bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic relationship between placental and fetal weights and markers of the metabolic syndrome in rat recombinant inbred strains
Authors: Buresova Martina , Zidek Vaclav , Musilova Alena , Simakova Miroslava , Fucikova Alena , Bila Vlasta , Kren Vladimir , Kazdova Ludmila , Di Nicolantonio Robert , Pravenec Michal
Published: August 2006

Epidemiological studies have shown a clear link between fetal growth retardation and an increased propensity for later cardiovascular disease in adults. It has been hypothesized that such early fetal deprivation “programs” individuals toward a life-long metabolical “thrifty phenotype” that predisposes adults to such diseases. Here we test this hypothesis, and its possible genetic basis, in rat recombinant inbred (RI) strains that uniquely allow the longitudinal studies necessary for its testing. Placental and fetal weights were determined on day 20 of pregnancy in (at least) 6 litters from each of 25 available BXH/HXB RI strains and from their SHR and BN-Lx progenitors and were correlated with metabolic traits determined in adult rats from the same inbred lines. Quantitative trait loci (QTLs) associated with placental and fetal weights were identified by total genome scanning of RI strains using the Map Manager QTX program. Heritabilities of placental and fetal weights were 56% and 62%, respectively, and total genome scanning of RI strains revealed QTLs near the D1Rat266 marker on chromosome 1 and near the D15Rat101 marker on chromosome 15 that were significantly associated with fetal and placental weights respectively. Placental weights correlated with fetal weights ( r = 0.60, P = 0.001), while reduced fetal weights correlated with increased insulin concentrations during glucose tolerance test ( r = −0.71, P = 0.0001) and with increased serum triglycerides ( r = −0.54, P = 0.006) in adult rats. Our results suggest that predisposition toward a thrifty phenotype associated with decreased placental weight and restricted fetal growth is in part genetically determined.
Analysis of the bovine neutrophil transcriptome during glucocorticoid treatment
Authors: Weber P. S. D. , Madsen-Bouterse S. A. , Rosa G. J. M. , Sipkovsky S. , Ren X. , Almeida P. E. , Kruska R. , Halgren R. G. , Barrick J. L. , Burton J. L.
Published: August 2006

The objective of this study was to characterize a large portion of the bovine neutrophil transcriptome following treatment with the anti-inflammatory glucocorticoid dexamethasone (Dex). Total RNA was isolated from blood neutrophils of healthy cattle (5 castrated male Holsteins) immediately following cell purification (0 h) or after ex vivo aging for 4 h with or without added Dex. Additional neutrophils were cotreated with a glucocorticoid receptor (GR) antagonist (RU486) and Dex for 4 h. RNA was amplified, dye labeled (Cy3 or Cy5), and hybridized to a series of National Bovine Functional Genomics Consortium (NBFGC) microarrays. LOWESS data normalization followed by mixture model analyses showed that 11.15% of the spotted NBFGC cDNAs (2,036/18,263) were expressed in 4-h (untreated) neutrophils. Subsequent two-step mixed-model analysis detected ( P ≤ 0.05) 1,109 differentially expressed genes, of which contrast analysis indicated those that were independently responsive to aging (1,064), Dex (502), RU486 + Dex (141), or RU486 (357). In silico analysis revealed that 416 of the differentially expressed genes are unknown, 59 did not cluster well based on known function, and 634 clustered into 20 ontological categories. Independent validation of differential expression was done for 14 of the putatively Dex-responsive genes across these categories. Results showed that Dex induced rapid translocation of GR into the neutrophil nucleus and signaled dramatic alterations in expression of genes that delay apoptosis, enhance bactericidal activity, and promote tissue remodeling without inflammation or fibrosis. Thus these findings revealed hitherto unappreciated plasticity of blood neutrophils and potentially novel anti-inflammatory/wound-healing actions of glucocorticoids.
Genetic, sex, and diet effects on body weight and obesity in the Berlin Fat Mouse Inbred lines
Authors: Wagener Asja , Schmitt Armin O. , Aksu Soner , Schlote Werner , Neuschl Christina , Brockmann Gudrun A.
Published: August 2006

Mouse lines long-term selected for high fatness offer the possibility to identify individual genes involved in the development of obesity. The Berlin Fat Mouse (BFM) line has been selected for low protein content and afterward for high fatness. Three Berlin Fat Mouse Inbred (BFMI) lines, which are derivates of the selection line BFM and an unselected control line (C57BL/6; B6) were systematically phenotyped between 3 and 20 wk. The body weights and body compositions were measured on a weekly basis. We demonstrated that the BFMI lines dispose of more body weight, body fat mass, and body lean mass than the control line B6 because of a better feed efficiency in these lines. In contrast to other growth-selected mouse lines, the BFMI lines exhibited a general increase in body fat mass but only a marginal increase in body lean mass. The three BFMI lines also showed line- and sex-specific patterns and varied in their response to high-fat diet. The phenotypic differences between the BFMI lines can be traced back to different sets of fixed alleles contributing to fat accumulation and diet-induced obesity. Our results demonstrate that the genetically related BFMI lines are novel models to study the genetic as well as the nutritional aspects of obesity.
Radiosensitivity Enhancement by Combined Treatment of Celecoxib and Gefitinib on Human Lung Cancer Cells
Authors: Park Ji Sun , Jun Hyun Jung , Cho Moon Jun , Cho Kwan Ho , Lee Jin Soo , Zo Jae Ill , Pyo Hongryull
Published: August 2006

Purpose: To characterize the radiation-enhancing effects and underlying mechanisms of combined treatment with celecoxib, a cyclooxygenase-2 selective inhibitor, and gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in human lung cancer cells.

Experimental Design: Clonogenic cytotoxicity assays and clonogenic radiation survival assays after treatments with celecoxib and gefitinib with or without radiation were done on three human lung cancer cell lines. Synergisms after combined treatment with celecoxib, gefitinib, and radiation were investigated using isobologram and statistical analyses according to an independent action model. Alterations in apoptosis and cell cycle were measured to identify the mechanisms underlying the cell killing or radiation-enhancing effects of celecoxib and gefitinib combination treatment. Western blots for phosphorylated EGFR, EGFR, cyclooxygenase-2, and G2 checkpoint molecules were conducted after treatment with celecoxib and/or gefitinib with or without radiation.

Results: Combination celecoxib, gefitinib, and radiation treatments were shown to be synergistic in causing clonogenic cell deaths in all cell lines tested, but the nature of synergism was cell type specific. The combined drug treatments induced apoptosis in an additive manner in A549 cells and in a synergistic manner in NCI-H460 and VMRC-LCD cells. Celecoxib or gefitinib attenuated radiation-induced G2-M arrest, and combined drug treatment additively attenuated radiation-induced G2-M arrest in all cell lines. Radiation-induced checkpoint kinase (Chk) 1 and Chk2 phosphorylation were inhibited by celecoxib and gefitinib treatment, respectively.

Conclusions: Combined celecoxib and gefitinib treatments were shown to synergistically enhance the effect of radiation on lung cancer cells. The mechanisms underlying these synergistic effects seem to involve the synergistic enhancement of apoptosis and cooperative attenuation of radiation-induced G2-M arrest, possibly via Chk1 and Chk2 inhibition, by the combined drug treatments.
Delivery of Telomerase Reverse Transcriptase Small Interfering RNA in Complex with Positively Charged Single-Walled Carbon Nanotubes Suppresses Tumor Growth
Authors: Zhang Zhuohan , Yang Xiaoying , Zhang Yuan , Zeng Bin , Wang Shujing , Zhu Tianhui , Roden Richard B.S. , Chen Yongsheng , Yang Rongcun
Published: August 2006

Purpose: To determine whether -CONH-(CH2)6-NH3+Cl− functionalized single-walled carbon nanotubes (SWNT) carrying complexed small interfering RNA (siRNA) can enter into tumor cells, wherein they release the siRNA to silence the targeted gene.

Experimental Design: -CONH-(CH2)6-NH3+Cl− was used to mediate the conjugation of telomerase reverse transcriptase (TERT) siRNA to SWNTs. The ability of TERT siRNA delivered via SWNT complexes to silence the expression of TERT was assessed by their effects on the proliferation and growth of tumor cells both in vitro and in mouse models.

Results: The functionalized SWNTs -CONH-(CH2)6-NH3+Cl− could facilitate the coupling of siRNAs that specifically target murine TERT expression to form the mTERT siRNA:SWNT+ complex. These functionalized SWNTs rapidly entered three cultured murine tumor cell lines, suppressed mTERT expression, and produced growth arrest. Injection of mTERT siRNA:SWNT+ complexes into s.c. Lewis lung tumors reduced tumor growth. Furthermore, human TERT siRNA:SWNT+ complexes also suppressed the growth of human HeLa cells both in vitro and when injected into tumors in nude mice.

Conclusions: -CONH-(CH2)6-NH3+Cl− functionalized SWNTs carry complexed siRNA into tumor cells, wherein they release the siRNA from the nanotube sidewalls to silence the targeted gene. The -CONH-(CH2)6-NH3+Cl− functionalized SWNTs may represent a new class of molecular transporters applicable for siRNA therapeutics.
Natural Killer Receptors on CD8 T Cells and Natural Killer Cells from Different HLA-C Phenotypes in Melanoma Patients
Authors: Campillo José A. , Martínez-Escribano Jorge A. , Moya-Quiles M. Rosa , Marín Luis A. , Muro Manuel , Guerra Natalia , Parrado Antonio , Campos Matilde , Frías José F. , Minguela Alfredo , García-Alonso Ana M. , Álvarez-López María Rocío
Published: August 2006

Purpose: Because immune mechanisms involved in cutaneous melanoma have not been fully elucidated, efforts have been made to achieve prognosis markers and potential targets for immune therapies, but they have not been entirely fruitful thus far. Therefore, the goal of this study was to investigate the involvement of early changes in CD8 T cells and CD56 natural killer (NK) cells expressing NK receptors in different HLA-C dimorphism groups of melanoma patients.

Experimental Design: CD8 T cells and CD56 NK cells were analyzed in 41 patients and 39 sex- and age-matched controls with different HLA-C genotypes by flow cytometry. HLA-C dimorphism at position 80 was tested by PCR sequence-specific primers and PCR sequence-specific oligonucleotide to examine whether it could mediate in the emergence of cells expressing killer cell immunoglobulin-like receptors.

Results: Thirty-five of 41 patients had benign sentinel node, and showed an imbalance in the absolute number of CD8+DR+ or CD8+CD161+ peripheral blood T cells according to the CD28 coexpression compared with controls. CD8+CD28−CD158a+ T and CD56+CD158a+ NK cells were significantly increased in HLA-CLys80 homozygous nonmetastatic patients, whereas only CD56+CD158a+ NK cells increased in heterozygous ones. An up-regulation of the CD158a KIR receptor was also seen on NK cells but not in T cells of patients at advanced disease stages.

Conclusions: This work provides, for the first time, evidence of immune activation in early stages of cutaneous melanoma, together with an increase of cells expressing CD158a in patients bearing the corresponding HLA-C ligand, which may be important to evaluate the disease progression and to use individualized immune therapeutic approaches.
Focal Adhesion Kinase Targeting UsingIn vivoShort Interfering RNA Delivery in Neutral Liposomes for Ovarian Carcinoma Therapy
Authors: Halder Jyotsnabaran , Kamat Aparna A. , Landen Charles N. , Han Liz Y. , Lutgendorf Susan K. , Lin Yvonne G. , Merritt William M. , Jennings Nicholas B. , Chavez-Reyes Arturo , Coleman Robert L. , Gershenson David M. , Schmandt Rosemarie , Cole Steven W. , Lopez-Berestein Gabriel , Sood Anil K.
Published: August 2006

Purpose: Focal adhesion kinase (FAK) plays a critical role in ovarian cancer cell survival and in various steps in the metastatic cascade. Based on encouraging in vitro results with FAK silencing, we examined the in vivo therapeutic potential of this approach using short interfering RNA (siRNA) in the neutral liposome 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC).

Experimental Design: Therapy experiments of FAK siRNA with or without docetaxel were done using human ovarian cancer cell lines SKOV3ip1, HeyA8, and HeyA8MDR in nude mice. Additional experiments with a cisplatin-resistant cell line (A2780-CP20) were also done. Assessments of angiogenesis (CD31), cell proliferation (proliferating cell nuclear antigen), and apoptosis (terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling) were done using immunohistochemical analysis.

Results: A single dose of FAK siRNA-DOPC was highly effective in reducing in vivo FAK expression for up to 4 days as assayed by Western blot and immunohistochemical analysis. Therapy experiments were started 1 week after injection of the ovarian cancer cells. Treatment with FAK siRNA-DOPC (150 μg/kg twice weekly) reduced mean tumor weight by 44% to 72% in the three cell lines compared with the control group (Ps < 0.05 for HeyA8, A2780-CP20, and SKOV3ip1). When FAK siRNA-DOPC was combined with docetaxel, there was even greater reduction in mean tumor weight in all models (all Ps < 0.05). Similar results were observed in combination with cisplatin. Treatment with FAK siRNA-DOPC plus docetaxel resulted in decreased microvessel density, decreased expression of vascular endothelial growth factor and matrix metalloproteinase-9, and increased apoptosis of tumor-associated endothelial cells and tumor cells.

Conclusions: Taken together, these findings suggest that FAK siRNA-DOPC plus docetaxel or platinum might be a novel therapeutic approach against ovarian cancer.
Copper Binding by Tetrathiomolybdate Attenuates Angiogenesis and Tumor Cell Proliferation through the Inhibition of Superoxide Dismutase 1
Authors: Juarez Jose C. , Betancourt Oscar , Pirie-Shepherd Steven R. , Guan Xiaojun , Price Melissa L. , Shaw David E. , Mazar Andrew P. , Doñate Fernando
Published: August 2006

Purpose: A second-generation tetrathiomolybdate analogue (ATN-224; choline tetrathiomolybdate), which selectively binds copper with high affinity, is currently completing two phase I clinical trials in patients with advanced solid and advanced hematologic malignancies. However, there is very little information about the mechanism of action of ATN-224 at the molecular level.

Experimental Design: The effects of ATN-224 on endothelial and tumor cell growth were evaluated in cell culture experiments in vitro. The antiangiogenic activity of ATN-224 was investigated using the Matrigel plug model of angiogenesis.

Results: ATN-224 inhibits superoxide dismutase 1 (SOD1) in tumor and endothelial cells. The inhibition of SOD1 leads to inhibition of endothelial cell proliferation in vitro and attenuation of angiogenesis in vivo. The inhibition of SOD1 activity in endothelial cells is dose and time dependent and leads to an increase in the steady-state levels of superoxide anions, resulting in the inhibition of extracellular signal-regulated kinase phosphorylation without apparent induction of apoptosis. In contrast, the inhibition of SOD1 in tumor cells leads to the induction of apoptosis. The effects of ATN-224 on endothelial and tumor cells could be substantially reversed using Mn(III)tetrakis(4-benzoic acid)porphyrin chloride, a catalytic small-molecule SOD mimetic.

Conclusions: These data provide a distinct molecular target for the activity of ATN-224 and provide validation for SOD1 as a target for the inhibition of angiogenesis and tumor growth.
Up-Regulation of Endothelial Delta-like 4 Expression Correlates with Vessel Maturation in Bladder Cancer
Authors: Patel Nilay S. , Dobbie Michael S. , Rochester Mark , Steers Graham , Poulsom Richard , Le Monnier Karena , Cranston David W. , Li Ji-Liang , Harris Adrian L.
Published: August 2006

Purpose: Angiogenesis and vascular endothelial growth factor (VEGF) expression are associated with a poor outcome in bladder cancer. To understand more about the mechanisms, we studied the role of delta-like 4 (DLL4), an endothelial-specific ligand of the Notch signaling pathway, in bladder cancer angiogenesis.

Experimental Design: The expression of DLL4, CD34, and VEGF were studied in a cohort of 60 bladder tumors and 10 normal samples using quantitative PCR. In situ hybridization was used to study the pattern of DLL4 expression in 22 tumor and 9 normal samples. Serial sections were also stained for CD34 and α-smooth muscle actin (α-SMA) using conventional immunohistochemistry.

Results: The expression of DLL4 was significantly up-regulated in superficial (P < 0.01) and invasive (P < 0.05) bladder cancers. DLL4 expression significantly correlated with CD34 (P < 0.001) and VEGF (P < 0.001) expression. The in situ hybridization studies showed that DLL4 was highly expressed within bladder tumor vasculature. Additionally, DLL4 expression significantly correlated with vessel maturation as judged by periendothelial cell expression of α-SMA, 98.7% of DLL4-positive tumor vessels coexpressed α-SMA, compared with 64.5% of DLL4-negative tumor vessels (P < 0.001). High DLL4 expression may have prognostic value in superficial and invasive bladder.

Conclusion: DLL4 expression is associated with vascular differentiation in bladder cancer; thus, targeting DLL4 may be a novel antiangiogenic therapy.
Th1 Response and Cytotoxicity Genes Are Down-Regulated in Cutaneous T-Cell Lymphoma
Authors: Hahtola Sonja , Tuomela Soile , Elo Laura , Häkkinen Tiina , Karenko Leena , Nedoszytko Boguslaw , Heikkilä Hannele , Saarialho-Kere Ulpu , Roszkiewicz Jadwiga , Aittokallio Tero , Lahesmaa Riitta , Ranki Annamari
Published: August 2006

Purpose: Increased production of Th2 cytokines characterizes Sezary syndrome, the leukemic form of cutaneous T-cell lymphomas (CTCL). To identify the molecular background and to study whether shared by the most common CTCL subtype, mycosis fungoides, we analyzed the gene expression profiles in both subtypes.

Experimental Design: Freshly isolated cells from 30 samples, representing skin, blood, and enriched CD4+ cell populations of mycosis fungoides and Sezary syndrome, were analyzed with Affymetrix (Santa Clara, CA) oligonucleotide microarrays, quantitative PCR, or immunohistochemistry. The gene expression profiles were combined with findings of comparative genomic hybridization of the same samples to identify chromosomal changes affecting the aberrant gene expression.

Results: We identified a set of Th1-specific genes [e.g., TBX21 (T-bet), NKG7, and SCYA5 (RANTES)] to be down-regulated in Sezary syndrome as well as in a proportion of mycosis fungoides samples. In both Sezary syndrome and mycosis fungoides blood samples, the S100P and LIR9 gene expression was up-regulated. In lesional skin, IL7R and CD52 were up-regulated. Integration of comparative genomic hybridization and transcriptomic data identified chromosome arms 1q, 3p, 3q, 4q, 12q, 16p, and 16q as likely targets for new CTCL-associated gene aberrations.

Conclusions: Our findings revealed several new genes involved in CTCL pathogenesis and potential therapeutic targets. Down-regulation of a set of genes involved in Th1 polarization, including the major Th1-polarizing factor, TBX21, was for the first time associated with CTCL. In addition, a plausible explanation for the proliferative response of CTCL cells to locally produced interleukin-7 was revealed.
A Phase 1 Study of ABT-751, an Orally Bioavailable Tubulin Inhibitor, Administered Daily for 7 Days Every 21 Days in Pediatric Patients with Solid Tumors
Authors: Fox Elizabeth , Maris John M. , Widemann Brigitte C. , Meek Kysa , Goodwin Anne , Goodspeed Wendy , Kromplewski Marie , Fouts Molly E. , Medina Diane , Cho Steve Y. , Cohn Susan L. , Krivoshik Andrew , Hagey Anne E. , Adamson Peter C. , Balis Frank M.
Published: August 2006

Purpose: To determine the toxicity profile, dose-limiting toxicities, and maximum tolerated dose of ABT-751 administered orally once daily for 7 days, repeated every 21 days.

Experimental Design: Patients who were ≤18 years of age, with relapsed or refractory solid tumors, and who were able to swallow capsules were eligible. The starting dose was 100 mg/m2/d (n = 3) and was escalated to 130 mg/m2/d (n = 6), 165 mg/m2/d (n = 6), 200 mg/m2/d (n = 6), and 250 mg/m2/d (n = 2) in cohorts of three to six patients. The maximum tolerated dose was determined from dose-limiting toxicities occurring during the first treatment cycle.

Results: Twenty-four children (median age, 13 years; range, 4-18 years) were enrolled; 23 were evaluable for toxicity. Diagnoses included neuroblastoma (n = 8), sarcomas (n = 8), primary brain tumors (n = 2), Wilms' tumor (n = 2), and other solid tumors (n = 3). Dose-limiting toxicities (grade 3 sensory and motor neuropathy, grade 3 hypertension, and grade 3 fatigue) were observed in patients enrolled at the 250 mg/m2/d dose level. The maximum tolerated dose of ABT-751 administered daily for 7 days every 21 days was 200 mg/m2/d. Non-dose-limiting toxicities at the maximum tolerated dose included anemia, fatigue, peripheral sensory neuropathy, abdominal pain, nausea, constipation, anorexia, fever, and weight loss. Myelosuppression was minimal at the maximum tolerated dose. The median number of cycles administered is 2 (range, 1-50). No significant ABT-751-related cumulative toxicities were observed.

Conclusion: ABT-751 is well tolerated in children. The recommended dose for phase 2 trials in solid tumors is 200 mg/m2/d administered orally, daily for 7 days every 21 days. This dose is >40% higher than the maximum tolerated dose in adults receiving the same dosing schedule.
Acute Myeloid Leukemia Subgroups Identified by Pathway-Restricted Gene Expression Signatures
Authors: Serrano Elena , Lasa Adriana , Perea Granada , Carnicer Maria J. , Brunet Salut , Aventín Anna , Sierra Jorge , Nomdedéu Josep F.
Published: August 2006

Acute myeloid leukemia (AML) is a heterogeneous group of disorders characterized by abnormal proliferation of myeloid precursors and a maturation block. Underlying genetic lesions determine an altered expression program (transcriptosome) that can be studied in depth by massive technologies. Alternatively, we selected a pathway profiling strategy based on the current knowledge in order to stratify de novo AML patients and identify those cases which would potentially benefit from the use of new chemotherapeutic agents. One hundred and thirty-two RNA samples obtained from de novo adult AML patients were tested for FLT3, FLT3-LG, NDST1, HDAC2, ATRX, FOS, DNMT1, DNMT3A, DNMT3B, NBS1, RAD50, MRE11A, Meis1 and Meis2 expression using quantitative PCR (qPCR) assays. Clinical and biologic findings were correlated with expression results. Cluster analysis was also performed. FLT3 expression defined three subgroups of patients. The best outcome was found in the group with the lowest FLT3 expression. Intermediate levels of FLT3 were associated with the worst outcome. Patients with low levels of ATRX more frequently presented an adverse karyotype whereas cases with preserved ATRX levels showed an excellent outcome. In accordance with previous results, Meis1 downregulation is a useful surrogate marker indicating a good prognosis in AML patients. Simple qPCR platforms may help to identify different biologic subgroups in AML.
Recombinant Factor VII (Activated) for Haemorrhagic Complications of Severe Sepsis Treated with Recombinant Protein C (Activated)
Authors: Michalska-Krzanowska Grażyna , Czuprynska Maria
Published: August 2006

We report on 2 cases of severe sepsis treated with drotrecogin-alpha (Xigris, Eli Lilly), where massive perioperative haemorrhage required administration of recombinant factor VIIa. The first patient developed severe sepsis after surgery (laparoscopic cholecystectomy, laparotomy due to peritonitis). After 18 h of treatment with Xigris, the patient developed massive, refractory gastrointestinal and abdominal bleeding. Effective haemostasis was achieved after 2 doses of NovoSeven (Novo Nordisk, Denmark). The patient died due to a cerebral bleed. The second patient developed septic shock in the course of pyelonephritis and right hydronephrosis. She was treated with Xigris and nephrectomy. Uncontrollable perioperative bleeding was effectively treated with 2 doses of NovoSeven. The patient survived.
Sexual Swellings of Female Gibbons
Authors: Cheyne Susan M. , Chivers David J.
Published: August 2006

Female gibbons were observed for labial swellings from March 2002 to August 2003. Data were collected on length of time each female was swollen, changes in swelling period as females matured, and cycle length (number of days between onsets of consecutive swellings). Data were also collected on the behaviour of the males when the females were swollen. There was a significant relationship between age of the female gibbon and number of days she had labial swelling. There was no significant relationship between the age of the gibbon and the cycle length, nor between species (Hylobates agilis albibarbis and Hylobates muelleri) and number of days swollen. Copulation was more common when females were swollen. Swelling in female gibbons may be related to copulatory behaviour and serve to provide the male with some certainty of paternity through fertilisation insurance.
Male Dominance Rank, Mating and Reproductive Success in Captive Bonobos (Pan paniscus)
Authors: Marvan R. , Stevens J.M.G. , Roeder A.D. , Mazura I. , Bruford M.W. , de Ruiter J.R.
Published: August 2006

In the recent past, application of DNA genotyping techniques has enabled researchers to more accurately test relationships between dominance rank (DR), mating success (MS) and reproductive success (RS). Paternity studies often reveal that reproductive outcome does not always correlate with male DR and/or MS and thus open room for discussion and interpretation of alternative reproductive tactics of both sexes. In this study, we analysed male DR, MS and RS in a group of bonobos at Twycross Zoo (UK). Genetic relationships were determined using 8 tetrameric microsatellite loci. Despite clear and asymmetric dominance relationships, analysed using normalised David’s scores based on a dyadic index of dominance among the group’s 3 mature males, we found that the most dominant male did not sire the most offspring. In fact, both infants conceived during the observation period were found to be sired by the lower-ranking males. Although the alpha male had almost exclusive mating access to one of the females during the time she was showing a maximal anogenital swelling, her infant was sired by the lowest-ranking male who mostly mated with her when outside the maximal swelling period. This result suggests that either sperm competition operates and/or ovulation is decoupled from the phase of maximal anogenital swelling which could allow greater female choice.
Short-Rib-Polydactyly Syndrome Presenting with Increased Nuchal Translucency in a High-Risk Family
Authors: Daskalakis G. , Souka A.P. , Kavalakis I. , Haritos T. , Basayiannis C. , Antsaklis P. , Antsaklis A.
Published: August 2006

Short-rib-polydactyly syndrome represents a group of rare, autosomal recessive, lethal skeletal dysplasias characterized by hypoplastic thorax, short ribs, short limbs, polydactyly, and visceral abnormalities. We describe an affected fetus from a high-risk family presenting with increased nuchal translucency at 13 weeks of pregnancy. The diagnosis was established in the 2nd trimester.
The Almodin–Moron Trocar for Uterine Entry during Fetal Surgery
Authors: Almodin C.G. , Moron A.F. , Cavaliero S. , Yamashita A. , Hisaba W. , Piassi J.
Published: August 2006

Objective: Compare the use of a newly designed and reusable metal trocar for initial uterine entry with the disposable Tulipan–Bruner trocar in creation of a hysterotomy for fetal surgery. Methods: Six consecutive patientsundergoing hysterotomy for intrauterine repair of myelomeningocele were randomized to uterine entry either with the Tulipan–Bruner trocar or with the Almodin–Moron trocar. Blood loss was estimated by the primary surgeon. Results: There was no statistically significant difference in the uterine entry times between the trocars. Blood loss was estimated to be approximately the same. The Almodin–Moron trocar was judged to provide easy handling with good safety. Conclusions: The Almodin–Moron trocar provides a uterine entry during creation of a hysterotomy that is as quick and causes as little trauma as the Tulipan–Bruner trocar.
Spontaneous Rupture of Fetal Sacrococcygeal Teratoma
Authors: Sy Edgar D. , Lee Hanmin , Ball Robert , Farrell Jody , Poder Liina , Nobuhara Kerilyn K. , Farmer Diana L. , Harrison Michael R.
Published: August 2006

With recent advances in technology, fetal sacrococcygeal teratoma is being diagnosed increasingly during the early prenatal period by ultrasound examination. In addition, early detection of tumor related complications such as polyhydramnios, congestive heart failure, hydrops, hemorrhage, urinary tract or bowel obstruction can be followed closely in utero. Active prenatal management can improve fetal perinatal outcome by allowing planned delivery for neonatal surgery [Chisholm, C.A. et al.: Am J Perinatol 1999;16:47–50] or in some cases, fetal intervention. Additionally, families can be counseled appropriately regarding the range of outcomes. We report a case of fetal sacrococcygeal teratoma Type I diagnosed at 20 weeks with a prominent vessel supplying the tumor mass. At 23 weeks, there was a sudden appearance of an additional lobular mass, consistent with intrauterine spontaneous ruptured of a sacrococcygeal teratoma mass.
Maternal Mirror Syndrome after in utero Aortic Valve Dilation
Authors: Mizrahi-Arnaud Arielle , Wilkins Haug Louise , Marshall Audrey , Silva Virginia
Published: August 2006

Fetal hydrops of various etiologies can be associated with maternal mirror syndrome. The exact pathophysiology of this rare disorder remains unclear, yet it can result in significant maternal and fetal morbidity. The recent advances in prenatal diagnosis and therapeutic interventions have focused on altering the course of pathologies associated with an expected poor prognosis. Severe fetal aortic valve stenosis with its potential for hypoplastic left heart fit this category. We report a case of maternal mirror syndrome in a parturient following intrauterine therapy for severe fetal aortic stenosis and hydrops. Despite a technically successful intervention, the mother required emergency cesarean section. We review the few reports of mirror syndrome as well as the current approaches to fetal aortic stenosis. This case reinforces the need for in depth risk analysis prior to fetal interventions. It also emphasizes the advantage of earlier detection and therapy with fetal aortic stenosis since fetal hydrops carries a somber prognosis.
Fetal Sheep Development on Ultrasound and Magnetic Resonance Imaging: A Standard for the in utero Assessment of Models of Congenital Abnormalities
Authors: Ward Valerie L. , Estroff Judy A. , Nguyen Hiep T. , Lakshmanan Yegappan , Hayward Alison , Jaramillo Diego , Zurakowski David , Dunning Patricia S. , Peters Craig A. , Barnewolt Carol E.
Published: August 2006

Objective: To establish normative data for the size, conspicuity, and imaging characteristics of normal developing fetal sheep organs on ultrasound (US) and magnetic resonance (MR) imaging. Methods: US and MR images of ten normal pregnant sheep, at 40, 65, 90, 115, and 140 gestational days (term = 145 days), were scored for organ conspicuity and imaging characteristics. Imaging biometry was correlated with specimens. Gestational age-based growth parameters were modeled using regression. Results: Imaging biometry showed excellent correlation with specimens. Kidney, bladder, stomach, lung, liver, and spine were seen well from 65 days to term by US. More organs were consistently visible from 90 days to term by MR than by US. Most organ imaging characteristics tended not to change throughout gestation. Conclusion: Normal fetal sheep biometry, organ conspicuity, and imaging characteristics are established for US and MR and have potential use for the in utero assessment of sheep models of congenital abnormalities.
Fetal Myocardial Thickening Measured by Ultrasonic-Based Technique Called ‘Phased-Tracking Method’
Authors: Kunii Shutaro , Sugawara Junichi , Kimura Yoshitaka , Imai Noriaki , Chisaka Hiroshi , Hasegawa Hideyuki , Koiwa Yoshiro , Kanai Hiroshi , Okamura Kunihiro
Published: August 2006

Objective: To evaluate fetal myocardial movement by using newly developed ultrasonic technique. Methods: We analyzed 50 normal fetuses between 25 and 41 weeks’ gestation for changes in thickness of fetal myocardium using the phased-tracking method, a technique with high vertical distance resolution and the potential to evaluate fine ventricular wall movements. We analyzed differences in the rate of change in ventricular wall thickness and in changes in the inner and outer wall layers with advancing gestation. We also analyzed myocardial thickening period and evaluated the ratio of increasing thickness period to stroke interval. Results: Mean thickness changing rate was significantly higher in the right (1.18 ± 0.34 m/s/m) than in the left ventricular wall (0.86 ±0.31 m/s/m) (p < 0.001). Mean ratio of increasing thickness period to stroke interval was significantly higher in the right (0.57 ± 0.064) than in the left ventricle (0.46 ± 0.075) (p < 0.001), indicating that myocardial contraction in the fetal right ventricle predominates. The thickness-changing rate of the bilateral ventricular walls was positively and linearly correlated with gestational age. The myocardial-wall thickness-changing rate was higher in the outer layer than in the inner layer in late gestation. Conclusions: We conclude that measurement of the thickness-changing rate of fetal ventricular walls using the phased-tracking method might be useful for evaluation of fetal cardiac function.
Methadone Doses upon Multiple Readmissions to Inpatient Detoxification: Clinical Evidence for Very Moderate Opioid Tolerance
Authors: Madlung Ekkehard , Haring Christian , Crespo Jose A. , Saria Alois , Grubinger Petra , Zernig Gerald
Published: August 2006

Escalation of drug use by addicts has traditionally been interpreted as tolerance to the drug’s effects. On the basis of animal behavioral data, several groups have recently proposed alternative explanations, i.e., that such an escalation of drug dose might not be based on tolerance but rather be indicative of (i) sensitization to the reinforcing effect or the incentive salience of the drug of abuse or (ii) shifts in baseline mood, i.e., allostasis. In the present study, the emergence of opioid tolerance or sensitization during the progression of opioid dependence was assessed by comparing the methadone doses that were initially required to alleviate the opioid withdrawal symptoms of intravenous opioid users who presented for detoxification upon 3–7 consecutive admissions over the course of up to 84 months. Upon the second admission, the 48 surveyed male patients needed 115 ± 6% (p = 0.012) and the 32 female patients needed 121 ± 12% (p = 0.01) of the methadone dose required upon the first admission. Upon the third admission, the respective values were 121 ± 8% (males; p = 0.013) and 111 ± 12% (females; n.s.), and upon the fourth admission, 125 ± 14% (males; p = 0.026) and 131 ± 14 (females; p = 0.01). Inter-admission intervals averaged 14 ± 1 months (n = 135) for males and 13 ± 1 months (n = 91) for females and were not significantly different across consecutive admissions, suggesting that tolerance did not develop faster upon repetition of abuse-withdrawal cycles. In conclusion, the intravenous opioid users surveyed in the present study developed only very moderate tolerance during the repeated abuse-detoxification cycles that were typical for their disease progression. The present data do not support the notion that sensitization to the opioids’ reinforcing effects occurred in this naturalistic clinical sample.
Investor Rights in Historical Perspective: Globalization and the Future of the Japanese Firm and Financial System
Authors: Teranishi Juro
Published: August 2006

The evolution of investor rights in Japan is examined in relation to the evolution in firm-specific skill formation. Asset holders (shareholders and landlords) delegated part of the control of their assets to actual producers (managers, workers, and tenant farmers) to maximize the benefits of firm-specific skill formation by the producers. A cautious approach is therefore needed in adjusting investor rights in Japan to global standards: stronger investor rights could enhance allocative efficiency of financial resources, but they could also be harmful to organizational efficiency based on investment by employees in firm-specific skills.
Financial Market Integration in East Asia: Regional or Global?
Authors: Jeon Jongkyou , Oh Yonghyup , Yang Doo Yong
Published: August 2006

This paper investigates whether financial markets in East Asia are integrated with global markets or with each other.We use two approaches: a volume-based approach and an asset price approach. Our overall results suggest global integration of these markets rather than regional integration and that there is no anchor market in the region that would match the advanced markets such as the United States. Though global integration is not a force that competes with regional integration, there seems to be no strong sign of the creation of an effective financial market mechanism in East Asia.
The Global Macroeconomic Consequences of a Demographic Transition
Authors: McKibbin Warwick J.
Published: August 2006

The world is in the midst of a significant demographic transition with potential implications for the macroeconomic performance of the global economy. This paper summarizes the key features of current and projected demographic change. It then applies a new 10-region global model (an extended version of the MSG-Cubed model) incorporating demographic dynamics, to examine the consequences of projected global demographic change on the world economy from 2005 to 2050. A distinction is made between the effects on each country of its own demographic transition and the effects on each country of demographic changes occurring in the rest of the world.
Contrasting Perspectives of Strategy Making: Applications in ‘Hyper’ Environments
Authors: Selsky John W. , Goes Jim , Babüroğlu Oğuz N.
Published: August 2006

We revisit the original meaning of turbulence in the socioecological tradition of organization studies and outline a perspective on strategy making grounded in that tradition. This entails a contrast of the socioecological perspective with the more well-known neoclassical perspective on strategy, based on their core decision premises and their different understandings of environmental turbulence. We argue that while some mainstream strategy approaches have taken important strides toward addressing advanced turbulence, many others remain tethered to the neoclassical origins of the strategy discipline and are insufficiently responsive to the new landscape of strategy that now characterizes many industries. This new landscape is construed as the ‘hyper environment’, in which positive feedback processes and emergent field effects produce high volatility. We use two case illustrations from the US healthcare sector to examine how neoclassical and socioecological perspectives contribute to strategizing in hyper environments. Implications for strategic management theory and practice flow from this analysis.
Molecular mimicry in the chronic myeloproliferative disorders: reciprocity between quantitative JAK2 V617F and Mpl expression
Authors: Moliterno Alison R. , Williams Donna M. , Rogers Ophelia , Spivak Jerry L.
Published: August 2006

An activating JAK2 mutation (JAK2 V617F) is present in the chronic myeloproliferative disorders (MPDs), polycythemia vera (PV), idiopathic myelofibrosis (IMF), and essential thrombocytosis (ET). JAK2 is also a chaperone for Mpl and responsible for its cell-surface expression. We observed a reciprocal relationship between neutrophil JAK2 V617F allele percentage and platelet Mpl expression in JAK2 V617F–positive PV, IMF, and ET patients. However, severely impaired platelet Mpl expression was present in JAK2 V617F–negative MPD patients. While JAK2 V617F allele status did not necessarily correlate with the clinical MPD phenotype, the degree of impaired platelet Mpl expression did. We conclude that multiple molecular abnormalities are involved in the pathogenesis of the MPDs and that aberrant Mpl expression may be a common denominator of aberrant signaling in both the JAK2 V617F–positive and JAK2 V617F–negative MPDs.
High meningioma 1 (MN1) expression as a predictor for poor outcome in acute myeloid leukemia with normal cytogenetics
Authors: Heuser Michael , Beutel Gernot , Krauter Juergen , Döhner Konstanze , von Neuhoff Nils , Schlegelberger Brigitte , Ganser Arnold
Published: August 2006

The translocation t(12;22) involves MN1 and TEL and is rarely found in acute myeloid leukemia (AML). Recently, it has been shown in a mouse model that the fusion protein MN1-TEL can promote growth of primitive hematopoietic progenitor cells (HPCs) and, in cooperation with HOXA9, induce AML. We quantified MN1 expression by real-time reverse transcriptase–polymerase chain reaction (RT-PCR) in 142 adult patients with AML with normal cytogenetics treated uniformly in trial AML-SHG 01/99. AML samples were dichotomized at the median MN1 expression. High MN1 expression was significantly correlated with unmutated NPM1 (P < .001), poor response to the first course of induction treatment (P = .02), a higher relapse rate (P = .03), and shorter relapse-free (P = .002) and overall survivals (P = .03). In multivariate analysis, MN1 expression was an independent prognostic marker (P = .02) in addition to age and Eastern Cooperative Oncology Group (ECOG) performance status. Excluding patients with NPM1mutated/FLT3ITDnegative, high MN1 expression was associated with shorter relapse-free survival (P = .057). MN1 was highly expressed in some patients with acute lymphoblastic but not chronic lymphocytic or myeloid leukemia. MN1 was highly expressed in HPCs compared with differentiated cells and was down-regulated during in vitro differentiation of CD34+ cells, suggesting a functional role in HPCs. In conclusion, our data suggest MN1 overexpression as a new prognostic marker in AML with normal cytogenetics.
Characterization of stem cell–like cancer cells in immune-competent mice
Authors: Kruger Jorg A. , Kaplan Charles D. , Luo Yunping , Zhou He , Markowitz Dorothy , Xiang Rong , Reisfeld Ralph A.
Published: August 2006

Recently, the cancer stem cell hypothesis has gained significant recognition as the descriptor of tumorigenesis. Although previous studies relied on transplanting human or rat tumor cells into immunecompromised mice, our study used the Hoechst 33342 dye–based side population (SP) technique to isolate and transplant stem cell–like cancer cells (SCLCCs) from the 4T1 and NXS2 murine carcinoma cell lines into the immune-competent microenvironment of syngeneic mice. 4T1 cells displayed an SP of 2% with a Sca-1highc-Kit–CD45– phenotype, whereas NXS2 cells contained an SP of 0.2% with a Sca-1highCD24highc-Kit–CD45–GD high2 phenotype. Reverse transcription–polymerase chain reaction (RT-PCR) further revealed up-regulation in SP cells of ABCG2, Sca-1, Wnt-1, and TGF-β2. Additionally, 4T1 and NXS2 SP cells exhibited increased resistance to chemotherapy, and 4T1 SP cells also showed an increased ability to efflux doxorubicin, which correlated with a selective increase in the percentage of SP cells found in the tumors of doxorubicin-treated mice. Most importantly, SP cells showed a markedly higher repopulation and tumorigenic potential in vivo, which correlated with an increased number of cells in the SP compartment of SP-derived tumors. Taken together, these results show that we successfully characterized SCLCCs from 2 murine carcinoma cell lines in the immune-competent microenvironment of syngeneic mice.
Retrotranspositions in orthologous regions of closely related grass species
Authors: Du Chunguang , Swigoňová Zuzana , Messing Joachim
Published: August 2006

Background

Retrotransposons are commonly occurring eukaryotic transposable elements (TEs). Among these, long terminal repeat (LTR) retrotransposons are the most abundant TEs and can comprise 50–90% of the genome in higher plants. By comparing the orthologous chromosomal regions of closely related species, the effects of TEs on the evolution of plant genomes can be studied in detail.

Results

Here, we compared the composition and organization of TEs within five orthologous chromosomal regions among three grass species: maize, sorghum, and rice. We identified a total of 132 full or fragmented LTR retrotransposons in these regions. As a percentage of the total cumulative sequence in each species, LTR retrotransposons occupy 45.1% of the maize, 21.1% of the rice, and 3.7% of the sorghum regions. The most common elements in the maize retrotransposon-rich regions are the copia-like retrotransposons with 39% and the gypsy-like retrotransposons with 37%. Using the contiguous sequence of the orthologous regions, we detected 108 retrotransposons with intact target duplication sites and both LTR termini. Here, we show that 74% of these elements inserted into their host genome less than 1 million years ago and that many retroelements expanded in size by the insertion of other sequences. These inserts were predominantly other retroelements, however, several of them were also fragmented genes. Unforeseen was the finding of intact genes embedded within LTR retrotransposons.

Conclusion

Although the abundance of retroelements between maize and rice is consistent with their different genome sizes of 2,364 and 389 Mb respectively, the content of retrotransposons in sorghum (790 Mb) is surprisingly low. In all three species, retrotransposition is a very recent activity relative to their speciation. While it was known that genes re-insert into non-orthologous positions of plant genomes, they appear to re-insert also within retrotransposons, potentially providing an important role for retrotransposons in the evolution of gene function.
Genome-wide gene expression profiling of human mast cells stimulated by IgE or FcεRI-aggregation reveals a complex network of genes involved in inflammatory responses
Authors: Jayapal Manikandan , Tay Hwee Kee , Reghunathan Renji , Zhi Liang , Chow Kah Kiong , Rauff Mary , Melendez Alirio J
Published: August 2006

Background

Mast cells are well established effectors of IgE-triggered allergic reactions and immune responses to parasitic infections. Recent studies indicate that mast cells may play roles in adaptive and innate immunity, suggesting an innovative view of the regulation of immune responses. Here, we profiled the transcriptome of human mast cells sensitized with IgE alone, or stimulated by FcεRI aggregation.

Results

Our data show that among 8,793 genes examined, 559 genes are differentially regulated in stimulated mast cells when compared with resting/unstimulated mast cells. The major functional categories of upregulated genes include cytokines, chemokines, and other genes involved in innate and adaptive immune-responses. We observed the increased expression of over 63 gene-transcripts following IgE-sensitization alone. Our data was validated using Real-Time-PCR; ELISA and western blot. We confirmed that IgE alone does not trigger mast cell-immediate responses, such as calcium signals, degranulation or protein-phosphorylation.

Conclusion

This report represents a substantial advance in our understanding of the genome wide effects triggered by "passive sensitization" or active stimulation of human mast cells, supporting mast cells' potential involvement in a wide range of inflammatory responses.