Biomedical subjects

M Edlund

Publications and source records attributed to M Edlund.

At least 19 recordsLinked to original sources

PubMed2002

Desmopressin in the treatment of menorrhagia in women with no common coagulation factor deficiency but with prolonged bleeding time.

The objective of this study was to investigate the efficacy and safety of desmopressin (1-desamino-8-D-arginine vasopressin) compared with placebo in the reduction of menstrual blood loss in women with menorrhagia and prolonged bleeding time, but without common coagulation factor deficiencies. We performed a randomized, double-blind, cross-over study using 300 microg desmopressin nasal inhalation or placebo treatment in one of the two first treatment cycles. Desmopressin was given only for the 2 days during which the bleeding had been at a maximum in the previous baseline cycle. A third open cycle involved combined treatment with desmopressin and tranexamic acid during the 2 days for all patients. Menstrual blood loss during the treatment periods was compared with blood loss during placebo-treated periods using objective measurement. A significant reduction of menstrual blood loss was found in the cycles treated with combined desmopressin and tranexamic acid compared with placebo. When analyzing the blood loss during the two treatment days, there was a significant reduction in blood loss for the 2 days with desmopressin alone versus placebo. The treatment was well tolerated and no serious adverse events were recorded. In conclusion, we find that nasal desmopressin is a possible complement for the medical treatment of menorrhagia.

Adult↗

PubMed2001

[Menorrhagia--a symptom not sufficiently surveyed. The path to diagnosis and treatment lined with ambiguity and misunderstandings].

Approximately 10 percent of all women of fertile age suffer from menorrhagia, a symptom defined as regular heavy menstrual bleeding. Finding the cause of the symptoms can often be the key to effective treatment. Apart from anatomical causes such as myomas and adenomyosis which underlie less than half of all cases, recent studies have been pointing toward a hitherto unrecognized over-representation of mild hemostatic disorders such as von Willebrands disease and platelet dysfunction. Efforts have been made to spread information about the problem, but as with most "new" information it has been met with some skepticism. Lately though, there have been nationwide campaigns in the USA and Canada in which targeted information and instruction is aimed at lay educators as well as health care providers, informing about these circumstances. Advantages of a correct diagnosis are not only the of to choosing more efficient treatment. When a hemostatic disorder has been diagnosed there follows a reduced risk of complications in connection with surgery, trauma and delivery.

Diagnosis, Differential↗

PubMed2001

Androgen receptor mediates the reduced tumor growth, enhanced androgen responsiveness, and selected target gene transactivation in a human prostate cancer cell line.

The growth and development of the prostate gland are regulated by the androgen and the androgen receptor (AR). Despite our molecular understanding of the roles of the AR regulating; a downstream target gene transcription, the direct or indirect (stromally mediated) actions of the androgen in controlling prostate cell growth and differentiation are still unclear. In this report, an invasive; and metastatic human prostate tumor cell line, androgen-repressed human prostate cancer cell line (ARCaP), either transduced with wild-type human AR (hAR) or a control neomycin-resistant plasmid DNA, was used to evaluate the direct role of AR in regulating prostate tumor cell growth and gene transcription. Results showed that: (a) introduction of wild-type hAR to ARCaP cells restored positive androgen regulation of prostate tumor cell growth in vitro through an enhanced cell-cycle progression from G(0)/G(1) to S and G(2)-M phases; (b) hAR was shown to transactivate glucocorticoid-responsive element but not prostate-specific antigen promoter-directed reporter gene expression; and (c) hAR-transduced ARCaP cells exhibited reduced growth, invasion, and migratory behavior in vitro and tumor growth in vivo. These results suggest that the introduction of hAR into the invasive human prostate cancer ARCaP cell line restored its androgen-regulated cell growth, decreased the rate of tumor growth, and selectively activated AR target gene expression. These cellular functions in response to androgen are commonly associated with increased differentiation of prostate epithelial cells.

Androgens↗

PubMed2001

Dynamics of alpha-actinin in focal adhesions and stress fibers visualized with alpha-actinin-green fluorescent protein.

Motile cells undergo changes in cell adhesion, behavior, and shape that are mediated by small-scale cytoskeletal rearrangements. These rearrangements have proven difficult to follow quantitatively in living cells, without disrupting the very structures and delicate protein balances under study. We have expressed a prominent cytoskeletal protein, alpha-actinin, as a fusion with green fluorescent protein (alpha AGFP), and have followed this construct's movements within transfected mouse Swiss 3T3 and BALB/c fibroblasts. alpha AGFP was expressed at low levels to avoid overexpression artifacts. alpha AGFP localized to cellular structures, including stress fibers, focal adhesions, microspikes, and lamellipodia. High-resolution video-microscopy revealed that the alpha AGFP construct could be seen relocating to focal adhesions early in their formation and shortly thereafter to stress-fiber dense bodies. By Fluorescent Recovery After Photo-bleaching (FRAP) techniques, alpha AGFP was found to have similar exchange rates and protein stability in focal adhesions and stress fibers (despite the known differences in protein composition in these two structures). This raises the possibility that the two structures share common key regulatory factors and may not be as affected by protein-protein binding interactions as previously suggested. Additionally, the exchange rates revealed by video-microscopy and FRAP analysis of alpha AGFP are more rapid than those reported previously, which were obtained using microinjection of large excesses of fluorescently-tagged protein.

3T3 Cells↗

PubMed2001

Inhibition of growth and cell cycle arrest of ARCaP human prostate cancer cells by ectopic expression of ER-alpha.

The estrogen receptor-alpha (ER-alpha) is a ligand-dependent transcription factor that regulates the growth, differentiation, and development of hormone-responsive target organs. While ER-alpha has been reported to play critical role in the pathogenesis and prognosis of breast and prostate cancers, its possible functional role in regulating prostate cancer cell growth in a ligand-dependent or -independent manner is poorly understood. We addressed this question by stably transfecting wild type (wt) ER-alpha cDNA into an invasive estrogen receptor-negative human prostate cancer cell line ARCaP. We isolated several clonal lines of transfected cells expressing varying levels of ER-alpha. The ectopic expression of wt ER-a markedly inhibited the growth of ARCaP cells in vitro in an ER-a dose-dependent but ligand-independent manner. Flow cytometric analysis of the wt ER-alpha-transfected ARCaP cells revealed that wt ER-alpha expression arrested cell growth in G1 phase. Our results suggest that ER-alpha may regulate prostate cell growth and participate in the pathogenesis of prostate cancer. ER-alpha may be delivered and expressed ectopically to target prostate cancer progression.

Blotting, Western↗

PubMed2001

Interactions of a hemidesmosome component and actinin family members.

Hemidesmosomes are multimeric protein complexes that attach epithelial cells to their underlying matrix and serve as cell surface anchorage sites for the keratin cytoskeleton. Two hemidesmosome components, the alpha6beta4 integrin heterodimer and a human autoantigen termed BP180, are transmembrane proteins that link the extracellular matrix to the keratin network in cells. Here, we report that actinin-4, an actin-bundling protein, is a potential binding partner for BP180. Using yeast two-hybrid, we have mapped the binding site for BP180 to the C-terminal region of actinin-4. This site contains two EF-hand, Ca2+ regulation domains and shares 87% sequence homology with the same region in actinin-1. Consistent with this, BP180 can bind actinin-1 in both the yeast two-hybrid assay and in immunoprecipitation assays. To determine whether the EF-hand domain is a consensus binding sequence for BP180, we tested whether other proteins with this domain bind BP180. None of the proteins tested including calmodulin, with 4 EF-hand domains, and myosin regulatory light chain, with 1 EF-hand domain, interacts with BP180 in yeast two-hybrid system and immunoprecipitation studies, suggesting that the interaction between BP180 and actinin family members is specific. We have compared the distribution of actinin-1 and actinin-4 with that of BP180 in MCF-10A and pp126 cells. Surprisingly, BP180 localizes not only to sites of cell-substratum interaction, but is also present at sites of cell-cell contacts where it co-distributes with both actinin-1 and actinin-4 as well as other adherens junction proteins. In oral tissues, BP180 is present along the basement membrane and at cell-cell contact sites in basal epithelial cells where it co-distributes with adherens junction proteins. Since BP180 antibodies inhibit association of junction proteins at sites of cell-cell contact in oral keratinocytes, these results suggest that BP180 may play a role in establishing cell-cell interactions. We discuss a role for BP180 in crosstalk between cell-matrix and cell-cell junctions.

Actinin↗

PubMed2001

Integrin expression and usage by prostate cancer cell lines on laminin substrata.

During prostate cancer progression, invasive glandular epithelial cells move out of the ductal-acinar architecture and through the surrounding basement membrane. Extracellular matrix proteins and associated soluble factors in the basal lamina and underlying stroma are known to be important regulators of prostate cell behaviors in both normal and malignant tissues. In this study, we assessed cell interactions with extracellular matrix and stromal factors during disease progression by characterizing integrin usage and expression in a series of parental and lineage-derived LNCaP human prostate cancer cell lines. Although few shifts in integrin expression were found to accompany disease progression, integrin heterodimer usage did change significantly. The more metastatic sublines were distinct in their use of alphavbeta3 and, when compared with parental LNCaP cells, showed a shift in alpha6 heterodimerization, a subunit critical not only for interaction with prostate basal lamina but also for interaction with the bone matrix, a favored site of prostate cancer metastases.

Adenocarcinoma↗

PubMed2000

Visualizing muscle cell migration in situ.

BACKGROUND: Cell migration has been studied extensively by manipulating and observing cells bathed in putative chemotactic or chemokinetic agents on planar substrates. This environment differs from that in vivo and, consequently, the cells can behave abnormally. Embryo slices provide an optically accessible system for studying cellular navigation pathways during development. We extended this system to observe the migration of muscle precursors from the somite into the forelimb, their cellular morphology, and the localization of green fluorescent protein (GFP)-tagged adhesion-related molecules under normal and perturbed conditions. RESULTS: Muscle precursors initiated migration synchronously and migrated in broad, rather than highly defined, regions. Bursts of directed migration were followed by periods of meandering or extension and retraction of cell protrusions. Although paxillin did not localize to discernible intracellular structures, we found that alpha-actinin localized to linear, punctate structures, and the alpha5 integrin to some focal complexes and/or vesicle-like concentrations. Alterations in the expression of adhesion molecules inhibited migration. The muscle precursors migrating in situ formed unusually large, long-lived protrusions that were polarized in the direction of migration. Unlike wild-type Rac, a constitutively active Rac localized continuously around the cell surface and promoted random protrusive activity and migration. CONCLUSIONS: The observation of cellular migration and the dynamics of molecular organization at high temporal and spatial resolution in situ is feasible. Migration from the somite to the wing bud is discontinuous and not highly stereotyped. In situ, local activation of Rac appears to produce large protrusions, which in turn, leads to directed migration. Adhesion can also regulate migration.

Animals↗

PubMed1999

Effects of the antiestrogenic environmental pollutant 3,3',4,4', 5-pentachlorobiphenyl (PCB #126) in rat bone and uterus: diverging effects in ovariectomized and intact animals.

The purpose of this study was to compare effects on rat bone and uterus of estrogen depletion and exposure to the coplanar PCB-congener 3,3',4,4',5-pentachlorobiphenyl (PCB #126) which exhibits anti-estrogenic properties. Half of the rats were ovariectomized (n = 20) and the other half were sham-operated. Ten of the ovariectomized rats and ten of the sham operated were exposed to PCB #126 (ip injections) for 3 months (total dose: 384 microgram/kg body wt). The remaining control rats were injected with corn oil (vehicle). The rats were killed and the tibiae and uteri were dissected. The left tibia was used for measurements of weight, length, and bone mineral density and the right for histomorphometrical analysis. The uteri were analyzed with respect to estrogen receptor content. PCB #126 exposure did not affect bone mineral density or trabecular bone volume of tibia in sham-operated rats. In ovariectomized rats PCB #126 exposure resulted in a decreased length and an increased bone mineral density of tibia. An obvious PCB #126 induced increase in osteoid surface was observed in sham-operated rats. The cortical thickness and the organic content of the tibia were also increased in these rats. In estrogen deprived tissue like the uteri of ovariectomized rats, PCB #126 showed weak estrogen agonistic activity. The observed effects of PCB #126 on bone and uterine tissues differed between ovariectomized and sham-operated rats.

Animals↗

PubMed1999

Past-year use of outpatient services for psychiatric problems in the National Comorbidity Survey.

OBJECTIVE: The authors present nationally representative descriptive data on 12-month use of outpatient services for psychiatric problems. They focused on the relationship between DSM-III-R disorders and service use in four broadly defined service sectors as well as the distribution of service use in multiple service sectors. METHOD: Data from the National Comorbidity Survey were examined. RESULTS: Summary measures of the seriousness and complexity of illness were significantly related to probability of use, number of sectors used, mean number of visits, and specialty treatment. One-fourth of the people in outpatient treatment were seen in multiple service sectors, but no evidence was found of multisector offset in number of visits. CONCLUSIONS: Use of outpatient services for psychiatric problems appears to have increased over the decade between the early 1980s and early 1990s, especially in the self-help sector. Aggregate allocation of treatment resources was related to need, highlighting the importance of making provisions for specialty care in the triage systems currently evolving as part of managed care.

Adolescent↗

PubMed1998

Characterization of protein kinase C-mediated phosphorylation of the short cytoplasmic domain isoform of C-CAM.

C-CAM is a ubiquitously expressed cell adhesion molecule belonging to the carcinoembryonic antigen family. Two co-expressed isoforms, C-CAM-L and C-CAM-S, are known, having different cytoplasmic domains both of which can be phosphorylated in vivo. Here we have characterized the PKC-mediated phosphorylation of the short cytoplasmic domain isoform, C-CAM-S. Phorbol myristyl acetate induced phosphorylation of C-CAM-S in transfected CHO cells. Using synthetic peptides and Edman degradation we identified Ser449 as the PKC-phosphorylated amino acid residue. Binding experiments with modified peptides indicated that this phosphorylation decreases the ability of the cytoplasmic domain of C-CAM-S to bind calmodulin.

Adenosine Triphosphatases↗

PubMed1998

Hospitalization for gastrointestinal and liver diseases: the effect of socioeconomic and medical supply factors.

A growing body of research has documented significant variation in health care use between communities. As the health care system is transformed, providers and payers should understand the interaction between a community, its sociodemographic characteristics, and its use of health resources. We describe the association between a population's demographic, socioeconomic, and medical resources and hospital use related to gastrointestinal and liver diseases. We used an all-payer hospital discharge database for Michigan from 1986 to 1988. We identified all medical and surgical hospital admissions during this period from two of the Diagnostic Related Group, Major Diagnostic Categories: No. 6, Diseases and Disorders of the Digestive System; and No. 7, Diseases and Disorders of the Hepatobiliary System and Pancreas. We analyzed age- and sex-specific use rates. Finally, we analyzed the influence of sociodemographic variables from the Area Resource File at the county level, on hospital use, using a Poisson regression model. We noted a significant association between increased hospitalizations and increased age in a community. Hospital beds per capita did not influence admission rates overall, although more hospital beds were associated with more medical admissions. Overall, the total physician supply was associated with more admissions. Finally, the most important socioeconomic variable was education. As the level of education of a county increased, hospital admissions decreased dramatically. The transformation of the health care delivery system presents opportunities and challenges. Understanding the underlying epidemiology of disease and how it interacts with a community's socioeconomic and medical resources or medical supply characteristics will be necessary to meet the community's health needs and to ensure the financial viability of providers. This is especially true when payers use a standard payment in a region, such as Medicare's managed care payment, without adjustments for the underlying population characteristics known to influence use.

Adolescent↗

PubMed1997

Differences in the use of psychiatric outpatient services between the United States and Ontario.

BACKGROUND: The relation between health insurance and the use of mental health services is unclear. We compared the use of outpatient services for psychiatric problems in the United States and Ontario, Canada, among young and middle-aged adults according to self-reports of disorders listed in the Diagnostic and Statistical Manual of Mental Disorders (third edition, revised) and to other indicators of need. METHODS: We analyzed two general-population surveys carried out separately in the United States and Ontario in 1990 that used identical assessments of need for services and questions about their use by persons 15 to 54 years of age. RESULTS: Respondents in the United States were significantly more likely than those in Ontario to report having had psychiatric disorders, poor mental health, or workdays lost or cut short because of psychiatric problems in the previous year. A significantly higher proportion of respondents in the United States (13.3 percent) than in Ontario (8.0 percent) had obtained outpatient treatment in the previous 12 months for psychiatric problems. However, an analysis of subgroups found that the higher probability of the use of services in the United States was confined to people with less severe mental illness. The average number of visits did not differ significantly between the two countries among patients who had similar numbers of psychiatric disorders over the same time periods. There was a stronger match in Ontario than in the United States between the use of services and the measures of perceived need we considered. CONCLUSIONS: Although the mental health care system in the United States provides treatment to a larger proportion of the population than that in Ontario, the match between some measures of need and treatment is not as strong in the United States. Any plans to expand coverage for psychiatric disorders in the United States must address this problem.

Adolescent↗

PubMed1997

The use of outpatient mental health services in the United States and Ontario: the impact of mental morbidity and perceived need for care.

OBJECTIVES: This study compared the associations of individual mental health disorders, self-rated mental health, disability, and perceived need for care with the use of outpatient mental health services in the United States and the Canadian province of Ontario. METHODS: A cross-sectional study design was employed. Data came from the 1990 US National Comorbidity Survey and the 1990 Mental Health Supplement to the Ontario Health Survey. RESULTS: The odds of receiving any medical or psychiatric specialty services were as follows: for persons with any affective disorder, 3.1 in the United States vs 11.0 in Ontario; for persons with fair or poor self-rated mental health, 2.7 in the United States vs 5.0 in Ontario; for persons with mental health-related disability. 3.0 in the United States vs 1.5 in Ontario. When perceived need was controlled for, most of the between country differences in use disappeared. CONCLUSIONS: The higher use of mental health services in the United States than in Ontario is mostly explained by the combination of a higher prevalence of mental morbidity and a higher prevalence of perceived need for care among persons with low mental morbidity in the United States.

Cross-Sectional Studies↗

PubMed1996

Evidence for regulated dimerization of cell-cell adhesion molecule (C-CAM) in epithelial cells.

C-CAM is a Ca(2+)-independent cell adhesion molecule (CAM) belonging to the immunoglobulin superfamily. Addition of chemical cross-linkers to isolated rat liver plasma membranes, intact epithelial cells and purified preparations of C-CAM stabilized one major C-CAM-containing product whose apparent molecular mass was approximately twice that of the C-CAM monomer. The failure to detect additional proteins after cleavage of the cross-linked species demonstrated that C-CAM exists as non-covalently linked dimers both in solution and on the cell surface. Dimerization occurred to the same extent in adherent monolayers and in single cell populations, indicating that dimer formation was the result of cis-interactions within the membranes of individual cells. Using isoform-specific anti-peptide antibodies, both C-CAM1 and C-CAM2 were found to be involved in dimerization, forming predominantly homo-dimeric species. Both calmodulin and Ca2+ ionophore modulated the level of dimer formation, suggesting a role for regulated self-association in the functional activity of C-CAM.

Adenosine Triphosphatases↗

PubMed1996

Calmodulin binds to specific sequences in the cytoplasmic domain of C-CAM and down-regulates C-CAM self-association.

C-CAM is a cell adhesion molecule belonging to the immunoglobulin supergene family and is known to mediate calcium-independent homophilic cell-cell binding. Two major isoforms, C-CAM1 and C-CAM2, which differ in their cytoplasmic domains, have been identified. Previous investigations have demonstrated that both cytoplasmic domains can bind calmodulin in a calcium-dependent reaction. In this investigation, peptides corresponding to the cytoplasmic domains of C-CAM were synthesized on cellulose membranes and used to map the binding sites for 125I-labeled calmodulin. Both C-CAM1 and C-CAM2 had one strong calmodulin-binding site in the membrane-proximal region. Those binding regions were conserved in C-CAM from rat, mouse, and man. In addition, C-CAM1 from rat and mouse contained a weaker binding site in the distal region of the cytoplasmic domain. Biosensor experiments were performed to determine rate and equilibrium constants of the C-CAM/calmodulin interaction. An association rate constants of 3.3 x 10(5) M-1 s-1 and two dissociation rate constants of 2.2 x 10(-2) and 3.1 x 10(-5) s-1 were determined. These correspond to equilibrium dissociation constants of 6.7 x 10(-8) and 9.4 x 10(-11) M, respectively. In dot-blot binding experiments, it was found that binding of calmodulin causes a down-regulation of the homophilic self-association of C-CAM. This suggests that calmodulin can regulate the functional activity of C-CAM.

Adenosine Triphosphatases↗

PubMed1996

On the value of menorrhagia as a predictor for coagulation disorders.

The value of menorrhagia as a predictor for mild bleeding disorders has been very little studied and the results are divergent. In the present study on 30 women with objectively verified menorrhagia, we found a significantly increased prevalence of von Willebrand's disease (20%). By keeping a strict sampling and laboratory routine, and by restricting sampling to cycle days 5-7, we also obtained a very low interindividual variation of von Willebrand factor and coagulation factor VIII. We conclude that menorrhagia is a valuable predictor for coagulation and platelet disorders, and that time of sampling is of importance. This should be considered in the investigation of menorrhagia, and can be a guideline in looking for mild bleeding disorders.

Adult↗

PubMed1996

Recombinant human bile salt-stimulated lipase: an example of defective O-glycosylation of a protein produced in milk of transgenic mice.

The expression of recombinant human bile salt-stimulated lipase (bssl) was targeted to the lactating mammary gland of transgenic mice. Expression of recombinant genes comprising bsslcDNA, or alternatively genomic bssl DNA, under control of regulatory elements derived from the murine whey acidic protein (wap) gene was achieved and evaluated. Constructs containing genomic bssl sequences mediated high levels (0.5-1 mg ml-1) of recombinant human BSSL in the milk. The recombinant BSSL produced was purified, biochemically characterized and compared to native BSSL and recombinant BSSL produced in mouse C127 and hamster CHO cells. Recombinant BSSL derived from transgenic mice showed a different migration and distribution after SDS-PAGE electrophoresis, lower apparent molecular mass on size-exclusion chromatography and no detectable interactions with a panel of lectins. These results indicate a significantly lower degree of O-glycosylation of recombinant BSSL in milk from transgenic mice than was found for the native enzyme or recombinant CHO- or C127 cell-produced BSSL. Despite these differences, mouse-milk-derived recombinant BSSL exhibited similar lipase activity, the same stability to low pH and similar sensitivity to elevated temperatures as the native enzyme. The observation that mouse-C127-cell-produced recombinant BSSL is heavily O-glycosylated makes species-related restrictions less attractive as an explanation for the reduced O-glycosylation.

Animals↗