share possible risk factors, such as intrauterine growth retardation. According to the data collected by the International Clearinghouse for Birth Defects Monitoring Systems (ICBDMS), apparently increasing trends in the incidence of hypospadias were found in Sweden during the 1960s, and in Norway, Denmark, England and Hungary during the 1970s. In Norway and Denmark, the increase continued in the 1980s, while in the USA it has continued from the 1970s to the 1990s. Finland has shown a lower reported rate of hypospadias than other Nordic countries. However, it is difficult to make comparisons between countries because of variable inclusion criteria. Furthermore, the reliability of the data depends on correct ascertainment and reporting of the cases. The ICBDMS has also collected data on cryptorchidism, but these appear to be unreliable because of a discrepancy with the data from cohort studies. According to two comparable English studies, the incidence of cryptorchidism in full‐ term boys approximately doubled between the 1950s and the 1980s. Regionally there are large differences: e.g. in Finland the incidence of cryptorchidism is clearly lower than in Denmark. Regional and temporal trends may help to identify environmental factors that might be associated with these disorders.
The birth rate of hypospadias in the Turku area in Finland
Authors: VIRTANEN H. E. , KALEVA M. , HAAVISTO A.‐M. , SCHMIDT I. M. , CHELLAKOOTY M. , MAIN K. M. , SKAKKEBAEK N. E. , TOPPARI J.
Published: October 2011

Reports based on national registers of congenital malformations have suggested that the birth rate of hypospadias has increased during the last few decades. Register‐based information may, however, have pitfalls because of changes in diagnostics, reporting accuracy and registration system. The aim of this study was to determine the current birth rate of hypospadias in Turku University Central Hospital (TUCH) in Finland. This was a prospective study on live‐born boys born in TUCH from 1997 to 1999. In the total birth cohort (n=5,798) as well as in a special subcohort group (n= 1,505) 0.3% of boys had hypospadias. Only one scrotal hypospadias was found in a boy who had a chromosomal anomaly. Other hypospadias were glandular or coronal. No increase was found in the birth rate of hypospadias when comparing our result with register‐based data of boys born in Finland during the years 1970 to 1986 and surgically treated for hypospadias by the age of 8 years. No difference was found either from malformation register‐based data concerning the nationwide birth rate of hypospadias during the years 1993 to 1998. Due to differences in national registration systems between countries, prospective studies with equal assessment criteria are needed in order to make reliable international comparisons.
Dose‐dependent effects of melengestrol acetate (MGA) on plasma levels of estradiol, progesterone and luteinizing hormone in cycling heifers and influences on oestrogen residues in edible tissues
Authors: HAGELEIT M. , DAXENBERGER A. , KRAETZL W.‐D. , KETTLER A. , MEYER H. H. D.
Published: October 2011

Melengestrol acetat (MGA) is widely used as a growth promoting feed additive in cattle breeding in the USA and several other non‐European countries. To explore the physiological effects of MGA four heifers were fed during 8 weeks with 0.5 mg MGA daily as registered in the USA and two heifers each received 0, 1.5 or 5 mg/day, respectively. Plasma samples were collected twice a week and concentrations of MGA, progesterone (P4) and estradiol‐17β (E2‐17β) were quantified. The pulsatile secretion of luteinizing hormone (LH) was investigated in 6‐hour profiles before and during treatment. After slaughter the reproductive organs were examined and oestrogen residues in edible tissues were measured. Four days after the beginning of MGA feeding MGA concentrations in plasma reached levels of 30 and 100–400 pg/mL depending on the dose received. Three weeks after the beginning of MGA feeding P4 plasma concentrations had dropped to base levels below 0.3 ng/mL in all three treatment groups. Mean plasma E2‐17β levels increased in physiological range from 1 to 5 pg/mL during 0.5 mg MGA/day feeding with many acyclic peaks. Overdosed MGA decreased E2 levels and suppressed cyclic peaks. Number and size of ovarian follicles were not altered by any treatment. Mean LH levels and pulse frequencies increased significantly during labelled treatment (0.5 mg/day), while higher doses had reducing effects. The development of corpus luteum was suppressed. E2‐17β residues in fat increased about 300% following labelled MGA treatment.
Oestrogenic potencies of Zeranol, oestradiol, diethylstilboestrol, Bisphenol‐A and genistein: implications for exposure assessment of potential endocrine disrupters
Authors: Leffers Henrik , Næsby Michael , Vendelbo Brian , Skakkebæk Niels E. , Jørgensen Marianne
Published: October 2011

We have compared the oestrogenic potency of the synthetic oestrogen Zeranol, used as a growth promoter in meat production, and five related compounds, with the potency of 17β‐oestradiol, diethylstilboestrol (DES), genistein, and Bisphenol‐A. The potency was assayed by analysing differences in expression levels of endogenous oestrogen‐regulated genes in human MCF7 cells, treated with different concentrations of the compounds. Zeranol, 17β‐oestradiol and DES were about equally potent, genistein was four to six orders of magnitude less potent than 17β‐oestradiol but an order of magnitude more potent than Bisphenol‐A. There were gene specific differences, the PS2 and TGFβ3 genes were about equally sensitive to Zeranol, 17β‐oestradiol and DES whereas a down‐regulation of MRG1/p35srj could be detected at fmol/l concentrations of Zeranol whereas 17β‐oestradioI was several orders of magnitude less potent. GST mu3 was sensitive to fmol/l concentrations of 17β‐oestradiol but much less sensitive to Zeranol and DES. The very high potency of Zeranol compared with other potential endocrine disrupters suggests that Zeranol intake from beef products could have greater impact on consumers than the amounts of the known or suspected endocrine disrupters that have been found in food. Since little data is available in man, there is an urgent need for reliable measurements of the concentration of Zeranol in human serum after ingestion of meat products from treated animals.
Semen quality and male reproductive health: the controversy about human sperm concentration decline
Authors: JOUANNET PIERRE , WANG CHRISTINA , EUSTACHE FLORENCE , KOLD‐JENSEN TINA , AUGER JACQUES
Published: October 2011

Concern about the effect of environmental changes on male reproductive health has grown in recent years to become a major preoccupation in some developed countries. A possible decline in human sperm concentration was suggested in the early seventies following studies in the US. In 1992 a metaanalysis of 61 articles published by Carlsen et al. concluded that the mean sperm count of healthy men had declined by 1% per year over the previous 50 years. From 1995 and onwards, some retrospective, longitudinal analyses of the sperm count of fertile or infertile men contradicted this while others did not. The demonstration of a geographical variation in sperm concentration, between and within countries or regions, appears to be less controversial. The amplitude of the difference observed cannot only be explained by methodological or confounding factors, and must to some extent be attributed to ethnic, genetic or environmental factors. As many of the published studies suffer from imprecision regarding the description of population characteristics and confounding factors, and were not designed with controlled and standardised methodology, the debate remains open. Prospective studies in well‐defined cohorts of men in various populations are required to evaluate the potential effect of external factors on male reproductive health. These studies should not be limited to the analysis of sperm concentration, as this may not be the best biomarker of testis function and human fertility.
Estrogenic activity of estradiol and its metabolites in the ER‐CALUX assay with human T47D breast cells
Authors: HOOGENBOOM L. A. P. , DE HAAN L. , HOOIJERINK D. , BOR G. , MURK A. J. , BROUWER A.
Published: October 2011

A number of metabolites of 17β‐estradiol were tested for their estrogenic activity using the ER‐CALUX assay based on the increased expression of luciferase in exposed T47D breast cancer cells. E2β and estrone showed similar potencies in the test, whereas E2α was 100 times less active. Incubation of cells with estrone (0.35 μM) resulted in the formation of E2β, whereas the reverse reaction was observed for E2β. The resulting equilibrium may explain the similar estrogenic potency of estrone in the test. The synthetic 17‐hydroxy benzoate ester of E2β was 3 times less active than the parent compound. The 17‐hydroxy palmitate and oléate esters of E2β, were respectively 25 and 200 times less active than the parent compound. The 2‐hydroxy metabolites of E2β and estrone showed a 5,000 to 10,000 fold lower activity. The 4‐hydroxy metabolites were more potent than the 2‐hydroxy metabolites, showing only a 20–200 times lower activity. The 2‐ and 4‐methoxyesters of estrone were 700 times less active. It is concluded that the estrogenic potency of metabolites formed in cattle after treatment with E2β, like estrone, E2α and especially the esters of E2β, may be significant with respect to the potential risk of the use of estradiol for growth promotion in domestic animals in certain countries.
Endocrine disruptors and children's sex‐dimorphic behaviour
Authors: SANDBERG D. E. , VENA J. E. , MEYER‐BAHLBURG H. F. L. , BEEHLER G. , SWANSON M. , WEINER J.
Published: October 2011

Environmental toxicants can modulate endocrine function. Interest has been directed at those chemicals which interact with sex hormone because of their potentially irreversible effects on brain development. Studies on the effects of in utero and lactational exposure to hormone‐modulating pollutants have focused on cognitive function. Study objectives included: a) identification of a combination of behaviours that differentiate between boys and girls; and b) determination if early chemical exposure affects variability in sex‐dimorphic behaviours. We utilized an established epidemiologic cohort (New York State Angler Cohort Study) assembled to assess the influence of contaminated sport fish consumption on health in adults and their offspring. Children 5 to 11 years of age were targeted. Using a postal questionnaire survey methodology in which a parent served as the informant, 1,112 of 1,692 households contacted (66%) returned completed questionnaires on 1,415 children (52% male, 48% female). Maternal report confirms both pre‐ and postnatal contaminant exposures: 40% of the mothers consumed sport fish for 1 yr and 28% of their offspring ate contaminated fish. Consumption durations do not differentiate respondents from nonrespondents. A discriminant function based upon gender behaviour scale scores was robust in differentiating boys and girls. Stepwise multiple regression analyses revealed that masculine behaviour increased among boys with age and the number of years of maternal sport fish consumption whereas feminine behaviour increased among girls with the duration of breast‐feeding. Increased age and previous live‐births were associated with more masculine behaviour in the girls. For both sexes, exposure was unrelated to the prevalence of learning problems, non‐right handedness, or behavioural problems. Although this study does not rule out differential gender socialization influences, the findings are consistent with an effect of contaminant exposure on sex‐dimorphic behaviours in humans. This study was in part funded with grants from the National Institute of Environmental Health Sciences, NIH (R03ES08500‐01), the Great Lakes Protection Fund (RM791‐3021), and the Agency for Toxic Substances and Disease Registry (H75/ATH298338).
Phytoestrogens and carcinogenesis—differential effects of genistein in experimental models of normal and malignant rat endometrium
Authors: Diel Patrick , Smolnikar Kai , Schulz Thorsten , Laudenbach‐Leschowski Ute , Michna Horst , Vollmer Günter
Published: October 2011

The phytoestrogen genistein was studied in normal and malignant experimental uterine models in vivo. The action of genistein on the uterus and vagina of ovariectomized DA/Han rats after 3 day oral administration (25, 50 or 100 mg/kg/BW/d) was compared to ethinyl oestradiol (0.1 mg/kg/BW/d). Effects on uterine and vaginal morphology, uterine growth and uterine gene expression were studied. A dose dependent increase of the uterine wet weight and the uterine and vaginal epithelial height, a dose dependent up‐regulation of complement C3, down‐regulation of clusterin mRNA expression and a stimulation of the vaginal cornification was observed after administration of genistein. Uterine gene expression and vaginal epithelium respond to genistein at doses where no significant effects on uterine wet weight were detectable. In general the vagina was more sensitive to genistein than the uterus. To analyse the action of genistein in malignant uterine tissue, the impact of a 28 d treatment with 50 mg/kg/d of genistein on the in‐vivo tumour growth of RUCA I endometrial adenocarcinoma cells, following subcutaneous inoculation into syngeneic DA/Han rats, was assessed. In contrast to ethinyl oestradiol (0.1 mg/kg/BW/d), a dose of 50 mg/kg/BW/d of genistein did not affect tumour growth. Nevertheless C3 and TRPM2 mRNA expression in the tumour were both significantly stimulated by ethinyl oestradiol and genistein. In comparison to ovariectomized animals genistein up‐regulated uterine wet weight and uterine dependent gene expression in tumour bearing animals. In conclusion, four independent uterine and vaginal parameters indicate genistein is a weak oestrogen receptor agonist in the uterus and vagina of female DA/Han rats, and evidence is provided for a selective oestrogen receptor modulator (SERM)‐like action of genistein in normal and malignant uterine tissue.
Threshold analysis of selected dose‐resmnse data for endocrine active chemicals
Authors: BLAIR ROBERT M. , FANG HONG , GAYLOR DAVID , SHEEHAN DANIEL M.
Published: October 2011

Using a biologically relevant mathematical model, the Michaelis‐Menten equation, we examined published data from endocrine active chemicals for evidence of no‐threshold dose‐response curves. Data were fit to a modified Michaelis‐Menten equation which accounted for total background response. Subsequently, the data sets were analyzed using non‐linear regression in order to estimate the four parameters of interest (non‐hormone controlled background (Bnh), maximum response (Rmax), endogenous hormone level (Do), and the dose at which a half‐maximal response was observed (ED50)) and to determine the fit to the fully modified Michaelis‐Menten equation. Subsequently, response data were adjusted to account for Bnh and then normalized to Rmax, while dose data were adjusted to account for Do and then normalized to the ED50, This data set was combined into a single, composite data set and fit to the fully modified Michaelis‐Menten equation. We examined 31 data sets (24 endpoints) from studies on 9 different chemical/hormone treatments. Twenty‐six of the data sets fit the modified Michaelis‐Menten equation with high multiple correlation coefficients (r>0.90). The normalized data demonstrated a good fit to the modified Michaelis‐Menten equation. These results indicate that a variety of biological responses fit the modified Michaelis‐Menten equation, which does not have a threshold dose term.
Semen quality of Japanese fertile men: A study of partners of pregnant women
Authors: IWAMOTO T. , HOSHINO T. , NISHIDA T. , BABA K. , MATSUSHITA K. , KANEKO S. , IZUNO T. , YOSHIIKE M. , NOZAWA S. , SUGITA M.
Published: October 2011

During the recent years conflicting information on possible changes in semen quality has been published. These publications also indicate that geographical differences in semen quality may exist. However, no definitive evidence has been provided and additionally very little information regarding semen quality of Japanese men are available. Therefore, we undertook a cross‐sectional study of partners of pregnant women following the same protocol, which has already been used in four European cities. 351 male partners of pregnant women living in the Kawasaki/Yokohama area of Tokyo participated in the study. Of these 232 were recruited from 3 University Hospitals (UH) and 119 were recruited from 2 Private Hospitals (PH). The raw data of the median sperm concentrations were 92.4 (mill/ml) and 99.8 (mill/ml) for the participants from UH and PH respectively. In the analysis of the data the following parameters were taken into account as confounders: men's age, season of year, and abstinence period. We detected a clear seasonal variation in sperm counts with lowest sperm concentration and total sperm count in spring season and highest counts in autumn season with counts in summer and winter seasons being in between. We estimated the semen quality of a “standardised man” (30‐year‐old, fertile, ejaculation abstinence of 96 hours) for both autumn and spring season. The sperm concentration (mill/ml) for autumn/spring were: UH 89/54 and PH 105/63; for total sperm counts (mill): UH 282/151 and PH 315/169. As in the European study we detected a seasonal variation in sperm counts. However, in our study highest counts were detected in autumn season whereas the highest counts in the European study were detected in winter season. Likewise, the lowest counts were in spring and summer in Japan and Europe respectively. The estimated sperm counts of a “standardised Japanese fertile man” seem to be higher than counts in Denmark (Copenhagen) and France (Paris) but lower than counts in Scotland (Edinburgh) and Finland (Turku). It remains to be seen whether regional differences in semen quality exist in Japan.

This study was supported by grant from the Ministry of Health and Welfare, Japan (1013201).
Epidemiology of breast cancer: an environmental disease?
Authors: SASCO ANNIE J.
Published: October 2011

Breast cancer is the leading cancer site in women, both in the developed and the developing world. Incidence rates are increasing in many countries, although, in some, mortality may be stable or slightly decreasing. Geographical differences exist, with high rates of disease in North America, North Europe and Oceania, intermediate rates in South and Central America as well as South and East Europe, and low rates in Africa and Asia. Most of the literature reports that genetic inherited factors account for less than 5% of cases, although some authors advance higher figures, up to about 10%. Risk factors for breast cancer are related to the reproductive life of women: early menarche, nulliparity or late age at first birth, late menopause, diet and physical exercise, as well as hormonal factors, be they endogenous (high levels of free or not bound to SHBG estrogens) or exogenous (long‐term use of oral contraceptives or menopausal hormone replacement). The present review does not aim to be exhaustive and fully comprehensive, or to present in detail domains currently well known and accepted by all. On the contrary, it modestly wishes to highlight potentially controversial conditions which could in the future be recognized as new risk factors.
Plerixafor and Filgrastim XM02 (Tevagastrim®) as a first line peripheral blood stem cell mobilisation strategy in patients with multiple myeloma and lymphoma candidated to autologous bone marrow transplantation
Authors: Andreola Giovanna , Babic Aleksandra , Rabascio Cristina , Negri Mara , Martinelli Giovanni , Laszlo Daniele
Published: October 2011

Plerixafor, a CXCR4 antagonist, has shown to be effective in increasing the number of circulating stem cells, even in patients failing a previous mobilisation attempt. Recently a number of non‐glycosylated recombinant human granulocyte‐colony stimulating factor (G‐CSF) has been clinically approved for the same indications as the originator G‐CSF for comparable safety and efficacy and their reduced cost. In an attempt to provide a less toxic strategy, 14 patients affected by haematological malignancies (non‐Hodgkin’s lymphoma = 4, Hodgkin’s disease = 2 and multiple myeloma = 8), received the combination of biosimilar filgrastim and plerixafor as a first line mobilising strategy. The median number of circulating CD34+ cells on day 4 was 16 (3–42); Plerixafor was administered to all, but one patient who had already 42 CD34+ cells per μL on day 4. On day 5, after plerixafor administration, the median number of circulating CD34+ cells had raised to 60 per μL (14–138). All the patients underwent leukapheresis and were able to collect a number of CD34+ cells ≥2.0 × 106/kg in a median number of procedures of one. Although preliminary, these data show the combination of biosimilar filgrastim and plerixafor is effective and provides a non‐toxic approach to mobilise stem cells.
The Medical Research Council Myeloma IX trial: the impact on treatment paradigms*
Authors: Richardson Paul G. , Laubach Jacob P. , Schlossman Robert L. , Ghobrial Irene M. , Mitsiades Constantine S. , Rosenblatt Jacalyn , Mahindra Anuj , Raje Noopur , Munshi Nikhil , Anderson Kenneth C.
Published: October 2011

Osteolytic bone disease is a hallmark of symptomatic multiple myeloma. Bisphosphonates have been the mainstay of treatment to preserve skeletal integrity and prevent skeletal‐related events in patients with myeloma‐related bone disease. Recently, the MRC Myeloma IX trial demonstrated for the first time improved survival and delayed disease progression with the use of an intravenous amino‐bisphosphonate, zoledronic acid, vs. an oral agent, clodronate, with intensive and non‐intensive anti‐myeloma treatment regimens in patients with newly diagnosed multiple myeloma. These results validate a large body of preclinical, translational and other clinical data suggesting anti‐myeloma effects of amino‐bisphosphonates. In addition, this trial also provided the first head‐to‐head evidence for superiority of one bisphosphonate over another (zoledronic acid vs. clodronate) for reducing skeletal morbidity in patients with multiple myeloma, as well as a prospective comparison of toxicities. Despite the use of non‐bortezomib containing anti‐myeloma treatment regimens in the MRC Myeloma IX trial, these results are encouraging and provide an impetus to continue to evaluate current treatment guidelines for myeloma‐associated bone disease.
Improvement and Repair: Architecture, Romance and the Politics of Gothic, 1790–1817
Authors: Townshend Dale
Published: October 2011

This article seeks to provide a politically nuanced reading of the treatment of acts of architectural modification in a selection of late 18th‐ and early 19th‐century Gothic fictions. Reading scenes of Gothic architectural restoration as they are figured in Ann Radcliffe’s The Romance of the Forest (1791); T. J. Horsley Curties’Ancient Records, Or, The Abbey of Saint Oswythe (1801); and Jane Austen’s Northanger Abbey (1817) alongside contemporary architectural debates, the argument pays particular attention to the extended cultural interchange between architect James Wyatt and Antiquarian John Carter, published in the Gentlemen’s Magazine between the years 1797 and 1817, concerning the architectural and political ‘improvement’ of the legacy of the English nation’s ancient Gothic past. Having considered the metaphors of architectural improvement, repair, restoration and demolition as they are appropriated in the political writings of Edmund Burke, Mary Wollstonecraft, John Thelwall and Hannah More during the 1790s, the article seeks to assess, via a reading of their architectural concerns, the various attitudes towards the Gothic past staged and negotiated in Charlotte Smith’s The Old Manor House (1793) and Ann Radcliffe’s The Mysteries of Udolpho (1794).
Geoffrey Hartman and the Affective Ecology of Romantic Form
Authors: Vermeulen Pieter
Published: October 2011

Geoffrey Hartman has not only been a leading voice in the study of Romanticism, but he has also made a major impact on our understanding of historical trauma and the memory of catastrophe. The combination of these two foci enables Hartman’s work to conceptualize a more indirect and subterranean relation between literary form and history than most historicist research paradigms assume. At a time when the historicist paradigms that have long dominated the study of Romanticism are increasingly being challenged by a return to literary form, a number of recent books have taken Hartman’s cue in conceiving of Romantic form as a medium that, precisely because it shields the self from the overwhelming and potentially traumatizing impact of history, paradoxically allows history to register as affect. These new approaches differ from the so‐called ‘new formalism’ in that, again like Hartman, they emphasize the phenomenological role of literary form – i.e. the role of form in our affective ecology, or the interanimation of mind and world. While these books are all firmly anchored in Romanticism, they extend the scope of Romantic studies by mobilizing the achievements of Romantic form as a vital modern phenomenon.
Dickens on the Chinese Screen
Authors: Guo Ting
Published: October 2011

As a sub‐project of the Global Circulation Project, this essay discusses how Dickens’s works have been adapted and translated for the screen in China (mainland and Hong Kong), particularly in the 1950s and 1960s. The essay examines the film Gu Xing Xue Lei (1955), a Cantonese adaptation of Dickens’s Great Expectations, and a dubbed version of David Lean’s Great Expectations (1946), respectively shown in Hong Kong and mainland Chinese cinemas, to explore the various factors affecting the rewriting process. Moreover, it argues that Dickens’s works were interpreted and consumed in two different ways in 1950s China; while the Hong Kong film industry regarded them as a rich source of inspiration, in mainland China film makers saw Dickens’s works as offering a model for the criticism of capitalist systems and social life. At the end of the essay it is argued that studying the circulation of literature via screens around the world enables researchers to observe not only the history of literary transmission but also the social, cultural and political forces driving the evolution of literature, as well as the connections between classic literature and popular culture.
The −1541 C>T and +4259 G>T of TIM‐3 polymorphisms are associated with rheumatoid arthritis susceptibility in a Chinese Hui population
Authors: Xu J. , Yang Y. , Liu X. , Wang Y.
Published: October 2011

The T‐cell immunoglobulin and mucin domain 3 (TIM‐3) has been shown to be associated with susceptibility to rheumatoid arthritis (RA). In this study, we investigated the association of four single‐nucleotide polymorphisms (SNPs) of the TIM‐3 gene with RA susceptibility in Chinese Hui and Han groups. Using restriction fragment length or sequence‐specific primer–polymerase chain reaction (PCR), patients with RA and nonarthritis control individuals from these two ethnicities were analysed for SNPs of −1541 C>T, −882 T>C, −574 T>G and +4259 G>T, in the TIM‐3 gene. Our results demonstrated that the polymorphisms of +4259 G>T SNP of TIM‐3 gene was associated with the RA susceptibility in both the Hui (P < 0.01) and Han populations (P < 0.05). However, the −1541 C>T and −574 T>G SNPs were distinctly associated with RA for the Hui and Han populations, respectively. In addition, haplotype analysis found no statistically differences in the distribution of nine detected haplotype frequency between patients with RA and controls in this study (P > 0.05). These findings suggest that polymorphism of +4259 G>T in TIM‐3 gene may be one of the most important genetic factors associated with the RA susceptibility among different populations, and genetic variations of TIM‐3 gene contribute to RA susceptibility among different populations.
Comparison of Anti‐Invasive Activity of Parthenolide and 3‐Isopropyl‐2‐Methyl‐4‐Methyleneisoxazolidin‐5‐One (MZ‐6) – A New Compound with α‐Methylene‐γ‐Lactone Motif – on Two Breast Cancer Cell Lines
Authors: Wyrębska Anna , Gach Katarzyna , Szemraj Janusz , Szewczyk Karolina , Hrabec Elżbieta , Koszuk Jacek , Janecki Tomasz , Janecka Anna
Published: October 2011

The biological activities of parthenolide, a sesquiterpene lactone isolated from feverfew, have been attributed to the presence of the α‐methylene‐γ‐lactone skeleton. The lactone skeleton can react via the Michael type addition with sulfhydryl groups of enzymes and other functional proteins, interfering with key biological processes in the cell. In the present study, we describe an efficient method of preparation of 3‐isopropyl‐2‐methyl‐4‐methyleneisoxazolidin‐5‐one (MZ‐6), a synthetic compound with α‐methylene‐γ‐lactone ring, as in parthenolide, additionally modified by introduction of a nitrogen atom. Furthermore, we investigated the cytotoxic activity and anti‐metastatic potential of MZ‐6 in comparison with parthenolide. Both compounds showed considerable cytotoxicity against breast cancer MCF‐7 and MDA‐MB‐231 adenocarcinoma cells in vitro and were then evaluated for their anti‐metastatic potential. The experimental results showed that MZ‐6 and parthenolide suppressed, to a similar degree, migration of MCF‐7, but not more aggressive MDA‐MB‐231 cells. In both cell lines, tested compounds down‐regulated mRNA and protein levels of metalloproteinase‐9 and urokinase plasminogen activator, the key proteases involved in the degradation of extracellular matrix and dissemination of cancer cells. The obtained results indicate that simple analogs of α‐methylene‐γ‐lactones can be good substitutes for more complex structures isolated from plants.
IL‐6 regulates exercise and training‐induced adaptations in subcutaneous adipose tissue in mice
Authors: Brandt C. , Jakobsen A. H. , Adser H. , Olesen J. , Iversen N. , Kristensen J. M. , Hojman P. , Wojtaszewski J. F. P. , Hidalgo J. , Pilegaard H.
Published: October 2011

Aim:  The aim of this study was to test the hypothesis that IL‐6 regulates exercise‐induced gene responses in subcutaneous adipose tissue in mice.

Methods:  Four‐month‐old male IL‐6 whole body knockout (KO) mice and C57B wild‐type (WT) mice performed 1 h of treadmill exercise, where subcutaneous adipose tissue (AT) was removed either immediately after, 4 h or 10 h after exercise as well as from mice not running acutely. Moreover, AT was sampled at resting conditions after 5 weeks of exercise training.

Results:  AT leptin mRNA decreased immediately after a single running exercise bout in both genotypes and returned to baseline within 10 h of recovery in IL‐6 KO mice, but not WT mice. Leptin mRNA content decreased in WT and increased in IL‐6 KO mice with training, but without significant alterations in leptin protein. Acute exercise induced a decrease in the AT TNFα mRNA content in WT, but not in IL‐6‐KO mice, while training lowered resting levels of TNFα mRNA in both genotypes. In addition, an exercise‐induced decline in AT PPARγ mRNA content was absent in IL‐6 KO mice and in line training increased PPARγ mRNA only in IL‐6 KO mice.

Conclusion:  The present findings indicate a role of IL‐6 in regulating exercise‐ and training‐induced leptin and PPARγ expression in adipose tissue. In addition, while IL‐6 is required for TNF‐α mRNA reduction in response to acute exercise, IL‐6 does not appear to be mandatory for anti‐inflammatory effects of exercise training in adipose tissue.
Recent Developments in Family Psychoeducation as an Evidence‐Based Practice
Authors: Lucksted Alicia , McFarlane William , Downing Donna , Dixon Lisa
Published: October 2011

Among potential resources for people with serious mental illnesses (SMI) and their families, professionally delivered family psychoeducation (FPE) is designed to engage, inform, and educate family members, so that they can assist the person with SMI in managing their illness. In this article, we review research regarding FPE outcomes and implementation since 2001, updating the previous review in this journal (McFarlane, Dixon, Lukens, & Lucksted,Journal of Marital and Family Therapy2003;29, 223). Research on a range of FPE variations continues to return mostly positive effects for adults with schizophrenia and increasingly, bipolar disorder. More recent studies include functional outcomes as well as the more common relapse and hospitalization. FPE research involving adults with other diagnoses is increasing, as is FPE research outside the United States In both cases, uneven methodologies and multiple FPE variations make drawing conclusions difficult, although the core utility of access to information, skill building, problem solving, and social support often shines though. Since the previous review, several FPE programs for parents of children or youth with mood disorders have also been developed, with limited research showing more positive than null results. Similarly, we review the developing inquiry into early intervention and FPE, short‐form FPE, and cost studies involving FPE. The second half of the article updates the paradox of FPE’s evidence base versus its persistently low use, via recent implementation efforts. Multiple challenges and facilitating factors across healthcare systems and financing, individual programs and providers, family members, and consumers shape this issue, and we conclude with discussion of the need for empirical evaluation of implementation strategies and models.
Angiotensinogen gene haplotype is associated with the prevalence of Japanese non‐alcoholic steatohepatitis
Authors: Ono Masafumi , Ochi Tsunehiro , Munekage Kensuke , Ogasawara Mitsunari , Hirose Akira , Nozaki Yasuko , Takahashi Masaya , Okamoto Nobuto , Saibara Toshiji
Published: October 2011

Aim:  Non‐alcoholic steatohepatitis (NASH) patients frequently have hypertension, which is considered to be an important predictive factor for the subsequent development of hepatic fibrosis. The renin‐angiotensin system is also known to contribute to the progression of NASH. Various types of functional single‐nucleotide polymorphisms (SNPs) involved in the development of NASH have been proposed. Angiotensinogen (AGT) gene SNPs related to cardiovascular diseases have been reported. We aimed to evaluate the involvement of the AGT gene haplotype in Japanese NASH patients.

Methods:  Previously described genotypes of SNPs of the AGT gene, rs4762 C/T polymorphism (T207M), rs699 C/T polymorphism (T268M), and rs7079 C/A polymorphism (C11537A), were determined in 124 Japanese biopsy‐proven NASH patients and 150 healthy volunteers (controls).

Results:  The allele and genotype frequencies in rs4762 and rs699 SNPs in NASH patients were similar to those in controls, while the frequency of the A allele and A/‐ genotype in rs7079 SNPs were much higher in NASH patients than in controls. In addition, the 3‐SNP haplotype CTA was significantly over‐represented in NASH patients compared with controls. Regarding clinical features of NASH patients, diastolic blood pressures in patients with the CTA/‐ genotype were much higher than in patients with other genotypes.

Conclusions:  We found a 3‐SNP haplotype of the AGT gene that is involved in the development of NASH and influences hypertension in NASH patients. These results provide new insight into the therapy of NASH patients with the CTA haplotype using ACE inhibitors or angiotensin II type 1 receptor blockers.
Strategies to produce hepatocytes and hepatocyte‐like cells from pluripotent stem cells
Authors: Chistiakov Dimitry A. , Chistiakov Pavel A.
Published: October 2011

Human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are a potent source for unlimited production of hepatocytes and hepatocyte‐like cells that may replace primary human hepatocytes in a variety of fields including liver cell therapy, liver tissue engineering, manufacturing bioartificial liver, modeling inherited and chronic liver diseases, drug screening and toxicity testing. Human ESCs are able to spontaneously form embryoid bodies, which then spontaneously differentiate to various tissue‐specific cell lineages containing a total of 10–30% albumin‐producing hepatocytes and hepatocyte‐like cells. Enrichment of embryoid bodies with the definitive endoderm, from which hepatocytes arise, yields increasing the final ratio of hepatocyte population up by 50–65%. Current strategies of the directed differentiation of human ESCs (and iPSCs) to hepatocytes that reproduce liver embryogenesis by sequential stimulation of culturing ESCs with tissue‐specific growth factors result in achieving the differentiation rate up to 60–80%. In the future, directed differentiation of human ESCs and iPSCs to hepatocytes should be further optimized towards generating homogeneous cultures of hepatocytes in order to avoid expensive procedures of separation and isolation of hepatocytes and hepatocyte‐like cells.
Useful Ethnographies
Authors: deRoche Constance
Published: October 2011

Books reviewed in this issue.

The Gift of a Bride: A Tale of Anthropology, Matrimony and Murder, Serena Nanda and Joan Gregg.

Assisted Dying: An Ethnographic Murder Mystery on Florida's Gold Coast, Serena Nanda and Joan Gregg.
Liraglutide is effective in type 2 diabetic patients with sustained endogenous insulin‐secreting capacity
Authors: Kozawa Junji , Inoue Kana , Iwamoto Ryuya , Kurashiki Yukiko , Okauchi Yukiyoshi , Kashine Susumu , Kitamura Tetsuhiro , Maeda Norikazu , Okita Kohei , Iwahashi Hiromi , Funahashi Tohru , Imagawa Akihisa , Shimomura Iichiro
Published: October 2011

Aims/Introduction:  Recently, glucagon‐like peptide‐1 (GLP‐1) receptor agonists of liraglutide have become available in Japan. It has not yet been clarified what clinical parameters could discriminate liraglutide‐effective patients from liraglutide‐ineffective patients.

Materials and Methods:  We reviewed 23 consecutive patients with type 2 diabetes admitted to Osaka University Hospital for glycemic control. All of the patients were treated with diet plus insulin (or plus oral antidiabetic drugs) to improve fasting plasma glucose (FPG) and postprandial glucose below 150 and 200 mg/dL, respectively. After insulin secretion and insulin resistance were evaluated, insulin was replaced by liraglutide. The efficacy of liraglutide was determined according to whether glycemic control was maintained at the target levels.

Results:  Liraglutide was effective in 13 of 23 patients. There were significant differences in the parameters of insulin secretion, including fasting C‐peptide (F‐CPR), C‐peptide index (CPI), insulinogenic index (I.I.) and urine C‐peptide (U‐CPR), between liraglutide‐effective and ‐ineffective patients. The duration of diabetes was significantly shorter in liraglutide‐effective patients than in liraglutide‐ineffective patients. In receiver operating characteristic analyses, the cut‐off value for predicting the efficacy of liraglutide was 0.14 for I.I., 1.1 for CPI, 1.5 ng/mL for F‐CPR, 33.3 μg/day for U‐CPR and 19.5 years for duration of type 2 diabetes.

Conclusions:  Insulin secretion evaluated by F‐CPR, CPI, I.I., U‐CPR and the duration of type 2 diabetes were useful parameters for predicting the efficacy of liraglutide in patients with type 2 diabetes. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00168.x, 2011)
Effects of 20-hydroxyecdysone, Leuzea carthamoides extracts, dexamethasone and their combinations on the NF-κB activation in HeLa cells
Authors: Peschel Wieland , Kump Alfred , Prieto José Maria
Published: October 2011

Objectives

The plant steroid 20-hydroxyecdysterone (20E) and 20E-containing extracts from Leuzea carthamoides (Willd.) DC are sold with claims of anabolic and immunomodulatory effects. Yet their effect on the activation of nuclear factor kappa B (NF-κB), a key player in immune response and cell fate, and their influence on the NF-κB-inhibiting activity of steroidal anti-inflammatory drugs is still unknown.

Methods

The ability of 20E, Leuzea extracts and selected steroidal/non-steroidal anti-inflammatory drugs to influence the activation of NF-κB was explored using, as the experimental model, human cervical cancer HeLa-IL-6 cells stably transfected with an IL-6-bound reporter gene. Effects on cell viability and proliferation were monitored (MTT assay). HPLC-DAD was used to establish links between chemical patterns of Leuzea extracts and their bioactivities.

Key findings

20E inhibited NF-κB activation (IC50 31.8 µm) but was less active than other plant metabolites (xanthohumol 3.8 µm, withaferin A 1.4 µm). Leuzea extracts with high content in 20E had a fair activating effect, but in contrast, some extracts with low 20E content significantly inhibited NF-κB activation at IC50s ranging from 3.5 to 6.2 µg/ml. Combination tests confirmed that 20E does not explain the NF-κB modulation achieved by Leuzea extracts. The extracts but not 20E itself showed a significant modulation of the NF-κB inhibitory effect of dexamethasone.

Conclusions

20E is unlikely a major player in the NF-κB inhibitory effects displayed by some Leuzea extracts in vitro. If confirmed in vivo, caution should prevail towards marketed Leuzea extracts that are non-standardised or standardised on 20E only, since different starting materials and extracts may even cause opposite effects. More importantly, our results indicate the interaction potential of Leuzea with steroidal anti-inflammatory drugs.
CPUYJ039, a newly synthesized benzimidazole-based compound, is proved to be a novel inducer of apoptosis in HCT116 cells with potent KSP inhibitory activity
Authors: Jiang Cheng , Yang Lei , Wu Wu-Tong , Guo Qing-Long , You Qi-Dong
Published: October 2011

Objectives

This study investigated the antiproliferative and apoptotic activities of CPUYJ039, a newly synthesized benzimidazole-based kinesin spindle protein (KSP) inhibitor, on HCT116 cell lines.

Methods

KSP-inhibitory activity was tested using the malachite-green method. The in-vitro cell proliferation inhibitory activity of the sample was measured using WST reagent. Flow-cytometric evaluation of cellular DNA content was performed. Apoptotic cells were quantified by annexin V-FITC-PI double staining. To confirm that the cytotoxic activity was a consequence of KSP inhibition, microtubule morphology and DNA segregation were observed by double staining of microtubules and DNA. The expression of Bcl-2 and Bax in CPUYJ039-treated HCT116 cells was detected by Western blotting.

Key findings

CPUYJ039 was evaluated and proved to have potent inhibitory activities in the KSP ATPase and HCT116 cell proliferation assays. CPUYJ039 inhibited the proliferation of HCT116 cells in a dose- and time-dependent manner and markedly induced G2/M phase cell-cycle arrest with characteristic monoastral spindles and subsequent cell death in HCT116 cells, which was associated with an increase of the Bax/Bcl-2 ratio.

Conclusions

These results suggest that CPUYJ039 may be a novel inducer of apoptosis in HCT116 cells with potent KSP inhibitory activity.
On the Effect of Shear on Plastic Deformation of Beams Under Transverse Impact Loading
Authors: Karunes B. , Onat E. T.
Published: October 2011

The impact problem for a rigid-plastic beam is formulated by using an interaction curve relating shearing force and bending moment for fully plastic action, and allowing for shear and rotary inertia effects. Using a simplified interaction diagram, the problem of point-impact loading is solved for a special case. The analysis shows that the shear effects are of considerable importance when the parameter μ0 = 2Q0l/M0 is less than 20 where Q0 and M0 are plastic-carrying capacities of the cross section for pure shear and bending, respectively, and 21 is the length of the beam.
Plastic-Wave Propagation Effects in Transverse Impact of Membranes
Authors: Karunes B. , Onat E. T.
Published: October 2011

The paper is concerned with the plane motion of a rigid-strain-hardening membrane attached to two parallel fixed supports. The membrane is subjected to a uniformly distributed transverse impulse and the subsequent motion of the membrane is to be determined with the particular emphasis on the variation of thickness in the final deflected shape. It is first shown that two essentially different initial modes of deformation exist depending on the average rate of hardening. For both modes, the analysis can be based on two types of waves of discontinuity until the moment when the compressive membrane forces occur in the middle region of the membrane. The presence of compressive forces will generally preclude the existence of a unique solution for further motion. The bending rigidity will probably have to be included into the analysis in order to obtain a unique solution. However, for the technically important rates of hardening and velocities, the kinetic energy of the membrane at the moment of occurrence of compressive forces is small compared with the initial energy, so that significant information could be obtained from the present analysis about the variation of thickness and hardening throughout the membrane.
An Analytical Method for Locating the Burmester Points for Five Infinitesimally Separated Positions of the Coupler Plane of a Four-Bar Mechanism
Authors: Wolford J. C.
Published: October 2011

A method is developed for analytically locating the Burmester points for the motion of the coupler plane of a four-bar mechanism through five infinitesimally separated positions. The results of an example are compared with the results obtained by the graphical method of Mu¨ller for locating the Burmester points. The two methods are found to give essentially identical results.
A Theory of Lubrication With Turbulent Flow and Its Application to Slider Bearings
Authors: Tao L. N.
Published: October 2011

The governing equation of turbulent lubrication in three dimensions, equivalent to the Reynolds equation of laminar lubrication, is derived. The problem of a slider bearing with no side leakage is then analyzed. An exact solution is found in closed form. Bearing characteristics are also established. It is found that the Reynolds number is an important parameter in the problem of turbulent lubrication. Furthermore, it is shown that the laminar lubrication may be considered as the special case of the present study. A numerical example is also included.