bluuebunny/crossref_metadata_2025 huggingface dataset:
Tailored total lymphoid irradiation in heart transplant patients: 10-years experience of one center
Authors: Ghadjar Pirus , Joos Daniela , Martinelli Michele , Hullin Roger , Zwahlen Marcel , Lössl Kristina , Carrel Thierry , Aebersold Daniel M , Mohacsi Paul
Published: January 2010

Background

To assess safety and efficacy of tailored total lymphoid irradiation (tTLI) in cardiac transplant patients.

Methods

A total of seven patients, of which five had recalcitrant cellular cardiac allograft rejection (RCCAR), confirmed by endomyocardial biopsies, and two had side effects of immunosuppressive drug therapy, were all treated with tTLI. tTLI was defined by the adjustment of both the fraction interval and the final irradiation dosage both being dependent on the patients general condition, irradiation-dependent response, and the white blood and platelet counts. A mean dose of 6.4 Gy (range, 1.6 - 8.8 Gy) was given. Median follow-up was 7 years (range, 1.8 - 12.2 years).

Results

tTLI was well tolerated. Two patients experienced a severe infection during tTLI (pneumocystis jirovecii pneumonia, urosepsis and generalized herpes zoster) and one patient developed a lymphoproliferative disorder after tTLI. The rate of rejection episodes before tTLI was 0.43 episodes/patient/month and decreased to 0.02 episodes/patient/month after tTLI (P < .001). At the end of the observation time, all patients except one were alive.

Conclusions

tTLI is a useful treatment strategy for the management of RCCAR and in patients with significant side effects of immunosuppressive drug therapy. In this series tTLI demonstrated significantly decreased rejection rates without causing relevant treatment-related toxicity.
HIV‐related restrictions on entry, residence and stay in the WHO European Region: a survey
Authors: Lazarus Jeffrey V , Curth Nadja , Weait Matthew , Matic Srdan
Published: January 2010

Background

Back in 1987, the World Health Organization (WHO) concluded that the screening of international travellers was an ineffective way to prevent the spread of HIV. However, some countries still restrict the entrance and/or residency of foreigners with an HIV infection. HIV‐related travel restrictions have serious implications for individual and public health, and violate internationally recognized human rights. In this study, we reviewed the current situation regarding HIV‐related travel restrictions in the 53 countries of the WHO European Region.

Methods

We retrieved the country‐specific information chiefly from the Global Database on HIV Related Travel Restrictions at hivtravel.org. We simplified and standardized the database information to enable us to create an overview and compare countries. Where data was outdated, unclear or contradictory, we contacted WHO HIV focal points in the countries or appropriate non‐governmental organizations. The United States Bureau of Consular Affairs website was also used to confirm and complement these data.

Results

Our review revealed that there are no entry restrictions for people living with HIV in 51 countries in the WHO European Region. In 11 countries, foreigners living with HIV applying for long‐term stays will not be granted a visa. These countries are: Andorra, Armenia, Cyprus (denies access for non‐European Union citizens), Hungary, Kazakhstan, Moldova, the Russian Federation, Tajikistan, Turkmenistan, Ukraine and Uzbekistan. In Uzbekistan, an HIV‐positive foreigner cannot even enter the country, and in Georgia, we were not able to determine whether there were any HIV‐related travel restrictions due to a lack of information.

Conclusions

In 32% of the countries in the European Region, either there are some kind of HIV‐related travel restrictions or we were unable to determine if such restrictions are in force. Most of these countries defend restrictions as being justified by public health concerns. However, there is no evidence that denying HIV‐positive foreigners access to a country is effective in protecting public health. Governments should revise legislation on HIV‐related travel restrictions. In the meantime, a joint effort is needed to draw attention to the continuing discrimination and stigmatization of people living with HIV that takes place in those European Region countries where such laws and policies are still in force.
PhenomiR: a knowledgebase for microRNA expression in diseases and biological processes
Authors: Ruepp Andreas , Kowarsch Andreas , Schmidl Daniel , Buggenthin Felix , Brauner Barbara , Dunger Irmtraud , Fobo Gisela , Frishman Goar , Montrone Corinna , Theis Fabian J
Published: January 2010

In recent years, microRNAs have been shown to play important roles in physiological as well as malignant processes. The PhenomiR database http://mips.helmholtz-muenchen.de/phenomir provides data from 542 studies that investigate deregulation of microRNA expression in diseases and biological processes as a systematic, manually curated resource. Using the PhenomiR dataset, we could demonstrate that, depending on disease type, independent information from cell culture studies contrasts with conclusions drawn from patient studies.
Thrombospondin-1 Inhibits Angiogenesis and Promotes Follicular Atresia in a Novel in Vitro Angiogenesis Assay
Authors: Garside Samantha A. , Harlow Christopher R. , Hillier Stephen G. , Fraser Hamish M. , Thomas Fiona H.
Published: January 2010

Thrombospondin-1 (TSP-1) is a putative antiangiogenic factor, but its role in regulating physiological angiogenesis is unclear. We have developed a novel in vitro angiogenesis assay to study the effect of TSP-1 on follicular angiogenesis and development. Intact preantral/early antral follicles dissected from 21-d-old rat ovaries were cultured for 6 d in the presence or absence of TSP-1. At the end of the culture period, angiogenic sprouting from the follicles was quantified using image analysis. Follicles were fixed and sectioned, and follicular apoptosis was assessed by immunohistochemistry for activated caspase-3 in granulosa cells. The results showed that TSP-1 inhibited follicular angiogenesis (P < 0.01) and promoted follicular apoptosis (P < 0.001) in a dose-dependent manner. To determine whether the proapoptotic activity of TSP-1 is mediated by direct effects on granulosa cells, isolated granulosa cells were cultured with TSP-1 (0, 10, 100, and 1000 ng/ml) for 48 h. Apoptosis was quantified using a luminescent caspase-3/7 assay. TSP-1 promoted apoptosis of granulosa cells in a dose-dependent manner (P < 0.05), suggesting that TSP-1 can act independently of the angiogenesis pathway to promote follicular apoptosis. These results show that TSP-1 can both inhibit follicular angiogenesis and directly induce apoptosis of granulosa cells. As such, it may have potential as a therapeutic for abnormal ovarian angiogenesis and could facilitate the destruction of abnormal follicles observed in polycystic ovary syndrome.
Limb Muscles Are Androgen Targets in an Acrobatic Tropical Bird
Authors: Feng Ni Y. , Katz Amnon , Day Lainy B. , Barske Julia , Schlinger Barney A.
Published: January 2010

Spectacular athleticism is a conspicuous feature of many animal courtship displays yet surprisingly little is known about androgen dependence of skeletal muscles underlying these displays. Testosterone (T) acts through androgen receptors (ARs) to stimulate muscular male Golden-collared manakins of Panama to perform a remarkably athletic courtship display that includes loud wingsnaps generated by the rapid and forceful lifting of the wings. We tested the hypothesis that androgen sensitivity, reflected in the expression levels of AR mRNA, is a muscular adaptation supporting these courtship displays. Quantitative PCR showed substantially greater AR mRNA expression in all limb muscles of wild male and female manakins compared with two other avian species that do not perform athletic displays, zebra finches and ochre-bellied flycatchers. AR expression levels in the massive skeletal muscles were comparable with the minute oscine syringeal muscle but greater than levels in nonmuscular androgen targets that did not differ across species. Compared with zebra finches, male manakins also had greater activity of the T-activating enzyme 5α-reductase in a wing-lifting muscle. In addition, low levels of estrogen receptor α (ER) mRNA were detected in all muscles of control, T-treated, and estradiol-treated manakins. Treatment of manakins with T, but not estradiol, significantly increased skeletal muscle ER expression, suggesting that ER expression is AR-dependent. These results confirm manakin limb muscles as important androgen targets where T may act to promote the speed, force, and/or endurance required for the manakin display. Androgen-sensitive muscular phenotypes may adapt males of many species to perform impressive athletic displays.
Involvement of Transducer of Regulated cAMP Response Element-Binding Protein Activity on Corticotropin Releasing Hormone Transcription
Authors: Liu Ying , Coello Ana G. , Grinevich Valery , Aguilera Greti
Published: January 2010

We have recently shown that phospho-cAMP response element-binding protein (CREB) is essential but not sufficient for activation of CRH transcription, suggesting the requirement of a coactivator. Here, we test the hypothesis that the CREB coactivator, transducer of regulated CREB activity (TORC), is required for activation of CRH transcription, using the cell line 4B and primary cultures of hypothalamic neurons. Immunohistochemistry and Western blot experiments in 4B cells revealed time-dependent nuclear translocation of TORC1,TORC 2, and TORC3 by forskolin [but not by the phorbol ester, phorbol 12-myristate 13-acetate (PMA)] in a concentration-dependent manner. In reporter gene assays, cotransfection of TORC1 or TORC2 potentiated the stimulatory effect of forskolin on CRH promoter activity but had no effect in cells treated with PMA. Knockout of endogenous TORC using silencing RNA markedly inhibited forskolin-activated CRH promoter activity in 4B cells, as well as the induction of endogenous CRH primary transcript by forskolin in primary neuronal cultures. Coimmunoprecipitation and chromatin immunoprecipitation experiments in 4B cells revealed association of CREB and TORC in the nucleus, and recruitment of TORC2 by the CRH promoter, after 20-min incubation with forskolin. These studies demonstrate a correlation between nuclear translocation of TORC with association to the CRH promoter and activation of CRH transcription. The data suggest that TORC is required for transcriptional activation of the CRH promoter by acting as a CREB coactivator. In addition, cytoplasmic retention of TORC during PMA treatment is likely to explain the failure of phorbolesters to activate CRH transcription in spite of efficiently phosphorylating CREB.
Disrupted Corticosterone Pulsatile Patterns Attenuate Responsiveness to Glucocorticoid Signaling in Rat Brain
Authors: Sarabdjitsingh R. Angela , Isenia Sheena , Polman Annelies , Mijalkovic Jona , Lachize Servane , Datson Nicole , de Kloet E. Ron , Meijer Onno C.
Published: January 2010

Chronically elevated circulating glucocorticoid levels are although to enhance vulnerability to psychopathology. Here we hypothesized that such sustained glucocorticoid levels, disturbing corticosterone pulsatility, attenuate glucocorticoid receptor signaling and target gene responsiveness to an acute challenge in the rat brain. Rats were implanted with vehicle or 40 or 100% corticosterone pellets known to flatten ultradian and circadian rhythmicity while maintaining daily average levels or mimic pathological conditions. Additionally, recovery from constant exposure was studied in groups that had the pellet removed 24 h prior to the challenge. Molecular markers for receptor responsiveness (receptor levels, nuclear translocation, promoter occupancy, and target gene expression) to an acute challenge mimicking the stress response (3 mg/kg ip) were studied in the hippocampal area. Implantation of 40 and 100% corticosterone pellets dose-dependently down-regulated glucocorticoid receptor and attenuated mineralocorticoid receptor and glucocorticoid receptor translocation to the acute challenge. Interestingly, whereas target gene Gilz expression to the challenge was already attenuated by tonic daily average levels (40%), Sgk-1 was affected only after constant high corticosterone exposure (100%), indicating altered receptor responsiveness due to treatment. Washout of 100% corticosterone recovered all molecular markers (partial), whereas removal of the 40% corticosterone pellet still attenuated responsiveness to the challenge. We propose that corticosteroid pulsatility is crucial in maintaining normal responsiveness to glucocorticoids. Whereas the results with 100% corticosterone are likely attributed to receptor saturation, subtle changes in the pattern of exposure (40%) induces changes at least as severe for glucocorticoid signaling as overt hypercorticism, suggesting an underlying mechanism sensitive to the pattern of hormone exposure.
Epidermal Growth Factor Receptor Is an Obligatory Intermediate for Oxytocin-Induced Cyclooxygenase 2 Expression and Prostaglandin F2α Production in Bovine Endometrial Epithelial Cells
Authors: Krishnaswamy Narayanan , Lacroix-Pepin Nicolas , Chapdelaine Pierre , Taniguchi Hiroaki , Kauffenstein Gilles , Chakravarti Arpita , Danyod Ghislain , Fortier Michel A.
Published: January 2010

Oxytocin (OT) triggers the luteolytic pulses of prostaglandin F2α (PGF2α) from the endometrial epithelial cells in ruminants. We have proposed that the embryonic signal interferon-τ exerts its antiluteolytic effect by disrupting the OT signaling axis. Accordingly, we have attempted to define the signaling pathway of OT-induced PGF2α production in the bovine endometrium using our newly characterized epithelial cell line (bEEL). OT receptor was coupled to the classical Gαq pathway as evidenced by calcium release and activation of phospholipase C. Similarly, OT-induced PGF2α production was mediated through the canonical ERK1/2 pathway. Because of the importance of receptor and nonreceptor tyrosine kinases in G protein-coupled receptor signaling, we studied the role of epidermal growth factor receptor (EGFR), c-Src, and phosphoinositide 3-kinase (PI3K) on OT-induced PGF2α production in association with cyclooxygenase 2 (COX2) expression and ERK1/2 and Akt phosphorylation. The EGFR inhibitor AG1478 (10 μm) nearly abolished basal and OT-induced PGF2α production and down-regulated COX2 expression and ERK1/2 phosphorylation. Because the transactivated EGFR can serve as a ligand for the signaling proteins with Src homology 2 (SH2) domain, we hypothesized a role for c-Src and PI3K in OT-induced PGF2α production. Inhibitors of c-Src (PP2, 10 μm) and PI3K (LY294002, 25 μm) produced a significant decrease in OT-induced PGF2α production and reduced COX2 expression. Also, PP2, but not LY294002, decreased OT-induced ERK1/2 phosphorylation. Because LY294002 did not affect ERK1/2 phosphorylation, but inhibited PGF2α production and down-regulated COX2 expression, it is likely that the Akt pathway is also involved in PGF2α production. Thus, EGFR may simultaneously activate c-Src and PI3K to amplify the OT signaling to increase the output of PGF2α in bEEL cells.
Hip Fracture Prevalence in Grandfathers Is Associated with Reduced Cortical Cross-Sectional Bone Area in Their Young Adult Grandsons
Authors: Rudäng Robert , Ohlsson Claes , Odén Anders , Johansson Helena , Mellström Dan , Lorentzon Mattias
Published: January 2010

Context: Parent hip fracture prevalence is a known risk factor for osteoporosis. The role of hip fracture prevalence in grandparents on areal bone mineral density (aBMD) and bone size in their grandsons remains unknown.

Objective: The objective of the study was to examine whether hip fracture prevalence in grandparents was associated with lower aBMD and reduced cortical bone size in their grandsons.

Design and Setting: This was a population-based cohort study in Sweden.

Study Subjects: Subjects included 1015 grandsons (18.9 ± 0.6) (mean ± sd) and 3688 grandparents.

Main Outcome Measures: aBMD, cortical bone size, volumetric bone mineral density and polar strength strain index of the cortex in the grandsons in relation to hip fracture prevalence in their grandparents were measured.

Results: Grandsons of grandparents with hip fracture (n = 269) had lower aBMD at the total body, radius, and lumbar spine, but not at the hip, as well as reduced cortical cross-sectional area at the radius (P < 0.05) than grandsons of grandparents without hip fracture. Subgroup analysis demonstrated that grandsons of grandfathers with hip fracture (n = 99) had substantially lower aBMD at the lumbar spine (4.9%, P < 0.001) and total femur (4.1%, P = 0.003) and lower cortical cross-sectional area of the radius (4.1%, P < 0.001) and tibia (3.3%, P < 0.011). Adjusting bone variables for grandson age, weight, height, smoking, calcium intake, and physical activity and taking grandparent age at register entry, years in register, and grandparent sex into account strengthened or did not affect these associations.

Conclusions: Family history of a grandfather with hip fracture was associated with reduced aBMD and cortical bone size in 19-yr-old men, indicating that patient history of hip fracture in a grandfather could be of value when evaluating the risk of low bone mass in men.
Congenital Lipoid Adrenal Hyperplasia: Functional Characterization of Three Novel Mutations in the STAR Gene
Authors: Bens Susanne , Mohn Angelika , Yüksel Bilgin , Kulle Alexandra E. , Michalek Matthias , Chiarelli Franco , Nuri Özbek Mehmet , Leuschner Ivo , Grötzinger Joachim , Holterhus Paul-Martin , Riepe Felix G.
Published: January 2010

Context: The steroidogenic acute regulatory protein (StAR) has been shown to be essential for steroidogenesis by mediating cholesterol transfer into mitochondria. Inactivating StAR mutations cause the typical clinical picture of congenital lipoid adrenal hyperplasia.

Objective: The objective of the investigation was to study the functional and structural consequences of three novel StAR mutations (p.N148K in an Italian patient; p.P129fs and p.Q128R in a Turkish patient).

Methods and Results: Transient in vitro expression of the mutant proteins together with P450 side-chain cleavage enzyme, adrenodoxin, and adrenodoxin reductase yielded severely diminished cholesterol conversion of the p.N148K mutant, the combined p.P129fs and p.Q128R mutant, and the p.P129fs mutant by itself. The p.Q128R mutant led to a higher cholesterol conversion than the wild-type StAR protein. As derived from three-dimensional protein modeling, the residue N148 is lining the ligand cavity of StAR. A positively charged lysine residue at position 148 disturbs the hydrophobic cluster formed by the α4-helix and the sterol binding pocket. The frame shift mutation p.P129fs truncates the StAR protein. Residue p.Q128 is situated at the surface of the molecule and is not part of any functionally characterized region of the protein.

Conclusion: The mutations p.N148K and p.P129fs cause adrenal insufficiency in both cases and lead to a disorder of sex development with complete sex reversal in the 46, XY case. The mutation p.Q128R, which is not relevant for the patient’s phenotype, is the first reported variant showing a gain of function. We speculate that the substitution of hydrophilic glutamine with basic arginine at the surface of the molecule may accelerate cholesterol transfer.
Phenotype-Genotype Correlations of 13 Rare CYP21A2 Mutations Detected in 46 Patients Affected with 21-Hydroxylase Deficiency and in One Carrier
Authors: Tardy V. , Menassa R. , Sulmont V. , Lienhardt-Roussie A. , Lecointre C. , Brauner R. , David M. , Morel Y.
Published: January 2010

Context: Steroid 21-hydroxylase deficiency is the most common enzymatic defect causing congenital adrenal hyperplasia with genotype/phenotype relationships for common mutations. Novel mutations of the CYP21A2 gene must be well studied to propose right genetic counseling for patients.

Objective: Thirteen CYP21 mutations have been studied. A detailed description of phenotype was performed for all mutations (p.I77T, p.L167P, p.I230T, p.R233K, p.G291S, p.G292D, p.E320K, p.R341P, p.R354H, p.R369W, p.R408C, p.G424S, and p.R426H). In vitro and in silico studies were performed only for those not previously described (p.L167P, p.I230T, p.R233K, p.G292D, p.E320K, and p.R369W).

Results: Regarding phenotype, patients with 10 of these mutations had a classical form. A patient with isolated p.I230T presented with nonclassical form and a patient with the association p.I230T + p.V281L in cis presented with a more severe phenotype. The p.R233K mutation was detected in a carrier partner. A patient with p.R369W presented with an intermediate form. Functional studies showed that all mutations except p.I230T and p.R369W decreased enzyme activity more than p.P30L: severity of p.R369W was intermediate between p.P30L and p.V281L, and finally p.I230T was less severe than p.V281L. Mutation analysis in a three-dimensional model structure of the CYP21 protein explained the observed in vitro effects, severe mutations being implicated in important functional domains of the protein.

Conclusion: According to phenotype and functional studies, 11 of the mutations described, except the isolated p.R369W and p.I230T, may be responsible for a severe phenotype underlying the necessity to manage children having them. The p.I230T is a nonclassical mutation, and for the p.R369W, we need more cases to precise its severity.
Growth Hormone and Insulin-Like Growth Factor I Insensitivity of Fibroblasts Isolated from a Patient with an IκBα Mutation
Authors: Wu Shufang , Walenkamp Marie J. , Lankester Arjan , Bidlingmaier Martin , Wit Jan M. , De Luca Francesco
Published: January 2010

Context: NF-κB is a family of transcription factors involved in cell proliferation, differentiation, and apoptosis.

Objective: We have recently demonstrated that NF-κB is expressed in the growth plate and it mediates the growth-promoting effects of IGF-I on chondrogenesis and longitudinal bone growth. Humans with defects of the NF-κB pathway exhibit growth failure, which suggests a possible regulatory role for NF-κB in statural growth. We have previously reported a child with ectodermal dysplasia, immunodeficiency, and growth retardation, harboring a heterozygous mutation of IκBα, an essential component of the NF-κB pathway. Since he was found with low IGF-l and IGFBP-3, and elevated GH secretion, an IGF-l generation test was carried out: baseline IGF-l was low and only responded to a high dose of GH. Thus, the diagnosis of GH resistance was made.

Results: To assess the underlying mechanisms of his GH resistance, we cultured the patient’s skin fibroblasts with GH and/or IGF-I. While both GH and IGF-l induced cell proliferation and NF-κB activity in controls’ fibroblasts, they had no effect on the patient’s fibroblasts. In the fibroblasts of the patient’s father (who displays mosaicism for the IκBα mutation), GH and IGF-l elicited an attenuated stimulatory effect. In addition, GH stimulated STAT5 phosphorylation and IGF-l mRNA expression in controls ’ and the father’s fibroblasts, while IGF-l induced PI3K activity and mRNA and protein expression of TDAG51, a target gene for IGF-I. In contrast, none of these effects was elicited by GH or IGF-l in the patient’s fibroblasts.

Conclusion: Our findings suggest that this patient’s IκBα mutation caused GH and IGF-l resistance which, in turn, contributed to his growth failure.
Delayed Remission after Transsphenoidal Surgery in Patients with Cushing’s Disease
Authors: Valassi Elena , Biller Beverly M. K. , Swearingen Brooke , Pecori Giraldi Francesca , Losa Marco , Mortini Pietro , Hayden Douglas , Cavagnini Francesco , Klibanski Anne
Published: January 2010

Background: Transsphenoidal surgery (TSS) is the treatment of choice for Cushing’s disease (CD). Postoperative hypercortisolemia mandates further therapy.

Objective: The aim of the study was to characterize patients without immediate postoperative remission who have a delayed decrease to normal or low cortisol levels without further therapy.

Design and Setting: A retrospective case series was conducted at three tertiary care centers.

Patients and Intervention: We reviewed the records of 620 patients (512 females, 108 males; mean age, 38 ± 13 yr) who underwent transsphenoidal pituitary surgery for CD between 1982 and 2007.

Results: Outcomes were classified into the following three groups based upon the postoperative pattern of cortisol testing: group IC (immediate control) included 437 of the 620 patients (70.5%) with hypocortisolism and/or cortisol normalization throughout the postoperative follow-up; group NC (no control) included 148 of 620 patients (23.9%) with persistent hypercortisolism; and group DC (delayed control) included 35 of 620 patients (5.6%) who had early elevated or normal UFC levels and developed a delayed and persistent cortisol decrease after an average of 38 ± 50 postoperative days. The total rate of recurrence was 13% at a median follow-up time of 66 months after TSS; the cumulative rate of recurrence at 4.5 yr was significantly higher in group DC vs. group IC (43 vs. 14%; P = 0.02).

Conclusions: Hormonal assessment in the immediate postoperative period after TSS for CD may be misleading because delayed remission can occur in a subset of patients. Expectant management and retesting may spare some patients from unnecessary further treatment. Optimal timing to determine the need for further therapy after TSS remains to be determined.
Impact of Growth Hormone Therapy on Quality of Life in Adults with Turner Syndrome
Authors: Amundson Emily , Boman Ulla Wide , Barrenäs Marie-Louise , Bryman Inger , Landin-Wilhelmsen Kerstin
Published: January 2010

Context: GH and/or oxandrolone are used to promote growth in Turner syndrome (TS).

Objective: The aim of this study was to compare quality of life (QoL) in TS women with controls and determine the impact of growth promoting therapy on QoL in TS women.

Design: This was a cross-sectional, case-control study.

Setting: The study was conducted at an outpatient clinic at Sahlgrenska University Hospital, Göteborg, Sweden.

Patients: Patients included 111 TS women (age range 18–59 yr) and 111 randomly selected, age-matched women (25–54 yr) from the World Health Organization Monitoring Trends and Determinants for Cardiovascular Disease project (Göteborg, Sweden) served as controls.

Main Outcome Measures: QoL was estimated by the Psychological General Well-Being scale (anxiety, depressed mood, positive well-being, self-control, general health and vitality) and the Nottingham Health Profile (physical mobility, pain, sleep, energy, social isolation, and emotional reactions).

Results: TS women reported more social isolation than controls (P < 0.001). After age adjustment, significantly less pain (<0.05) was reported attributable to GH treatment within TS. No significant difference in any other subscales used could be shown. In TS, QoL was negatively affected by higher current age and age at diagnosis and positively affected by better body balance, fine motor function, and higher bone mineral density.

Conclusions: Social isolation was more commonly reported in the whole TS cohort than in the population. Except for less pain, no significant impact on QoL attributable to GH treatment could be found, despite the mean +5.1 cm final height.
Change in Amniotic Fluid Levels of Multiple Anti-Angiogenic Proteins before Development of Preeclampsia and Intrauterine Growth Restriction
Authors: Wang Chao-Nin , Chang Shuenn-Dyh , Peng Hsiu-Huei , Lee Yun-Shien , Chang Yao-Lung , Cheng Po-Jen , Chao An-Shine , Wang Tzu-Hao , Wang Hsin-Shih
Published: January 2010

Context: The cause of preeclampsia remains unknown. Excessive antiangiogenic proteins have been proposed to play a pathogenic role in preeclampsia.

Objective: Our objective was to determine the differences in soluble endoglin (sEndoglin), soluble fms-like tyrosine kinase receptor-1 (sFLT1), leptin, adiponectin, and endothelin 1 concentrations between normal and preeclampsia amniotic fluid (AF). Such results may help us understand the pathophysiology of preeclampsia.

Methods: We performed a nested case-control study. Seventy-one women with preeclampsia were matched to 71 normotensive controls. The preeclamptic women were broken into two subgroups according to the association with fetal intrauterine growth restriction (IUGR). AF concentrations of sEndoglin, sFLT1, leptin, adiponectin, and endothelin 1 were measured by ELISA. Receiver-operating characteristics curve analysis was used to compare the discriminative values of these potential biomarkers. Functional network analysis was performed using MetaCore to reveal the common functions of the interacting proteins.

Results: Increased AF concentrations of sFLT1, sEndoglin, endothelin 1, and leptin were found in women who later developed preeclampsia. sFLT1, sEndoglin, leptin, and adiponectin were significantly higher in the preeclampsia with IUGR than those without IUGR. Leptin has the largest area under the curve (0.753). Network analysis revealed that elevated amniotic proteins are involved in the inflammatory process of the human placenta.

Conclusions: Significant elevation of leptin can be detected in AF 2 months earlier than the appearance of symptoms; thus, it may be used as a predictive marker for preeclampsia. The increase of these antiangiogenic proteins supports the roles of inflammation and oxidative stress in pathogenesis of preeclampsia.
A Link between mir-100 and FRAP1/mTOR in Clear Cell Ovarian Cancer
Authors: Nagaraja Ankur K. , Creighton Chad J. , Yu Zhifeng , Zhu Huifeng , Gunaratne Preethi H. , Reid Jeffrey G. , Olokpa Emuejevoke , Itamochi Hiroaki , Ueno Naoto T. , Hawkins Shannon M. , Anderson Matthew L. , Matzuk Martin M.
Published: January 2010

MicroRNAs (miRNAs) are small noncoding RNAs that direct gene regulation through translational repression and degradation of complementary mRNA. Although miRNAs have been implicated as oncogenes and tumor suppressors in a variety of human cancers, functional roles for individual miRNAs have not been described in clear cell ovarian carcinoma, an aggressive and chemoresistant subtype of ovarian cancer. We performed deep sequencing to comprehensively profile miRNA expression in 10 human clear cell ovarian cancer cell lines compared with normal ovarian surface epithelial cultures and discovered 54 miRNAs that were aberrantly expressed. Because of the critical roles of the phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog 1/mammalian target of rapamycin (mTOR) pathway in clear cell ovarian cancer, we focused on mir-100, a putative tumor suppressor that was the most down-regulated miRNA in our cancer cell lines, and its up-regulated target, FRAP1/mTOR. Overexpression of mir-100 inhibited mTOR signaling and enhanced sensitivity to the rapamycin analog RAD001 (everolimus), confirming the key relationship between mir-100 and the mTOR pathway. Furthermore, overexpression of the putative tumor suppressor mir-22 repressed the EVI1 oncogene, which is known to suppress apoptosis by stimulating phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog 1 signaling. In addition to these specific effects, reversing the expression of mir-22 and the putative oncogene mir-182 had widespread effects on target and nontarget gene populations that ultimately caused a global shift in the cancer gene signature toward a more normal state. Our experiments have revealed strong candidate miRNAs and their target genes that may contribute to the pathogenesis of clear cell ovarian cancer, thereby highlighting alternative therapeutic strategies for the treatment of this deadly cancer.
Contamination with E1A-Positive Wild-Type Adenovirus Accounts for Species-Specific Stimulation of Islet Cell Proliferation by CCK: A Cautionary Note
Authors: Lavine Jeremy A. , Raess Philipp W. , Davis Dawn B. , Rabaglia Mary E. , Presley Brent K. , Keller Mark P. , Beinfeld Margery C. , Kopin Alan S. , Newgard Christopher B. , Attie Alan D.
Published: January 2010

We have previously reported that adenovirus-mediated expression of preprocholecystokin (CCK) stimulates human and mouse islet cell proliferation. In follow-up studies, we became concerned that the CCK adenovirus might have been contaminated with a wild-type E1A-containing adenovirus. Here we show conclusively that the proliferative effects reported in the original paper in mouse and human islets were not due to CCK expression but rather to a contaminating E1A-expressing wild-type adenovirus. We also show, however, that CCK expression does have a proliferative effect in rat islets. We hope that our report of the steps taken to detect the wild-type virus contamination, and purification of the contributing viral stocks, will be helpful to other investigators, and that our experience will serve as a cautionary tale for use of adenovirus vectors, especially for studies on cellular replication.
Operationalizing Style: Quantifying the Use of Style Shift in the Speech of African American Adolescents
Authors: Renn Jennifer , Terry J. Michael
Published: January 2010

The vast majority of research to date on African American Vernacular English style shift has taken the form of qualitative analyses of individual case studies; however, despite its great success, in focusing on individual rather than group style and style shifting, such work by itself is unable to answer key questions about style and style shift at the level of social groups, communities of practice, and broader based communities. Recent quantitative analyses, such as Craig and Washington's (2006) Dialect Density Measure (DDM), have sought to capture stylistic variation at the group level by analyzing dozens of linguistic features meant to represent a dialect, but use of such large numbers of features severely restricts the types of statistical analyses that can be applied to a given data set and therefore limits the utility of the technique. To test whether a smaller subset of features can be used to quantify stylistic variation, we analyzed a sample of 108 sixth-grade students observed in two conditions that differed in formality. Three measures were used to track changes in style, two large-scale DDMs constructed from a set of more than 40 variables and a subset measure that used only 6 variables. Analyses indicate that the larger DDMs were highly correlated with the subset measure, thus indicating that a small number of features can be used to reliably reflect shifting styles.
The Epicene Pronoun in Contemporary Newspaper Prose
Authors: Balhorn Mark
Published: January 2010

This article is about the use of plural third-person pronouns with grammatically singular, indefinite, generic antecedents in the prose of current U.S. newspapers. After a review of studies of the statistical prominence of usage patterns such as A criminal is a criminal no matter what they wear in spoken English and the presence of such patterns in written English since the gender-neutral language reform movement of the 1970s, an argument is made for why they is an effective and at times optimal choice as an epicene pronoun. Then, a systematic sampling of pronoun chains in contemporary newspapers is used to investigate the effect of such factors as quoted versus nonquoted text, writers' sex, and antecedent type on rates of they usage relative to two other epicene alternatives: historically prescribed he and currently available he or she. The results indicate that although male and female writers use they at similar rates, females use he less often than males do. The results also indicate that with lexical NP antecedents, both male and female writers exhibit lower rates of they and greater use of the disjunction he or she. This is especially true with sex-stereotyped, occupational NP antecedents, such as a CEO or a doctor. It is argued that this pattern of use in contemporary newspaper prose is because of heightened sensitivity to sexism and because of psycholinguistic factors that allow male but not female writers to see themselves included in a generic he-reference chain.
The Engrailed homeobox genes determine the different foliation patterns in the vermis and hemispheres of the mammalian cerebellum
Authors: Cheng Yulan , Sudarov Anamaria , Szulc Kamila U. , Sgaier Sema K. , Stephen Daniel , Turnbull Daniel H. , Joyner Alexandra L.
Published: January 2010

Little is known about the genetic pathways and cellular processes responsible for regional differences in cerebellum foliation, which interestingly are accompanied by regionally distinct afferent circuitry. We have identified the Engrailed (En) homeobox genes as being crucial to producing the distinct medial vermis and lateral hemisphere foliation patterns in mammalian cerebella. By producing a series of temporal conditional mutants in En1 and/or En2, we demonstrate that both En genes are required to ensure that folia exclusive to the vermis or hemispheres form in the appropriate mediolateral position. Furthermore, En1/En2 continue to regulate foliation after embryonic day 14, at which time Fgf8 isthmic organizer activity is complete and the major output cells of the cerebellar cortex have been specified. Changes in spatially restricted gene expression occur prior to foliation in mutants, and foliation is altered from the onset and is accompanied by changes in the thickness of the layer of proliferating granule cell precursors. In addition, the positioning and timing of fissure formation are altered. Thus, the En genes represent a new class of genes that are fundamental to patterning cerebellum foliation throughout the mediolateral axis and that act late in development.
Lighting up developmental mechanisms: how fluorescence imaging heralded a new era
Authors: Mavrakis Manos , Pourquié Olivier , Lecuit Thomas
Published: January 2010

Embryology and genetics have given rise to a mechanistic framework that explains the architecture of a developing organism. Until recently, however, such studies suffered from a lack of quantification and real-time visualization at the subcellular level, limiting their ability to monitor the dynamics of developmental processes. Live imaging using fluorescent proteins has overcome these limitations, uncovering unprecedented insights that call many established models into question. We review how the study of patterning, cell polarization and morphogenesis has benefited from this technology and discuss the possibilities offered by fluorescence imaging and by the contributions of quantitative disciplines.
Endothelial cell plasticity: how to become and remain a lymphatic endothelial cell
Authors: Oliver Guillermo , Srinivasan R. Sathish
Published: January 2010

Lineage commitment and differentiation into mature cell types are mostly considered to be unidirectional and irreversible processes. However, recent results have challenged this by showing that terminally differentiated cell types can be reprogrammed into other cell types, an important step towards devising strategies for gene therapy and tissue regeneration. In this Review, we summarize recent data on the earliest steps in the development of the mammalian lymphatic vasculature: the specification of lymphatic endothelial cells (LECs). We elaborate on a developmental model that integrates the different steps leading to LEC differentiation and lymphatic network formation, discuss evidence that suggests that LEC fate is plastic, and consider the potentially far-reaching implications of the ability to convert one cell type into another.
Domain-specific control of neurogenesis achieved through patterned regulation of Notch ligand expression
Authors: Marklund Ulrika , Hansson Emil M. , Sundström Erik , de Angelis Martin Hrabé , Przemeck Gerhard K. H. , Lendahl Urban , Muhr Jonas , Ericson Johan
Published: January 2010

Homeodomain (HD) transcription factors and components of the Notch pathway [Delta1 (Dll1), Jagged1 (Jag1) and the Fringe (Fng) proteins] are expressed in distinct progenitor domains along the dorsoventral (DV) axis of the developing spinal cord. However, the internal relationship between these two regulatory pathways has not been established. In this report we show that HD proteins act upstream of Notch signalling. Thus, HD proteins control the spatial distribution of Notch ligands and Fng proteins, whereas perturbation of the Notch pathway does not affect the regional expression of HD proteins. Loss of Dll1 or Jag1 leads to a domain-specific increase of neuronal differentiation but does not affect the establishment of progenitor domain boundaries. Moreover, gain-of-function experiments indicate that the ability of Dll1 and Jag1 to activate Notch is limited to progenitors endogenously expressing the respective ligand. Fng proteins enhance Dll1-activated Notch signalling and block Notch activation mediated by Jag1. This finding, combined with the overlapping expression of Fng with Dll1 but not with Jag1, is likely to explain the domain-specific activity of the Notch ligands. This outcome is opposite to the local regulation of Notch activity in most other systems, including the Drosophila wing, where Fng co-localizes with Jagged/Serrate rather than Dll/Delta, which facilitates Notch signalling at regional boundaries instead of within domains. The regulation of Notch activation in the spinal cord therefore appears to endow specific progenitor populations with a domain-wide autonomy in the control of neurogenesis and prevents any inadequate activation of Notch across progenitor domain boundaries.
Gata3 regulates trophoblast development downstream of Tead4 and in parallel to Cdx2
Authors: Ralston Amy , Cox Brian J. , Nishioka Noriyuki , Sasaki Hiroshi , Chea Evelyn , Rugg-Gunn Peter , Guo Guoji , Robson Paul , Draper Jonathan S. , Rossant Janet
Published: January 2010

The mouse blastocyst and stem cells derived from its tissue lineages provide a unique genetic system for examining the establishment and loss of pluripotency. The transcription factor Cdx2 plays a central role by repressing pluripotency genes, such as Oct4, and promoting extraembryonic trophoblast fate at the blastocyst stage. However, genetic evidence has suggested that Cdx2 does not work alone in the trophoblast lineage. We have used bioinformatic and functional genomic strategies to identify the transcription factor Gata3 as a trophoblast factor. We show Gata3 to be capable of inducing trophoblast fate in embryonic stem cells and driving trophoblast differentiation in trophoblast stem cells. In addition, Cdx2 is not required for Gata3-induced expression of a subset of trophoblast genes in embryonic stem cells. We show that Gata3 is coexpressed with Cdx2 in the blastocyst, but this does not depend on Cdx2. In the embryo, expression of Gata3, like that of Cdx2, depends on Tead4, and the expression of both factors becomes restricted to trophoblast by a mechanism that does not initially rely on Oct4. These observations suggest that Gata3 and Cdx2 can act in parallel pathways downstream of Tead4 to induce the expression of common and independent targets in the trophoblast lineage, whereas Oct4 is required for continued repression of trophoblast fate in the embryonic lineage.
The transcription factor Foxg1 regulates the competence of telencephalic cells to adopt subpallial fates in mice
Authors: Manuel Martine , Martynoga Ben , Yu Tian , West John D. , Mason John O. , Price David J.
Published: January 2010

Foxg1 is required for development of the ventral telencephalon in the embryonic mammalian forebrain. Although one existing hypothesis suggests that failed ventral telencephalic development in the absence of Foxg1 is due to reduced production of the morphogens sonic hedgehog (Shh) and fibroblast growth factor 8 (Fgf8), the possibility that telencephalic cells lacking Foxg1 are intrinsically incompetent to generate the ventral telencephalon has remained untested. We examined the ability of Foxg1−/− telencephalic cells to respond to Shh and Fgf8 by examining the expression of genes whose activation requires Shh or Fgf8 in vivo and by testing their responses to Shh and Fgf8 in culture. We found that many elements of the Shh and Fgf8 signalling pathways continue to function in the absence of Foxg1 but, nevertheless, we were unable to elicit normal responses of key ventral telencephalic marker genes in Foxg1−/− telencephalic tissue following a range of in vivo and in vitro manipulations. We explored the development of Foxg1−/− cells in Foxg1−/− Foxg1+/+ chimeric embryos that contained ventral telencephalon created by normally patterned wild-type cells. We found that Foxg1−/− cells contributed to the chimeric ventral telencephalon, but that they retained abnormal specification, expressing dorsal rather than ventral telencephalic markers. These findings indicate that, in addition to regulating the production of ventralising signals, Foxg1 acts cell-autonomously in the telencephalon to ensure that cells develop the competence to adopt ventral identities.
The EVERSHED receptor-like kinase modulates floral organ shedding inArabidopsis
Authors: Leslie Michelle E. , Lewis Michael W. , Youn Ji-Young , Daniels Mark J. , Liljegren Sarah J.
Published: January 2010

Plant cell signaling triggers the abscission of entire organs, such as fruit, leaves and flowers. Previously, we characterized an ADP-ribosylation factor GTPase-activating protein, NEVERSHED (NEV), that regulates membrane trafficking and is essential for floral organ shedding in Arabidopsis. Through a screen for mutations that restore organ separation in nev flowers, we have identified a leucine-rich repeat receptor-like kinase, EVERSHED (EVR), that functions as an inhibitor of abscission. Defects in the Golgi structure and location of the trans-Golgi network in nev abscission zone cells are rescued by a mutation in EVR, suggesting that EVR might regulate membrane trafficking during abscission. In addition to shedding their floral organs prematurely, nev evr flowers show enlarged abscission zones. A similar phenotype was reported for plants ectopically expressing INFLORESCENCE DEFICIENT IN ABSCISSION, a predicted signaling ligand for the HAESA/HAESA-LIKE2 receptor-like kinases, indicating that this signaling pathway may be constitutively active in nev evr flowers. We present a model in which EVR modulates the timing and region of abscission by promoting the internalization of other receptor-like kinases from the plasma membrane.
Exploring the effects of mechanical feedback on epithelial topology
Authors: Aegerter-Wilmsen Tinri , Smith Alister C. , Christen Alix J. , Aegerter Christof M. , Hafen Ernst , Basler Konrad
Published: January 2010

Apical cell surfaces in metazoan epithelia, such as the wing disc of Drosophila, resemble polygons with different numbers of neighboring cells. The distribution of these polygon numbers has been shown to be conserved. Revealing the mechanisms that lead to this topology might yield insights into how the structural integrity of epithelial tissues is maintained. It has previously been proposed that cell division alone, or cell division in combination with cell rearrangements, is sufficient to explain the observed epithelial topology. Here, we extend this work by including an analysis of the clustering and the polygon distribution of mitotic cells. In addition, we study possible effects of cellular growth regulation by mechanical forces, as such regulation has been proposed to be involved in wing disc size regulation. We formulated several theoretical scenarios that differ with respect to whether cell rearrangements are allowed and whether cellular growth rates are dependent on mechanical stress. We then compared these scenarios with experimental data on the polygon distribution of the entire cell population, that of mitotic cells, as well as with data on mitotic clustering. Surprisingly, we observed considerably less clustering in our experiments than has been reported previously. Only scenarios that include mechanical-stress-dependent growth rates are in agreement with the experimental data. Interestingly, simulations of these scenarios showed a large decrease in rearrangements and elimination of cells. Thus, a possible growth regulation by mechanical force could have a function in releasing the mechanical stress that evolves when all cells have similar growth rates.