bluuebunny/crossref_metadata_2025 huggingface dataset:
Cystic fibrosis presenting as recurrent pancreatitis in a young child with a normal sweat test and pancreas divisum: a case report
Authors: Conklin Laurie , Zeitlin Pamela L. , Cuffari Carmen
Published: May 2008

Introduction

Pancreatitis is a rare manifestation of cystic fibrosis (CF) and may rarely be the presenting symptom in adolescent or adult patients with CF. We report a case of a 4 year-old female who initially presented with recurrent pancreatitis, a normal sweat test, and a diagnosis of pancreas divisum. She was subsequently diagnosed with cystic fibrosis at the age of 6 years, despite normal growth and no pulmonary symptoms, after nasal potential difference measurements suggested possible CF and two known CF-causing mutations (ΔF508 and L997F) were detected.

Case Presentation

An otherwise healthy 4 year-old female developed chronic pancreatitis and was diagnosed with pancreas divisum. Sphincterotomy was performed without resolution of her pancreatitis. Sweat test was negative for cystic fibrosis, but measurement of nasal potential differences suggested possible cystic fibrosis. These results prompted extended Cystic Fibrosis Transmembrane Regulator Conductance (CFTR) mutational analysis that revealed a compound heterozygous mutation: ΔF508 and L997F.

Conclusion

CFTR mutations should be considered in cases of chronic or recurrent pancreatitis despite a negative sweat test and the presence of pancreas divisum. Children with CFTR mutations may present with recurrent pancreatitis, lacking any other signs or symptoms of cystic fibrosis. It is possible that the combination of pancreas divisum and abnormal CFTR function may contribute to the severity and frequency of recurrent pancreatitis.
Successful treatment of kasabach-merritt syndrome with vincristine and surgery: a case report and review of literature
Authors: Abass Kotb , Saad Hekma , Kherala Mostafa , Abd-Elsayed Alaa A
Published: May 2008

Introduction

Haemangiomas are vascular lesions resulting from abnormal proliferation of blood vessels. They are the most common pediatric neoplasm. Kasabach-Merritt syndrome is a rare type of vascular lesion with peculiar characteristics. The diagnosis is based upon three basic findings; enlarging haemangioma, thrombocytopenia and consumption coagulopathy.

Case presentation

A 5 month old boy was admitted to the Pediatrics department for the management of an abdominal wall mass. He was the first child of consanguineous parents, born in a private hospital following uncomplicated pregnancy and delivery. At birth a bluish birth mark 5 cm × 5 cm was noted below the umbilicus. Over the next five months, this birth mark increased in size and evolved into a swelling. As a result, the patient was admitted to Maternal and Child Health (MCH) unit for the management of this swelling.

The clinical findings and imagining studies followed by laboratory investigations strongly suggested the diagnosis of Kasabach-Merritt syndrome.

Vincristine was initiated after a trial of corticosteroids when the platelet count was 6000/cmm. One week after the start of vincristine the size of the lesion started to decrease. At the end of 6th week the lesion size decreased to half and the platelet count increased to 49,000/cmm. Vincristine was continued for another 2 weeks, no further improvement in lesion size or platelet count was observed. Vincristine was discontinued and the patient was shifted to the paediatric surgery department. A fresh platelet transfusion was given and the haemangioma was excised completely.

The histopathological examination of the excised mass revealed a caverno-capillary haemangioma with infiltration into skeletal muscles.

Conclusion

Six weeks treatment with vincristine in a dose of 0.5 mg/kg/week followed by surgical excision may be the best management in selected cases of Kasabach-Merritt syndrome.
Antiproliferative and cytostatic effects of the natural product eupatorin on MDA-MB-468 human breast cancer cells due to CYP1-mediated metabolism
Authors: Androutsopoulos Vasilis , Arroo Randolph RJ , Hall John F , Surichan Somchaiya , Potter Gerry A
Published: May 2008

Introduction

The natural product eupatorin has been reported to have antiproliferative activity in tumour cell lines, but the exact mechanism is unclear. The cytochromes P450 CYP1B1, CYP1A1, and CYP1A2 have been shown to participate in the activation of various xenobiotics, compounds derived from the diet as well as chemotherapeutic drugs. CYP1B1 and CYP1A1 have also been proposed as targets for cancer chemotherapy for their differential and selective overexpression in tumour cells. In this study, we aimed to identify a possible mechanism of action for the antiproliferative effect of eupatorin, which can be attributed to CYP1 family-mediated metabolism.

Methods

The study focuses on the antiproliferative action of eupatorin on the human breast carcinoma cell line MDA-MB-468 and on a cell line derived from normal mammary tissue, MCF-10A. The cytotoxicity of the flavone, its effect on the cell cycle of the abovementioned cell lines, and its metabolism by CYP1 family enzymes were examined.

Results

Eupatorin showed a dose-dependent inhibitory effect of cell growth on MDA-MB-468 cells with a submicromolar median inhibition concentration (IC50) whereas the IC50 of this compound in MCF-10A cells was considerably higher. The antiproliferative effect, as measured by EROD (ethoxyresorufin-O-deethylase) assay and Western immunoblotting, was attributed mainly to CYP1A1 expression in MDA-MB-468 cells but not in MCF-10A cells. Moreover, CYP1 family enzymes were shown to metabolise eupatorin in vitro to the flavone cirsiliol and two other unidentified metabolites. Metabolism of eupatorin was also detected in MDA-MB-468 cell cultures, whereas metabolism by MCF-10A cells was negligible. Eupatorin was further shown to arrest the cell cycle of the CYP1-expressing cell line MDA-MB-468 in G2/M phase, whereas no effect was observed in MCF-10A cells, which do not express CYP1 enzymes. The effect of eupatorin on the MDA-MB-468 cell cycle could be reversed by co-application of the CYP1 inhibitor acacetin.

Conclusion

The flavone eupatorin is selectively activated in breast cancer cells, but not in normal breast cells, due to CYP1 family metabolism. This provides a basis for selectivity which is desired against breast tumour cells. In this sense, eupatorin is shown by this study to be a very promising chemopreventative candidate that should be examined further in an in vivo study.
GeneCount: genome-wide calculation of absolute tumor DNA copy numbers from array comparative genomic hybridization data
Authors: Lyng Heidi , Lando Malin , Brøvig Runar S , Svendsrud Debbie H , Johansen Morten , Galteland Eivind , Brustugun Odd T , Meza-Zepeda Leonardo A , Myklebost Ola , Kristensen Gunnar B , Hovig Eivind , Stokke Trond
Published: May 2008

Absolute tumor DNA copy numbers can currently be achieved only on a single gene basis by using fluorescence in situ hybridization (FISH). We present GeneCount, a method for genome-wide calculation of absolute copy numbers from clinical array comparative genomic hybridization data. The tumor cell fraction is reliably estimated in the model. Data consistent with FISH results are achieved. We demonstrate significant improvements over existing methods for exploring gene dosages and intratumor copy number heterogeneity in cancers.
Laterally filtered 1D inversions of small-loop, frequency-domain EMI data from a chemical waste site
Authors: Martinelli Patricia , Duplaá María Celeste
Published: May 2008

We made a study in the backyard of an agrochemical plant using a small-loop, frequency-domain electromagnetic induction (EMI) system. Such systems are very sensitive to conductive structures buried at shallow depths. Frequently, they are only used to locate and delimit these structures by direct observation of data. However, much more information can be obtained by applying numerical modeling techniques to the data. First we mapped an anomalous zone that indicates the possible presence of buried waste or some other underground contamination by visualizing data. Then we applied a 1D inversion method to the data from this zone. By joining 1D inversion results, this method builds 2D images of the subsoil structure below survey lines. Because the code applies smoothness constraints to the 1D inversions, the subsoil properties in these 2D images change gradually with depth. The code does not impose any correlation between the data or 1D models corresponding to neighboring points, so sharp lateral changes can appear. Several of them do not represent real features of the subsoil. We designed and applied two spatial filters to smooth the spurious lateral variations in our models. One correlates the data acquired at adjacent points prior to inversions. The other applies an analogous correlation to the inverse models obtained from the original data. Both filters greatly improve the quality of the 2D images. Compiling these results, we obtained a 3D model of the subsoil that characterizes the anomalous structure. Excavations made later at the site confirmed the results.
Partial Deletion of Pten in the Hypothalamus Leads to Growth Defects that Cannot be Rescued by Exogenous Growth Hormone
Authors: Choi Diana , Nguyen Kinh-Tung T. , Wang Linyuan , Schroer Stephanie A. , Suzuki Akira , Mak Tak W. , Woo Minna
Published: May 2008

The GH/IGF-I axis plays a critical role in mammalian body growth. GH is secreted by the anterior pituitary, and its actions are primarily mediated by IGF-I that is secreted by the liver and other tissues. Local and circulating IGF-I action is largely mediated by the phosphoinositide 3-kinase signaling pathway, and phosphatase with tensin homology (PTEN) is a potent negative regulator of this pathway. Here we show that RIPcre+Ptenfl/fl mice, which exhibit PTEN deletion in insulin-transcribing neurons of the hypothalamus in addition to pancreatic β-cells, result in a small-body phenotype that is associated with an unexpected increase in serum IGF-I levels. We tested whether exogenous GH can override the growth defect in RIPcre+Ptenfl/fl mice. Our results showed no significant difference in their growth between the RIPcre+Ptenfl/fl mice injected with GH or vehicle. Together, PTEN in the hypothalamic insulin-transcribing neurons plays an essential role in body size determination, and systemic GH cannot overcome the growth defect in these mice.
Organic Anion Transporter 1B1: An Important Factor in Hepatic Thyroid Hormone and Estrogen Transport and Metabolism
Authors: van der Deure Wendy M. , Friesema Edith C. H. , de Jong Frank Jan , de Rijke Yolanda B. , de Jong Frank H. , Uitterlinden André G. , Breteler Monique M. B. , Peeters Robin P. , Visser Theo J.
Published: May 2008

Sulfation is an important pathway in the metabolism of thyroid hormone and estrogens. Sulfation of estrogens is reversible by estrogen sulfatase, but sulfation of thyroid hormone accelerates its degradation by the type 1 deiodinase in liver. Organic anion transporters (OATPs) are capable of transporting iodothyronine sulfates such as T4 sulfate (T4S), T3S, and rT3S or estrogen sulfates like estrone sulfate (E1S), but the major hepatic transporter for these conjugates has not been identified. A possible candidate is OATP1B1 because model substrates for this transporter include the bilirubin mimic bromosulfophthalein (BSP) and E1S, and it is highly and specifically expressed in liver. Therefore, OATP1B1-transfected COS1 cells were studied by analysis of BSP, E1S, and iodothyronine sulfate uptake and metabolism. Two Caucasian populations (155 blood donors and 1012 participants of the Rotterdam Scan Study) were genotyped for the OATP1B1-Val174Ala polymorphism and associated with bilirubin, E1S, and T4S levels. OATP1B1-transfected cells strongly induced uptake of BSP, E1S, T4S, T3S, and rT3S compared with mock-transfected cells. Metabolism of iodothyronine sulfates by cotransfected type 1 deiodinase was greatly augmented in the presence of OATP1B1. OATP1B1-Val174 showed a 40% higher induction of transport and metabolism of these substrates than OATP1B1-Ala174. Carriers of the OATP1B1-Ala174 allele had higher serum bilirubin, E1S, and T4S levels. In conclusion, OATP1B1 is an important factor in hepatic transport and metabolism of bilirubin, E1S, and iodothyronine sulfates. OATP1B1-Ala174 displays decreased transport activity and thereby gives rise to higher bilirubin, E1S, and T4S levels in carriers of this polymorphism.
Opposite Effects of Transforming Growth Factor-β Activation and Rho-Associated Kinase Inhibition on Human Trophoblast Migration in a Reconstituted Placental-Endometrial Coculture System
Authors: Fafet Patrick , Rebouissou Cosette , Maudelonde Thierry , Vignais Marie-Luce
Published: May 2008

Placental implantation involves highly regulated trophoblast invasion of the endometrial stroma. TGFβ is a known regulator of this process. This study examines the effect of TGFβ on extravillous cytotrophoblastic cell (EVCT) migration in cocultures of first-trimester human chorionic villus explants and primary human endometrial fibroblasts. Migration of EVCTs was followed by phase-contrast time-lapse microscopy and was shown to highly depend on the endometrial fibroblast matrix. Interstitial EVCT invasion was also analyzed by confocal microscopy of fluorescently prelabeled trophoblasts and endometrial fibroblasts. As expected, addition of TGFβ led to inhibition of EVCT invasion of the endometrial cell layer. This inhibition was characterized by formation of compact EVCT stacks at migration fronts and displacement of endometrial fibroblasts. We tested the role of the RhoA/Rho-associated kinase (ROCK) pathway, a TGFβ-dependent pathway known to regulate cell migration. Interestingly, blocking ROCK with the chemical inhibitor Y27632 had an effect opposite to TGFβ activation because it promoted superficial EVCT migration on the endometrial cell layer. These data suggest a role for ROCK in the TGFβ-dependent control of trophoblast migration. Furthermore, they indicate that even though ROCK signaling plays a role in human trophoblast cell invasion, EVCT migration can still occur in the absence of ROCK activity.
Sexual Differentiation of Vasopressin Innervation of the Brain: Cell Death Versus Phenotypic Differentiation
Authors: de Vries Geert J. , Jardon Michelle , Reza Mohammed , Rosen Greta J. , Immerman Eleanor , Forger Nancy G.
Published: May 2008

In most vertebrates studied, males have more vasopressin (VP) cells in the bed nucleus of the stria terminalis, or homologous vasotocin cells in nonmammalian species, than females. Previous research excluded differential cell birth and migration as likely mechanisms underlying this difference, leaving just differential cell death and phenotypic differentiation of existing cells. To differentiate between these remaining possibilities, we compared VP cell number in wild-type mice vs. mice overexpressing the anti-cell death factor, Bcl-2. All animals were gonadectomized in adulthood and given testosterone capsules. Three weeks later, brains were processed for in situ hybridization to identify VP cells. Bcl-2 overexpression increased VP cell number in both sexes but did not reduce the sex difference. We repeated this experiment in mice with a null mutation of the pro-cell death gene, Bax, and obtained similar results; cell number was increased in Bax−/− mice of both sexes, but males had about 40% more VP cells, regardless of Bax gene status. Taken together, cell death is unlikely to account for the sex difference in VP cell number, leaving differentiation of cell phenotype as the most likely underlying mechanism. We also used immunocytochemistry to examine VP projections in Bcl-2-overexpressing mice. As expected, males showed denser VP-immunoreactive fibers than females in the lateral septum, a projection area of the bed nucleus of the stria terminalis. However, even though Bcl-2 overexpression increased VP cell number, it did not affect fiber density. Thus, a compensatory mechanism may control total septal innervation regardless of the number of contributing cells.
Queuing for Expert Services
Authors: Debo Laurens G. , Toktay L. Beril , Van Wassenhove Luk N.
Published: May 2008

We consider a monopolist expert offering a service with a “credence” characteristic. A credence service is one in which the customer cannot verify, even after a purchase, whether or not the amount of prescribed service was appropriate; examples include legal, medical, or consultancy services, and car repair. This creates an incentive for the expert to “induce service,” that is, to provide unnecessary services that add no value to the customer, but that allow the expert to increase his revenues. We focus on the impact of an operations phenomenon on service inducement—workload dynamics due to the stochasticity of interarrival and service times. To this end, we model the expert's service operation as a single-server queue. The expert determines the service price within a fixed and variable fee structure and determines the service inducement strategy. We characterize the expert's combined optimal price structure and service inducement strategy as a function of service capacity, market potential, inducement opportunity, value of service and waiting cost. We find that service inducement is a means to dynamically skim customer surplus with state-independent prices and provision of slower service to customers that arrive when the expert is idle. We conclude with design implications of our results in limiting service inducement.
Use of Proximity Ligation to Screen for Inhibitors of Interactions between Vascular Endothelial Growth Factor A and Its Receptors
Authors: Gustafsdottir Sigrun M , Wennström Stefan , Fredriksson Simon , Schallmeiner Edith , Hamilton Andrew D , Sebti Said M , Landegren Ulf
Published: May 2008

Background: Improved methods are required to screen drug candidates for their influences on protein interactions. There is also a compelling need for miniaturization of screening assays, with attendant reductions in reagent consumption and assay costs.

Methods: We used sensitive, miniaturized proximity ligation assays (PLAs) to monitor binding of vascular endothelial growth factor A (VEGF-A) to 2 of its receptors, VEGFR-1 and VEGFR-2. We measured the effects of proteins and low molecular weight compounds capable of disrupting these interactions and compared the results with those obtained by immunoblot analysis. We analyzed 6 different inhibitors: a DNA aptamer, a mixed DNA/RNA aptamer, a monoclonal VEGF-A neutralizing antibody, a monoclonal antibody directed against VEGFR-2, a recombinant competitive protein, and a low molecular weight synthetic molecule.

Results: The PLAs were successful for monitoring the formation and inhibition of VEGF-A–receptor complexes, and the results correlated well with those obtained by measuring receptor phosphorylation. The total PLA time is just 3 hours, with minimal manual work and reagent additions. The method allows evaluation of the apparent affinity [half-maximal inhibitory concentration (IC50)] from a dose–response curve.

Conclusions: The PLA may offer significant advantages over conventional methods for screening the interactions of ligands with their receptors. The assay may prove useful for parallel analyses of large numbers of samples in the screening of inhibitor libraries for promising agents. The technique provides dose–response curves, allowing IC50 values to be calculated.
Music Training and Vocal Production of Speech and Song
Authors: Stegemöller Elizabeth L. , Skoe Erika , Nicol Trent , Warrier Catherine M. , Kraus Nina
Published: May 2008

Studying similarities and differences between speech and song provides an opportunity to examine music's role in human culture. Forty participants divided into groups of musicians and nonmusicians spoke and sang lyrics to two familiar songs. The spectral structures of speech and song were analyzed using a statistical analysis of frequency ratios. Results showed that speech and song have similar spectral structures, with song having more energy present at frequency ratios corresponding to those ratios associated with the 12-tone scale. This difference may be attributed to greater fundamental frequency variability in speech, and was not affected by musical experience.Higher levels of musical experience were associated with decreased energy at frequency ratios not corresponding to the 12-tone scale in both speech and song. Thus, musicians may invoke multisensory (auditory/vocal-motor) mechanisms to fine-tune their vocal production to more closely align their speaking and singing voices according to their vast music listening experience.
Development of single mouse blastomeres into blastocysts, outgrowths and the establishment of embryonic stem cells
Authors: Lorthongpanich Chanchao , Yang Shang-Hsun , Piotrowska-Nitsche Karolina , Parnpai Rangsun , Chan Anthony W S
Published: May 2008

The recently developed technique of establishing embryonic stem (ES) cell lines from single blastomeres (BTMs) of early mouse and human embryos has created significant interest in this source of ES cells. However, sister BTMs of an early embryo might not have equal competence for the development of different lineages or the derivation of ES cells. Therefore, single BTMs from two- and four-cell embryos of outbred mice were individually placed in sequential cultures to enhance the formation of the inner cell mass (ICM) and the establishment of embryonic outgrowth. The outgrowths were then used for the derivation of ES cell lines. Based on the expression of ICM (Sox2) and trophectoderm (Cdx2) markers, it was determined that ICM marker was lacking in blastocysts derived from 12% of BTMs from two-cell stage and 20% from four-cell stage. Four ES cell lines (5.6%; 4/72) were established ater culture of single BTMs from two-cell embryos, and their pluripotency was demonstrated by their differentiation into neuronal cell types. Our results demonstrate that sister BTMs of an early embryo are not equally competent for ICM marker expression. However, we demonstrated the feasibility of establishing ES cells from a single BTM of outbred mice.
Generation of multipotent cell lines from a distinct population of male germ line stem cells
Authors: Izadyar Fariborz , Pau Francis , Marh Joel , Slepko Natalia , Wang Tracy , Gonzalez Rafael , Ramos Thomas , Howerton Kyle , Sayre Chauncey , Silva Francisco
Published: May 2008

Spermatogonial stem cells (SSCs) maintain spermatogenesis by self-renewal and generation of spermatogonia committed to differentiation. Under certainin vitroconditions, SSCs from both neonatal and adult mouse testis can reportedly generate multipotent germ cell (mGC) lines that have characteristics and differentiation potential similar to embryonic stem (ES) cells. However, mGCs generated in different laboratories showed different germ cell characteristics, i.e., some retain their SSC properties and some have lost them completely. This raises an important question: whether mGC lines have been generated from different subpopulations in the mouse testes. To unambiguously identify and track germ line stem cells, we utilized a transgenic mouse model expressing green fluorescence protein under the control of a germ cell-specificPou5f1(Oct4) promoter. We found two distinct populations among the germ line stem cells with regard to their expression of transcription factorPou5f1and c-Kit receptor. Only the POU5F1+/c-Kit+ subset of mouse germ line stem cells, when isolated from either neonatal or adult testes and cultured in a complex mixture of growth factors, generates cell lines that express pluripotent ES markers, i.e.,Pou5f1,Nanog,Sox2,Rex1,Dppa5,SSEA-1, and alkaline phosphatase, exhibit high telomerase activity, and differentiate into multiple lineages, including beating cardiomyocytes, neural cells, and chondrocytes. These data clearly show the existence of two distinct populations within germ line stem cells: one destined to become SSC and the other with the ability to generate multipotent cell lines with some pluripotent characteristics. These findings raise interesting questions about the relativity of pluripotency and the plasticity of germ line stem cells.
Post-translational modifications in glycosylation status during epididymal passage and significance in fertility of a 33 kDa glycoprotein (MEF3) of rhesus monkey (Macaca mulatta)
Authors: Chandra Abhishek , Srinivasan Kokattam Rama , Jamal Farrukh , Mehrotra Puroshottam Kumar , Singh Ram Lakhan , Srivastav Archana
Published: May 2008

The present study reports data on post-translational modifications in the glycosylation status during epididymal passage and significance in fertility of a 33 kDa glycoprotein of rhesus monkey (Macaca mulatta), designated as MEF3 (monkey epididymal fluid protein 3). MEF3 exhibited strong affinity for N-linked α-d-mannose groups and O-linkedN-Ac-galactosamine linkages in epididymal fluids and exhibited moderate affinity forN-Ac-glucosaminylated (wheat germ agglutinin), fucosylated (Tetragonolotus purpurea), andN-Ac-galactosamine (peanut agglutinin) residues on more mature corpus and caudal spermatozoa in a maturation-dependent manner on Western blots probed with specific biotinylated lectins. Polyclonal antiserum raised against affinity-purified MEF3 from caudal epididymal fluid (CEF) cross-reacted specifically with CEF and caudal sperm membrane of macaque and with Triton X-100 extract of ejaculated human spermatozoa, suggesting the existence of antigenically related components in both species. The tangled agglutination caused by anti-33 kDa serum of human spermatozoa, along with localization of MEF3 on entire sperm surface of epididymal and testicular sperm of monkey and human spermatozoa, suggest the significance of MEF3 in sperm function. The 100% inhibition of fertility of immunized female rabbits with this proteinin vivoand inhibition of human sperm penetration in zona-free hamster eggsin vitrosuggests the functional significance of MEF3 in fertility. Together, these results clearly indicate that MEF3 has potential significance as a target for antibodies that inhibit sperm function and fertility.
Regulation of testicular tight junctions by gonadotrophins in the adult Djungarian hamster in vivo
Authors: Tarulli Gerard A , Meachem Sarah J , Schlatt Stefan , Stanton Peter G
Published: May 2008

This study aimed to assess the effect of gonadotrophin suppression and FSH replacement on testicular tight junction dynamics and blood–testis barrier (BTB) organisationin vivo, utilising the seasonal breeding Djungarian hamster. Confocal immunohistology was used to assess the cellular organisation of tight junction proteins and real-time PCR to quantify tight junction mRNA. The effect of tight junction protein organisation on the BTB permeability was also investigated using a biotin-linked tracer. Tight junction protein (claudin-3, junctional adhesion molecule (JAM)-A and occludin) localisation was present but disorganised after gonadotrophin suppression, while mRNA levels (claudin-11, claudin-3 and occludin) were significantly (two- to threefold) increased. By contrast, both protein localisation and mRNA levels for the adaptor protein zona occludens-1 decreased after gonadotrophin suppression. FSH replacement induced a rapid reorganisation of tight junction protein localisation. The functionality of the BTB (as inferred by biotin tracer permeation) was found to be strongly associated with the organisation and localisation of claudin-11. Surprisingly, JAM-A was also recognised on spermatogonia, suggesting an additional novel role for this protein in trans-epithelial migration of germ cells across the BTB. It is concluded that gonadotrophin regulation of tight junction proteins forming the BTB occurs primarily at the level of protein organisation and not gene transcription in this species, and that immunolocalisation of the organised tight junction protein claudin-11 correlates with BTB functionality.
Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen-only contraceptives
Authors: Morison Naomi B , Kaitu'u-Lino Tu'uhevaha J , Fraser Ian S , Salamonsen Lois A
Published: May 2008

Many women using progestogen (P)-only contraceptives experience uterine bleeding problems. In clinical trials, a single low dose of mifepristone, given to Implanon users at the beginning of a bleeding episode reduced the number of bleeding days by ∼50% compared with controls. In this study, a single dose of mifepristone was administered to etonogestrel (ENG)-exposed pseudo-pregnant mice, 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding. Control mice received vehicle alone. Mice were culled 12-, 18-, 24- and 48-h post-treatment. In the continued presence of ENG, a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair: most treated tissues were fully restored to the pre-decidualized state by 48 h post-treatment. During repair, proliferating cells (Ki67 immunostained) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands. Progesterone receptor-positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls. Oestrogen receptor-positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues. It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity: such action may be a key event in reducing the number of bleeding days observed in women using Implanon who were treated with a single dose of mifepristone.
Tenascin-R Promotes Neuronal Differentiation of Embryonic Stem Cells and Recruitment of Host-Derived Neural Precursor Cells After Excitotoxic Lesion of the Mouse Striatum
Authors: Hargus Gunnar , Cui Yifang , Schmid Janinne-Sylvie , Xu Jinchong , Glatzel Markus , Schachner Melitta , Bernreuther Christian
Published: May 2008

Loss of GABAergic projection neurons under excitotoxic conditions in the striatum is associated with a disturbance of motor and cognitive functions as seen, for instance, in Huntington's disease. Since current treatments cannot replace degenerated neurons, research on alternative therapeutic approaches needs to be pursued. In this context, the transplantation of genetically modified stem cells into lesioned brain areas of patients is a possible alternative. In this study, green fluorescent protein-labeled murine embryonic stem cells (ESCs) were stably transfected to overexpress the extracellular matrix molecule tenascin-R (TNR), which is expressed by striatal GABAergic neurons. TNR-overexpressing ESCs were analyzed in comparison with their parental cells regarding neural differentiation and migration in vitro, and after transplantation into the striatum of quinolinic acid-treated mice, which serve as a model for Huntington's disease. In comparison with sham-transfected control cells, TNR-overexpressing ESCs showed enhanced differentiation into neurons in vitro, reduced migration in vitro and in vivo, and increased generation of GABAergic neurons and decreased numbers of astrocytes 1 month and 2 months after transplantation, but without significant effects on locomotor functions. Interestingly, TNR-overexpressing ESCs transplanted into the striatum attracted host-derived neuroblasts from the rostral migratory stream and promoted stem cell-mediated recruitment of host-derived newborn neurons within the grafted area. Thus, we show for the first time that overexpression of an extracellular matrix molecule by in vitro predifferentiated ESCs exerts beneficial effects on tissue regeneration in a mouse model of neurodegenerative disease.

Disclosure of potential conflicts of interest is found at the end of this article.
Adult Human Dental Pulp Stem Cells Differentiate Toward Functionally Active Neurons Under Appropriate Environmental Cues
Authors: Arthur Agnes , Rychkov Grigori , Shi Songtao , Koblar Simon Andrea , Gronthos Stan
Published: May 2008

Human adult dental pulp stem cells (DPSCs) reside within the perivascular niche of dental pulp and are thought to originate from migrating cranial neural crest (CNC) cells. During embryonic development, CNC cells differentiate into a wide variety of cell types, including neurons of the peripheral nervous system. Previously, we have demonstrated that DPSCs derived from adult human third molar teeth differentiate into cell types reminiscent of CNC embryonic ontology. We hypothesized that DPSCs exposed to the appropriate environmental cues would differentiate into functionally active neurons. The data demonstrated that ex vivo-expanded human adult DPSCs responded to neuronal inductive conditions both in vitro and in vivo. Human adult DPSCs, but not human foreskin fibroblasts (HFFs), acquired a neuronal morphology, and expressed neuronal-specific markers at both the gene and protein levels. Culture-expanded DPSCs also exhibited the capacity to produce a sodium current consistent with functional neuronal cells when exposed to neuronal inductive media. Furthermore, the response of human DPSCs and HFFs to endogenous neuronal environmental cues was determined in vivo using an avian xenotransplantation assay. DPSCs expressed neuronal markers and acquired a neuronal morphology following transplantation into the mesencephalon of embryonic day-2 chicken embryo, whereas HFFs maintained a thin spindle fibroblastic morphology. We propose that adult human DPSCs provide a readily accessible source of exogenous stem/precursor cells that have the potential for use in cell-therapeutic paradigms to treat neurological disease.

Disclosure of potential conflicts of interest is found at the end of this article.
Global gene expression profiles of ovarian surface epithelial cells in vivo
Authors: Gava Natalie , L. Clarke Christine , Bye Chris , Byth Karen , deFazio Anna
Published: May 2008

Epithelial ovarian cancer, the leading cause of death from gynecological malignancy in Western countries, is thought to arise from the ovarian surface epithelium (OSE). It has been postulated that the constant rounds of proliferation and repair following ovulation contributes to neoplastic transformation. However, there is little information on the genes and pathways which are involved in the normal functions of the ovarian epithelium, in particular genes that are hormone responsive and those central to functions such as proliferation and apoptosis during ovulation. We used laser microdissection and cDNA microarrays to profile gene expression specifically in mouse ovarian epithelial cells, first compared with other ovarian cells, and secondly between ovarian epithelium collected at different physiological stages. We identified over 1000 transcripts that were consistently more highly expressed in the ovarian epithelium compared with remaining ovarian cell types, including genes involved in cell growth, transcription, and cell adhesion. At the various physiological stages examined, the highest number of regulated genes was found during the estrous cycle, specifically on the evening of proestrus, coincident with the ovulatory surge of hormones and just prior to ovulation. The expression of several selected genes, identified by the microarray analysis, including Villin 2, Keratin 8, Arginine-rich mutated in epithelial tumors, and Tumor-associated calcium signal transducer 1, was validated by independent methods. The identification of genes expressed and regulated in the OSE, and characterization of the pathways involved, will contribute to a more detailed understanding of the ovarian epithelium transcriptome and ultimately lead to a better understanding of the aberrations leading to malignant transformation in the ovarian epithelium.
Tumour necrosis factor superfamily member 11 gene promoter polymorphisms modulate promoter activity and influence bone mineral density in postmenopausal women with osteoporosis
Authors: Mencej Simona , Albagha Omar M E , Preželj Janez , Kocjan Tomaž , Marc Janja
Published: May 2008

Tumour necrosis factor superfamily member 11 (TNFSF11) gene, that codes for receptor activator of nuclear factor-κB ligand, is one of the candidate genes for the genetic susceptibility to osteoporosis. As variations in the TNFSF11 gene promoter could alter its expression, the aim of the study was to evaluate the functional influence of three polymorphisms in the promoter and to investigate their association with bone mineral density (BMD) and biochemical markers in postmenopausal women. A total of 404 postmenopausal women were genotyped for the presence of TNFSF11 gene promoter polymorphisms −290C>T, −643C>T and −693G>C. Two common haplotypes, CCG and TTC, which occur in 44.3 and 49.3% of subjects respectively, were subjected to functional analysis. Amplified fragments were cloned into pGL3-basic reporter plasmid, which was co-transfected with pRL-TK plasmid into HEK293 cells. Dual luciferase reporter assay was performed. BMD and biochemical markers were measured. Reporter gene analysis showed significantly higher luciferase activity in CCG than in TTC haplotype (P=0.018). Both showed association with lumbar spine BMD (BMD-ls; P=0.005 and 0.007 for TTC and CCG respectively), whereas in femoral neck there was no association with BMD. In postmenopausal osteoporosis, association with BMD-ls was established in −290C>T, −643C>T and −693G>C (P values: 0.001, 0.041 and 0.013 respectively). Association with femoral neck BMD was shown in −693G>C (P=0.049). No association was found with biochemical markers in any of the groups. Our results suggest that in postmenopausal osteoporosis, TNFSF11 gene promoter polymorphisms −290C>T, −643C>T and −693G>C play a functional role in the genetic regulation of BMD.
Effects of somatostatin analog SOM230 on cell proliferation, apoptosis, and catecholamine levels in cultured pheochromocytoma cells
Authors: Pasquali Daniela , Rossi Valentina , Conzo Giovanni , Pannone Giuseppe , Bufo Pantaleo , De Bellis Annamaria , Renzullo Andrea , Bellastella Giuseppe , Colao Annamaria , Vallone Gianfranco , Bellastella Antonio , Sinisi Antonio A
Published: May 2008

Surgery is the primary therapy for pheochromocytoma (PHEO), a catecholamine-producing tumor. Benign and malignant PHEO could develop recurrences, and the intraoperative risk of recurrent PHEO is an important unresolved issue. Non-surgical treatments of PHEO recurrence would therefore better prepare patients for reintervention as well as provide them with palliative management. We investigated the effects of the new somatostatin analog (pasireotide) SOM230 versus octreotide (OCT) in primary PHEO cell cultures (Pheo-c). Pheo-c from six benign surgical samples were set up and characterized by immunocytochemistry. Real-time PCR, using both PHEO tissues and Pheo-c, showed different levels of somatostatin receptor1–5 mRNA expression. Cells treated with various doses of OCT or SOM230 for 48 and 72 h were analyzed to assess their effects on cell proliferation and apoptosis and catecholamine levels. Even if reduction of cell viability was observed in Pheo-c treated for 48 h with either OCT or SOM230 and this effect increased after 72 h, a more significant inhibition of cell growth as well as a significantly higher induction of apoptosis was seen in Pheo-c treated with SOM230 versus OCT. In particular, apoptosis in Pheo-c was detected after 48 h and was associated with increased expression and activation of caspase-3 and cleaved poly(ADP-ribose) polymerase. OCT 10−6 M and SOM230 10−7 M significantly reduced catecholamine levels. Our results indicate that while both OCT and SOM230 modulate cell growth and apoptosis and catecholamine levels in Pheo-c through specific receptors, SOM230 is more effective. This improves our knowledge on the mechanism of SOM230 action in PHEO and supports a possible therapeutic use in benign PHEO recurrence.
Effects of long-term treatment with 8-prenylnaringenin and oral estradiol on the GH–IGF-1 axis and lipid metabolism in rats
Authors: Böttner Martina , Christoffel Julie , Wuttke Wolfgang
Published: May 2008

After the heart and estrogen/progestin replacement study and the women's health initiative study, the prospect of hormone replacement therapy (HRT) on cardiovascular diseases (CVD) has changed dramatically. These findings led to various attempts to search for alternatives for classical HRT, e.g. phytoestrogens. The flavanone 8-prenylnaringenin (8-PN) was identified as a phytoestrogen with strong estrogen receptor-α activity. As the pituitary and the liver are targets for estrogen action, we assessed the effect of ovariectomy (OVX) and long-term treatment (3 months) with 17-β estradiol benzoate (E2B) and 8-PN on pituitary and liver functions in adult OVX rats. Tested doses were 6.8 and 68.4 mg/kg body weight (BW) of 8-PN and 0.17 and 0.7 mg/kg BW of E2B. Our results demonstrate that 8-PN and E2B decreased BW and increased uterus weight. The high doses of E2B and 8-PN increased serum GH and decreased serum IGF-1 levels. E2B dose dependently decreased cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) concentrations in OVX rats. The high dose of 8-PN showed an estrogenic activity regarding cholesterol and LDL regulation but had no effect on HDL concentrations. By contrast, the low dose of 8-PN augmented HDL levels compared with intact rats. Triglyceride levels were raised in response to the high E2B dose but unaffected by 8-PN treatment. Taken together, 8-PN displays an anti-atherosclerotic profile that appears to be even more beneficial than the one displayed by E2B, and thus might demonstrate a remarkable potential for the prevention of CVD associated with estrogen deficiency.
Improving the Psychosomatic Competence of Medical Doctors in China, Vietnam and Laos—The Asia-Link Program
Authors: Fritzsche Kurt , Scheib Peter , Wirsching Michael , Schübler Gerhard , Wu Wenyuan , Cat Nguyen Huu , Vongphrachanh Sisouk , Linh Ngo Tich ,   Asia-Link Workgroup
Published: May 2008

Objective:

The European Union is supporting a 3-year cooperation project coordinated by the Freiburg University Clinic for the development and promotion of psychosomatic medicine in China, Vietnam, and Laos. The main objective is the development and performance of post-graduate training for medical doctors to improve doctor-patient communication and to acquire psychosomatic knowledge, skills, and attitudes.

Method:

The project is based on contacts which have existed for several years with the Tongji University and the affiliated Tongji Hospital in Shanghai. Medical doctors in all disciplines are to learn to promptly recognize emotional disorders which frequently present in the primary care setting, to offer limited treatment themselves, and to cooperate with mental health specialists.

Results:

In the first year of the project, 50 medical doctors from different medical fields were trained as future teachers. In the second year, we are starting a pilot curriculum which will include 60 hours of theory and psychosocial interventions, divided into three blocks.

Conclusions:

Future developments will involve setting up a psychosomatic network in Southeast Asia to establish advanced training in psychosomatic medicine and psychotherapy and to promote psychiatric and psychosomatic consultation and liaison services in the general hospitals.
Relationship between Depression and Quality of Life in Persons with Hiv Infection in Nigeria
Authors: Adewuya Abiodun O. , Afolabi Mohammed O. , Ola Bola A. , Ogundele Olorunfemi A. , Ajibare Adeola O. , Oladipo Bamidele F. , Fakande Ibiyemi
Published: May 2008

Objective:

Despite the fact that two-thirds of all the people with HIV live in sub-Saharan Africa, little is known about the emotional state and quality of life (QOL) of subjects with HIV in this region. The objective of this study was to evaluate the association between clinical depression and quality of life in a group of HIV sero-positive subjects in Nigeria.

Methods:

Subjects with HIV infection ( n=87) completed a questionnaire detailing sociodemographic and HIV related variables. The subjects were assessed for the diagnosis of depression using the Mini International Neuropsychiatric Interview (MINI) and their subjective health related quality of life (QOL) was assessed using the short version of the WHO quality of life scale (WHOQOL-BREF).

Results:

There were 25 (28.7%) subjects with diagnosis of depression. Lower educational level correlated with poorer QOL in all the domains of WHOQOL-BREF except the “social relationship” domain. Also, poor social support correlated with poorer QOL scores on domains of “physical health” and “social relationship” and presence of medical problems was significantly associated with poorer scores on domains of “physical health” and “psychological health.” Diagnosis of depression was significantly correlated with poorer QOL in all domains except the “social relationship” domain.

Conclusion:

Poorer health related QOL in Nigerian subjects with HIV was associated with depression, lower educational and socioeconomic levels, and poor social support. Early identification and referral of patients with depression needs to be incorporated into intervention programs designed for HIV infected individuals in this region.
Borderline Personality Symptomatology and Sexual Impulsivity
Authors: Sansone Randy A. , Barnes Jacqueline , Muennich Elizabeth , Wiederman Michael W.
Published: May 2008

Objective:

According to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, borderline personality disorder (BPD) is an Axis II phenomenon that is characterized by impulsivity, including sexual impulsivity. However, little empirical research has been undertaken to confirm and/or define the nature of sexual impulsivity in patients with BPD, which is the focus of the present study.

Method:

Using a cross-sectional approach and sample of convenience, we surveyed 76 women who were being seen as outpatients in an internal medicine clinic regarding: a) borderline personality symptoms using two measures (i.e., the borderline personality scale of the Personality Diagnostic Questionnaire-4, McLean Screening Inventory for Borderline Personality Disorder); and b) their sexual histories.

Results:

We found two statistically significant differences—those with borderline personality symptomatology were more likely to have an earlier onset of sexual intercourse as well as to report date rape.

Conclusions:

Individuals with borderline personality symptomatology report earlier sexual exposure as well as date rape, but not other aspects of sexual impulsivity such a greater number of sexual partners, more frequent treatment for sexually transmitted diseases, etc.