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PubMed1993

Casein accumulation by rat mammary epithelial cells grown within a reconstituted basement membrane is modulated by fatty acids in a hormone- and time-dependent manner.

The mammary gland is under complex regulation involving the participation of hormones, growth factors, and stromal components, including lipids. Our laboratory has developed a unique primary culture system that allows undifferentiated mammary epithelial cells from immature virgin rats to proliferate and differentiate to an extent equivalent to the lactating mammary gland. Using this model system we have examined the effects of the unsaturated fatty acids oleate and linoleate on mammary epithelial cell proliferation as well as both morphological and functional differentiation. Neither fatty acid showed any effect on cell proliferation whether added to cells in the presence of optimal serum-free medium or under suboptimal conditions of epidermal growth factor (EGF) and prolactin. Morphological differentiation also was not affected by fatty acid addition under either optimal or suboptimal conditions, although a decrease was observed when medium depleted in EGF and prolactin was compared to optimal medium. The notable finding in this study was that both oleate and linoleate modulated functional differentiation, as assessed by casein accumulation, in a time- and hormone-dependent manner. At early times in culture, casein levels were stimulated by both oleate and linoleate; this effect was most dramatic under suboptimal conditions of prolactin and EGF. In marked contrast, however, linoleate decreased casein levels by approximately 50% in optimal medium, at all concentrations tested, after at least 7 days in culture. This decrease was also observed in suboptimal medium, although the concentration of EGF and prolactin influenced the extent of the reduction. Although the mechanism is currently unknown, it is tempting to speculate that the cellular and biochemical events that result in linoleate-induced inhibition of functional differentiation may also be involved in the tumor-enhancing properties of this fatty acid.

Animals↗
PubMed2001

Differential item functioning in a Spanish translation of the Beck Depression Inventory.

Brief and culturally compatible measures of depression are necessary, yet most depression scales are translated without regard for cultural biases. In this study, 292 medical outpatients completed an English or a Spanish-translated and back-translated version of the Beck Depression Inventory (BDI). The BDI items were analyzed for bias between Spanish and English-speaking patients to determine the equivalence of the scale. A Differential Item Function (DIF) using a Mantel Haenszel Approach for Ordered Response Categories was used to analyze how likely subjects in the two ethnic groups were to endorse each response category. The results suggest that regardless of level of depression, Latinos are more likely to endorse items reflecting tearfulness and punishment, and less likely to endorse inability to work. Cultural interpretations and recommendations for use of the BDI are discussed.

Adult↗
PubMed2006

Comparing translations of the EORTC QLQ-C30 using differential item functioning analyses.

The European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 is one of the most widely used quality of life instruments for cancer patients. The aim of this study was to assess whether there were linguistic differences in the way an international sample answered the EORTC QLQ-C30 questionnaire. Thirteen translations of the EORTC QLQ-C30, representing 22 countries, were investigated using a database of 27,891 respondents, incorporating 103 separate studies. Differential item functioning (DIF) analyses were conducted using logistic regression to identify items which, after controlling for subscale, were answered differently by language of administration. Both uniform and non-uniform DIF were assessed. Although most languages showed similar results to English, at least one instance of statistically significant DIF was identified for each translation, and a few of these differences were large. In some cases, the patterns were supported by the results of qualitative interviews with bilingual people. Although, overall, there appeared to be good linguistic equivalence for most of the EORTC QLQ-C30 items, several scales showed strongly discrepant results for some translations. Some of these effects are large enough to impact on the results of clinical trials. Based on our experience in this study, we suggest that validation of translations of health-related quality of life instruments should include exploration of DIF.

Attitude to Health↗
PubMed2006

The use of differential item functioning analyses to identify cultural differences in responses to the EORTC QLQ-C30.

INTRODUCTION: The European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 is a widely used health-related quality of life instrument. The main aim of this study is to investigate whether there are international differences in response to the questionnaire that can be explained by cultural factors. METHODS: Analyses involved a database of 106 separate studies including data from over 28,000 respondents. Differential item functioning (DIF) analyses using logistic regression were conducted for each item of the EORTC QLQ-C30 with respect to cultural/geographic group. Results were qualitatively compared with previously reported DIF analyses by translation to explore whether the source of the DIF was more likely to be linguistic or cultural in nature. RESULTS: Although most response patterns were similar, there were a number of international differences in how the questionnaire was answered. The largest variations were found in the results for Eastern Europe and East Asia. Results for the UK, the US and Australia tended to be similar. Many of the European results followed patterns that were more clearly explained when grouped by translation than when grouped by geographical region. DISCUSSION: Our results suggest that, in general, the EORTC QLQ-C30 is suitable for use in a wide variety of countries and settings. Some response variations that have the potential to affect the results of international studies were identified, but it was not always clear whether the source of the variation was primarily linguistic or cultural.

Adult↗
PubMed2005

Labeling of cells with ferumoxides-protamine sulfate complexes does not inhibit function or differentiation capacity of hematopoietic or mesenchymal stem cells.

Two FDA-approved agents, ferumoxides (Feridex), a suspension of superparamagnetic iron oxide (SPIO) nanoparticles and protamine sulfate, a drug used to reverse heparin anticoagulation, can be complexed and used to label cells magnetically ex vivo. Labeling stem cells with ferumoxides-protamine sulfate (FePro) complexes allows for non-invasive monitoring by MRI. However, in order for stem cell trials or therapies to be effective, this labeling technique must not inhibit the ability of cells to differentiate. In this study, we examined the effect of FePro labeling on stem cell differentiation. Viability, phenotypic expression and differential capacity of FePro labeled CD34 + hematopoietic stem cells (HSC) and mesenchymal stem cells (MSC) were compared with unlabeled control cells. Colony-forming unit (CFU) assays showed that the capacity to differentiate was equivalent for labeled and unlabeled HSC. Furthermore, labeling did not alter expression of surface phenotypic markers (CD34, CD31, CXCR4, CD20, CD3 and CD14) on HSC, as measured by flow cytometry. SDF-1-induced HSC migration and HSC differentiation to dendritic cells were also unaffected by FePro labeling. Both FePro-labeled and unlabeled MSC were cultured in chondrogenesis-inducing conditions. Alcian blue staining for proteoglycans revealed similar chondrogenic differentiation for both FePro-labeled and unlabeled cells. Furthermore, collagen X proteins, indicators of cartilage formation, were detected at similar levels in both labeled and unlabeled cell pellets. Prussian blue staining confirmed that cells in labeled pellets contained iron oxide, whereas cells in unlabeled pellets did not. It is concluded that FePro labeling does not alter the function or differentiation capacity of HSC and MSC. These data increase confidence that MRI studies of FePro-labeled HSC or MSC will provide an accurate representation of in vivo trafficking of unlabeled cells.

Biomarkers↗
PubMed1996

Fluorine-18-FDG and iodine-131-iodide uptake in thyroid cancer.

UNLABELLED: We conducted a prospective study to define the sensitivity of 131I scintigraphy and 18FDG PET whole-body scanning in the detection of thyroid cancer and metastases. METHODS: Forty-one patients with differentiated thyroid carcinoma who underwent thyroidectomy and 131I elimination of the remaining thyroid were studied by 18FDG whole-body PET in 52 examinations and by 131I whole-body scanning. RESULTS: Combined 18FDG and 131I imaging resulted in a sensitivity of about 95%, with alternating uptake of 131I and 18FDG in the metastases: 131I trapping metastases with no 18FDG uptake and 18FDG trapping metastases with no 131I uptake. Five uptake types were differentiated. Alternating uptake was found in about 90% of the patients, which was nearly identical to the sensitivity of the combined 131I/18FDG investigation. In six patients with increasing human thyroglobulin levels, we found that 18FDG whole-body PET localized positive neck metastases of papillary thyroid carcinomas that were histologically confirmed after extirpation. CONCLUSION: Combination 18FDG and 131I whole-body imaging protocol enables detection of local recurrence or metastases on whole-body scans that are often not shown by other imaging methods. Biochemical grading of thyroid cancer may also be possible with this method: Tumors with remaining functional differentiation for hormone synthesis and iodine uptake have low glucose metabolism in more than 95%; tumors without this functional differentiation of 131I uptake show high, glucose metabolism. Fluorine-18-FDG uptake seems to be an indicator of poor functional differentiation, and possibly higher malignancy, in thyroid cancer.

Adenocarcinoma↗
PubMed2004

Estrogen affects the differentiation and function of splenic monocyte-derived dendritic cells from normal rats.

AIM: To explore the mechanism resulting in the preventive effect of estrogen on experimental autoimmune encephalomyelitis (EAE), which is an animal model for multiple sclerosis (MS), and examine if estrogen can affect the immune response in EAE at dendritic cell (DC) level. METHODS: Flow cytometry was used to reveal the surface marker expression. 3H-thymidine incorporation was applied to examine the cellular proliferation. Levels of anti-myelin basic protein (MBP)(68-86) antibody and cytokines were determined by enzyme-linked immunospot and ELISA, respectively. RESULTS: 17beta-estradiol (E2) could dose-dependently accelerate the differentiation process of DCs by up-regulating CD11c, B7-2 and CD40 expressions, but exert no effect on its antigen presentation ability. MBP-specific T cells cocultured with E2-treated DCs (E2-DC) produced more IL-10 and less IFN-gamma in the supernatant than those without E2 pretreatment (ctr-DC). In contrast to ctr-DC, E2-DC, if injected i.v. into EAE rats on day 5 post immunization, could initiate antigen nonspecific hyper-responsivity in T cells in terms of enhanced proliferation and cytokine secretion of mononuclear cells in LN, but suppressed antibody secretion from splenocytes. CONCLUSION: These results suggest that estrogen can affect the differentiation and function of DCs, which leads T cells switching to Th2 secretion. This may account partly for the protective effect of estrogen on EAE.

Animals↗
PubMed1980

Establishment of a fetal rat liver cell line that retains differentiated liver functions.

Fetal rat liver cells were transformed with a temperature-sensitive A mutant (tsA255) of simian virus 40. A CLONAL CELL LINE, RLA255-4, which was temperature sensitive in the maintenance of the transformed phenotype, was isolated. This cell line expressed the transformed phenotype (rapid growth, high cell density, overgrowth of normal cells, and cloning in soft agar) at the permissive temperature (33 degrees C) and the nontransformed phenotype (slower growth, lower saturation density, decreased efficiency of overgrowth of normal cells, and lower cloning efficiency in soft agar) at the restrictive temperature (40 degrees C). The tsA255-transformed cells expressed differentiated liver functions under controllable conditions. At the permissive temperature, they produced low levels of albumin and transferrin, whereas at the restrictive temperature the transformed phenotype was lost and the production of these hepatic proteins was greatly enhanced. RLA255-4 cells contained functional receptors for glucagon, as shown by the stimulation of intracellular cyclic AMP accumulation by glucagon. The response to glucagon was dose dependent (Kact = 5 x 10(-8) M) and could be demonstrated in cells grown at both permissive and restrictive temperatures after 7 days in culture (i.e., at a cell density of approximately 4 x 10(5) cells per cm2 or higher). Addition of cortisol to the culture medium enhanced the glucagon response selectively at the restrictive temperature.

Albumins↗
PubMed2006

Identification of measurement differences between English and Spanish language versions of the Mini-Mental State Examination. Detecting differential item functioning using MIMIC modeling.

BACKGROUND: Knowledge of the extent to which measurement of adult cognitive functioning differs between Spanish and English language administrations of the Mini-Mental State Examination (MMSE) is critical for inclusive, representative, and valid research of older adults in the United States. OBJECTIVES: We sought to demonstrate the use of an item response theory (IRT) based structural equation model, that is, the MIMIC model (multiple indicators, multiple causes), to evaluate MMSE responses for evidence of differential item functioning (DIF) attributable to language of administration. SUBJECTS: We studied participants in a dementia case registry study (n = 1546), 42% of whom were examined with the Spanish language MMSE. RESULTS: Twelve of 21 items were identified as having significant uniform DIF. The 4 most discrepant included orientation to season, orientation to state, repeat phrase, and follow command. DIF accounted for two-thirds of the observed difference in underlying level of cognitive functioning between Spanish- and English-language administration groups. CONCLUSIONS: Failing to account for measurement differences may lead to spurious inferences regarding language group differences in level of underlying level of cognitive functioning. The MIMIC model can be used to detect and adjust for such measurement differences in substantive research.

Aged↗
PubMed2002

Differential item functioning in a Spanish translation of the PTSD checklist: detection and evaluation of impact.

This study demonstrated the application of an innovative item response theory (IRT) based approach to evaluating measurement equivalence, comparing a newly developed Spanish version of the Posttraumatic Stress Disorder Checklist-Civilian Version (PCL-C) with the established English version. Basic principles and practical issues faced in the application of IRT methods for instrument evaluation are discussed. Data were derived from a study of the mental health consequences of community violence in both Spanish speakers (n = 102) and English speakers (n = 284). Results of differential item functioning (DIF) analyses revealed that the 2 versions were not fully equivalent on an item-by-item basis in that 6 of the 17 items displayed uniform DIF. No bias was observed, however, at the composite PCL-C scale score, indicating that the 2 language versions can be combined for scale-level analyses.

Adolescent↗
PubMed1991

The interaction of signal transduction pathways in FRTL5 thyroid follicular cells: studies with stable expression of beta 2-adrenergic receptors.

Multiple signal transduction pathways interact in FRTL5 cells to promote thyroid follicular cell differentiated function and cell proliferation. In these cells, TSH is a tissue-specific mitogen that promotes DNA synthesis primarily through activation of adenylate cyclase. To further test the role of adenylate cyclase in regulating cell growth and differentiated function we have introduced into FRTL5 the human beta 2-adrenergic receptor (BAR) complementary DNA and have studied the ability of isoproterenol, alone and in combination with insulin-like growth factor I (IGF-I), to stimulate cAMP accumulation, iodide transport, [3H]thymidine incorporation into DNA, and cell growth. Wild-type FRTL5 were infected with a PLJ retroviral construct containing the BAR in either a sense (FRTL BAR) or antisense (FRTL RBAR) orientation, and cell populations were selected on the basis of resistance to the antibiotic geneticin. FRTL BAR expressed approximately 1.3 x 10(5) high affinity binding sites per cell for the beta 2-specific ligand, CGP-12177, while neither FRTL5 wild-type nor RBAR cells demonstrated any specific binding. FRTL BAR had significantly higher levels of intracellular cAMP, [3H]thymidine incorporation, and iodide uptake in the absence of added isoproterenol than FRTL RBAR or wild-type cells. In FRTL BAR, but not RBAR cells, isoproterenol stimulated a dose-dependent accumulation of cAMP, iodide uptake, [3H]thymidine incorporation, and cell growth. FRTL BAR and RBAR cells were equally responsive to TSH and to IGF-I. Isoproterenol enhanced the ability of IGF-I to stimulate [3H]thymidine incorporation in BAR but not RBAR cells. Isoproterenol partially inhibited the ability of TSH to stimulate cAMP generation and DNA synthesis. These studies demonstrate that activation of adenylate cyclase through the BAR introduced into FRTL5 cells by retroviral infection reproduces the range of biological effects in these cells stimulated by TSH and suggest that activation of adenylate cyclase is sufficient to stimulate thyroid differentiated function and cell growth. FRTL BAR cells will provide an interesting model system with which to study the heterologous regulation of both TSH and BARs through activation of a common signal transduction pathway, adenylate cyclase.

Adenylyl Cyclases↗
PubMed2004

Assessing and adjusting for cross-cultural validity of impairment and activity limitation scales through differential item functioning within the framework of the Rasch model: the PRO-ESOR project.

INTRODUCTION: In Europe it is common for outcome measures to be translated for use in other languages. This adaptation may be complicated by culturally specific approaches to certain tasks; for example, bathing. In this context the issue of cross-cultural validity becomes paramount. OBJECTIVE: To facilitate the pooling of data in international studies, a project set out to evaluate the cross-cultural validity of impairment and activity limitation measures used in rehabilitation from the perspective of the Rasch measurement model. METHODS: Cross-cultural validity is assessed through an analysis of Differential Item Functioning (DIF) within the context of additive conjoint measurement expressed through the Rasch model. Data from patients undergoing rehabilitation for stroke was provided from 62 centers across Europe. Two commonly used outcome measures, the Mini-Mental State Examination (MMSE) and the Functional Independence Measure (FIM) motor scale are used to illustrate the approach. RESULTS: Pooled data from 3 countries for the MMSE were shown to fit the Rasch model with only 1 item displaying DIF by country. In contrast, many items from the FIM expressed DIF and misfit to the model. Consequently they were allowed to be unique across countries, so resolving the lack of fit to the model. CONCLUSIONS: Where data are to be pooled for international studies, analysis of DIF by culture is essential. Where DIF is observed, adjustments can be made to allow for cultural differences in outcome measurement.

Activities of Daily Living↗
PubMed1997

The POU gene ceh-18 promotes gonadal sheath cell differentiation and function required for meiotic maturation and ovulation in Caenorhabditis elegans.

In Caenorhabditis elegans, specialized contractile myoepithelial cells of the somatic gonad, the gonadal sheath cells, are closely apposed to oocytes and are required for normal meiotic maturation and ovulation. Previously we found that mutations in the ceh-18 gene, which encodes a POU-class homeoprotein expressed in sheath cells, result in oocyte defects. To determine the basis for these oocyte defects, we have used time-lapse video Nomarski microscopy to observe meiotic maturation, ovulation, and early embryogenesis in ceh-18 mutants. In ceh-18 mutants sheath cell contractions are weaker, less frequent, and uncoordinated throughout the sequence of ovulation events, and ovulation is defective. Defective ovulation can result in the formation of endomitotic oocytes in the gonad, the formation of haploid embryos, and reversals in embryonic polarity. ceh-18 mutant oocytes exhibit defects prior to nuclear envelope breakdown, suggesting that they are physiologically different from the wild type. We observed delays in meiotic maturation, as well as maturation out of the normal spatial and temporal sequence, suggesting that proximal sheath cells directly or indirectly promote and spatially restrict meiotic maturation. Analysis of sheath cell differentiation in ceh-18 mutants using antibodies to proteins of the contractile apparatus reveals that although contractile proteins are expressed, the sheath cells appear disorganized. Transmission electron microscopy reveals that ceh-18 mutant sheath cells are morphologically irregular and only loosely cover oocytes. Taken together, these observations indicate that ceh-18 is a crucial determinant of sheath cell differentiation, a function required for normal meiotic maturation and ovulation.

Animals↗
PubMed1988

Population density functions: a differential equation approach.

"This paper introduces a new mathematical technique to describe population density functions. Two length scales, which characterize the variation of these density functions within a region, are identified. A differential equation is derived and asymptotic solutions obtained. Two specific techniques, the method of matched asymptotic expansions and the method of multiple scales, are introduced and illustrated by application to population densities at both the metropolitan and regional levels."

Demography↗
PubMed1992

Regulation of differentiation and proliferation of rat hepatocytes by lactose-carrying polystyrene.

We noticed that hepatocytes recognize the structure of oligosaccharides via asialoglycoprotein receptors and synthesized lactose-carrying styrene polymer (PVLA) as an asialoglycoprotein model. We found that the regulation of differentiated function and proliferation of hepatocytes that were cultured on polystyrene dishes can be achieved by varying the amount of PVLA coated on the dishes. The 3H-thymidine uptake of cultured hepatocytes is low for cells cultured on dishes coated with high amounts of PVLA in which the hepatocytes are round and is highest for those cultured on dishes with a low PVLA coating level in which the hepatocytes are spread in shape. Moreover, bile acid release as a typical differentiated function of hepatocytes was maintained at higher levels in hepatocytes attached on dishes coated with a high level of PVLA. Our results indicated that regulation of differentiated function and proliferation in hepatocytes could be achieved by specific ligand-mediated recognition of microscopic surface structure. Thus, it may be possible to regulate proliferation and differentiation of hepatocytes by design of the culturing substrata.

Animals↗
PubMed2005

Identification of expandable human hepatic progenitors which differentiate into mature hepatic cells in vivo.

BACKGROUND: Liver diseases include a wide spectrum of both acute and chronic conditions which are associated with significant morbidity and mortality worldwide. Hepatocyte transplantation has therapeutic potential in the treatment of liver diseases, but its clinical use is hampered by the lack of donor tissue. Generation of hepatocytes in vitro from adult or fetal liver cell progenitors or, alternatively, identification of a progenitor population which in vivo can generate mature liver cells could solve this problem. METHODS: CD117+/CD34+/Lin- human fetal liver cells were isolated by magnetic cell sorting and expanded in culture. Both freshly isolated and in vitro expanded cells in various passages were studied for their ability to be functional in hepatic parenchyma following d-galactosamine (GalN) induced injury in nude C57 black mice. RESULTS: Freshly isolated and in vitro expanded CD117+/CD34+/Lin- cells, when transplanted intrasplenically into GalN treated mice, morphologically and functionally differentiated into hepatocytes and cholangiocytes. Human specific albumin, alpha fetoprotein, cytokeratin 19, and antitrypsin mRNA were expressed in mouse liver. In addition, the human progenitor cells expressed glucose-6-phosphatase, glycogen, albumin, gamma glutamyl transpeptidase, and dipeptidyl peptidase IV after transplantation. Expanded cells in various passages maintained their capacity to differentiate into functional liver cells. CONCLUSIONS: Fetal liver CD117+/CD34+/Lin- progenitors and their progeny proliferated in vitro and also functionally differentiated into mature hepatic cells in an acute liver injury model. Successful in vitro expansion of liver progenitor cells provides a basis for developing cell therapy strategies, metabolic and toxicity testing systems, and may serve as a vehicle for gene therapy.

Animals↗
PubMed1994

Comparative IL-6 effects on FSH and hCG-induced functions in porcine granulosa cell cultures.

Gonadotropin regulation of granulosa cell (GC) differentiation can be modulated by non-steroidal factors, including cytokines. Interleukin-6 (IL-6), a broad spectrum cytokine, has been previously demonstrated to be produced by GCs and to directly influence follicle stimulating hormone (FSH) differentiated functions of ovarian GCs. In the present study, primary cultures of GCs were prepared from prepubertal sow ovaries. No significant amount of biological active IL-6 was detected in these cultures using the B9 cell growth bioassay. Although our findings suggest that GCs are not source of IL-6 in the porcine ovary, this cytokine may be released by leukocytes present in the ovary and modulate ovarian functions by acting on GCs. Here, adding recombinant human (rh)IL-6 to GC cultures inhibited differentiated functions induced by FSH such as aromatase activity, LH receptor (LHr) expression measured by specific 125I-hCG binding and progesterone (P) production. On the opposite, rhIL-6 did not modulate stimulatory human chorionic hormone (hCG) effects on P release by GCs and did not prevent hCG binding to LHr. These preliminary results clearly showed that IL-6 acted differently on FSH and hCG induced functions although these gonadotropins act primarily through the same transduction pathway involving generation of cyclic AMP. We suggest that IL-6 might act more likely by reducing FSH binding capacity than by modulating transduction pathways. Inhibitory IL-6 effects on FSH-induced functions were not neutralized by adding to culture media a monoclonal antibody against the human IL-6 signal transducer gp130, previously reported to inhibit IL-6 mediated effects in human cell lines.

Animals↗
PubMed2006

Using effect sizes for research reporting: examples using item response theory to analyze differential item functioning.

The psychological literature currently emphasizes reporting the "effect size" of research findings in addition to the outcome of any tests of significance. However, some confusion may result from the fact that there are three distinct uses of effect sizes in the psychological literature, namely, power analysis, research synthesis, and research reporting. The authors review these uses of effect sizes and develop a case study of the description of effect size for research reporting in the context of item response theory. For many parametric models, hypotheses are tested by comparing the values of directly interpretable parameters. The authors show that the size of the effect can be expressed by a presentation of the values of the parameter estimates derived from the fitted model. Studies that use item response theory to detect differential item functioning provide illustrations.

Humans↗