ABSTRACT
Large-scale structures have been observed in many shear flows which are the fluid generated between two surfaces moving with different velocity. A better understanding of the physics of the structures (especially large-scale structures) in shear flows will help explain a diverse range of physical phenomena and improve our capability of modeling more complex turbulence flows. Many efforts have been made in order to capture such structures; however, conventional methods have their limitations, such as arbitrariness in parameter choice or specificity to certain setups. To address this challenge, we propose to use Multi-Resolution Dynamic Mode Decomposition (mrDMD), for large-scale structure extraction in shear flows. In particular, we show that the slow motion DMD modes are able to reveal large-scale structures in shear flows that also have slow dynamics. In most cases, we find that the slowest DMD mode and its reconstructed flow can sufficiently capture the large-scale dynamics in the shear flows, which leads to a parameter-free strategy for large-scale structure extraction. Effective visualization of the large-scale structures can then be produced with the aid of the slowest DMD mode. To speed up the computation of mrDMD, we provide a fast GPU-based implementation. We also apply our method to some non-shear flows that need not behave quasi-linearly to demonstrate the limitation of our strategy of using the slowest DMD mode. For non-shear flows, we show that multiple modes from different levels of mrDMD may be needed to sufficiently characterize the flow behavior.
ABSTRACT
Taylor-Couette flow (TCF) is the turbulent fluid motion created between two concentric and independently rotating cylinders. It has been heavily researched in fluid mechanics thanks to the various nonlinear dynamical phenomena that are exhibited in the flow. As many dense coherent structures overlap each other in TCF, it is challenging to isolate and visualize them, especially when the cylinder rotation ratio is changing. Previous approaches rely on 2D cross sections to study TCF due to its simplicity, which cannot provide the complete information of TCF. In the meantime, standard visualization techniques, such as volume rendering / iso-surfacing of certain attributes and the placement of integral curves/surfaces, usually produce cluttered visualization. To address this challenge and to support domain experts in the analysis of TCF, we developed a visualization framework to separate large-scale structures from the dense, small-scale structures and provide an effective visual representation of these structures. Instead of using a single physical attribute as the standard approach which cannot efficiently separate structures in different scales for TCF, we adapt the feature level-set method to combine multiple attributes and use them as a filter to separate large- and small-scale structures. To visualize these structures, we apply the iso-surface extraction on the kernel density estimate of the distance field generated from the feature level-set. The proposed methods successfully reveal 3D large-scale coherent structures of TCF with different control parameter settings, which are difficult to achieve with the conventional methods.
ABSTRACT
BACKGROUND: In many countries, in-hospital survival from tetanus is increasing, but long-term outcome is unknown. In high-income settings, critical illness is associated with muscle wasting and poor functional outcome, but there are few data from resource-limited settings. In this study we aimed to assess muscle wasting and long-term functional outcome in adults with tetanus. METHODS: In a prospective observational study involving 80 adults with tetanus, sequential rectus femoris ultrasound measurements were made at admission, 7 days, 14 days and hospital discharge. Functional outcome was assessed at hospital discharge using the Timed Up and Go test, Clinical Frailty Score, Barthel Index and RAND 36-item Short Form Health Survey (SF-36) and 3 and 6 months after discharge using the SF-36 and Barthel Index. RESULTS: Significant muscle wasting occurred between hospital admission and discharge (p<0.01), particularly in severe disease, where a median 23.49% (interquartile range 10.01-26.07) reduction in rectus femoris cross-sectional area occurred in those with severe (Ablett grades 3 and 4) disease. Muscle mass at discharge was related to objective and subjective measures of physical and emotional function at discharge and 3 and 6 months after discharge. In patients >70 y of age, functional recovery at 6 months was reduced compared with younger patients. Hospital-acquired infection and age were risk factors for muscle wasting. CONCLUSIONS: Significant muscle wasting during hospitalization occurred in patients with tetanus, the extent of which correlates with functional outcome.
Subject(s)
Muscle Weakness/etiology , Muscle Weakness/physiopathology , Tetanus/complications , Tetanus/physiopathology , Adult , Critical Illness , Follow-Up Studies , Hospitalization/statistics & numerical data , Humans , Male , Middle Aged , Prospective Studies , Time FactorsABSTRACT
BACKGROUND: The cost of treatment for infectious shock in intensive care in Vietnam is unknown. METHODS: We prospectively investigated hospital bills for adults treated for septic and dengue shock in Vietnam and calculated the proportion who faced catastrophic health care expenditures. RESULTS: The median hospital bills were US$617 for septic shock (n=100) and US$57 for dengue shock (n=88). Catastrophic payments were incurred by 47% (47/100) and 13% (11/88) of patients with septic shock and dengue shock, respectively, and 56% (25/45) and 84% (5/6) fatal cases of septic shock and dengue shock respectively. CONCLUSIONS: Further advocacy is required to moderate insurance co-payments for costly critical care interventions.
Subject(s)
Catastrophic Illness/economics , Health Expenditures/statistics & numerical data , Severe Dengue/economics , Shock, Septic/economics , Adult , Cost Sharing/statistics & numerical data , Female , Hospitalization/economics , Hospitalization/statistics & numerical data , Humans , Insurance, Health/economics , Insurance, Health/statistics & numerical data , Male , Middle Aged , Prospective Studies , Severe Dengue/epidemiology , Shock, Septic/epidemiology , Vietnam/epidemiology , Young AdultABSTRACT
Background. Vietnam has a low age-standardized incidence of breast cancer, but the incidence is rising rapidly with economic development. We report data from a matched case-control study of risk factors for breast cancer in the largest cancer hospital in Vietnam. Methods. 492 incident breast cancer cases unselected for family history or age at diagnosis and 1306 control women age 25-75 were recruited from the National Cancer Hospital (BVK), Hanoi. Structured interviews were conducted and pathology data was centrally reported at the National Cancer Hospital of Vietnam, in Hanoi. Results. Our analysis included 294 matched pairs. Mean age at diagnosis was 46.7 years. Lower mean parity, older age at first parity, increasing weight and BMI at age 18, and increasing BMI at diagnosis were positively correlated with breast cancer cases compared to controls. Age at first menarche and duration of breastfeeding were not statistically different between cases and controls. Conclusions. In this study we demonstrate that breast cancer in Vietnam is associated with some but not all of the published risk factors from Western populations. Our data is consistent with other studies of breast cancer in Asian populations.
ABSTRACT
The purpose of this report is to estimate the proportions of familial and hereditary breast cancers among unselected cases of breast cancer in Vietnam. Two hundred and ninety-two unselected cases of incident breast cancer were recruited from the National Cancer Hospital, Hanoi, the largest cancer centre in Vietnam. Family histories were collected for 292 cases and a DNA sample was obtained for 259 cases. DNA samples were screened for mutations in the large exons of BRCA1 and BRCA2 using the protein truncation test and by allele-specific testing for 17 founder mutations which have been reported in other Asian populations. Complete gene sequencing was performed on two cases of familial breast cancer. Seven of 292 cases reported a relative with breast cancer and one patient reported a relative with ovarian cancer. A pathogenic BRCA mutation was detected in 2 of 259 cases; one BRCA1 carrier was diagnosed at age 51 and one BRCA2 carrier was diagnosed at age 42. Neither case reported a relative with breast or ovarian cancer. A family history of breast cancer is very uncommon among Vietnamese breast cancer patients. The frequency of pathogenic BRCA mutations in Vietnamese breast cancer patients is among the lowest reported worldwide.
Subject(s)
BRCA1 Protein/genetics , BRCA2 Protein/genetics , Breast Neoplasms/genetics , Adult , Aged , Asian People/genetics , Breast Neoplasms/epidemiology , Female , Humans , Middle Aged , Mutation , Vietnam/epidemiology , Young AdultABSTRACT
SETTING: Human immunodeficiency virus/acquired immune-deficiency syndrome (HIV/AIDS) program, An Giang Province, Vietnam. OBJECTIVE: To evaluate the coverage and yield of a chest radiography (CXR) screening program for tuberculosis (TB) among people living with HIV/AIDS (PLHA), risk factors for a TB CXR, inter-rater reliability of CXR readings and direct costs. DESIGN: Retrospective review of routine public health program records and CXRs. RESULTS: An increasing proportion of PLHAs received a screening CXR each year of the program (range 21% in 2001 to 61% in 2004, P<0.001). Of 876 screening CXRs performed, 191 (22%) were classified as suspicious for active TB ('TB CXR'). Compared to PLHAs with a CXR not suspicious for active TB, PLHAs with a TB CXR were more likely to be aged between 24 and 64 years, male and previously treated for TB (P<0.01 for each comparison). Agreement between the expert and local program CXR readings was 81% (kappa 0.50). Direct costs were approximately US$40 per TB suspect identified. Among TB suspects, <10% were followed up with sputum smear examination and enrolled for treatment. CONCLUSION: In An Giang Province, a large proportion of PLHAs are screened for TB annually, and one in five persons screened is classified as a TB suspect based on CXR. Annual CXRs may be a high-yield, inexpensive method for TB screening in PLHAs, but the follow-up of TB suspects to confirm diagnosis and initiate treatment is crucial.
Subject(s)
AIDS-Related Opportunistic Infections/diagnostic imaging , Mass Chest X-Ray , Tuberculosis, Pulmonary/diagnostic imaging , AIDS-Related Opportunistic Infections/epidemiology , Adolescent , Adult , Aged , Child , Child, Preschool , Female , HIV Infections/complications , HIV Infections/epidemiology , Humans , Infant , Infant, Newborn , Male , Mass Chest X-Ray/economics , Middle Aged , Reproducibility of Results , Sputum/microbiology , Tuberculosis, Pulmonary/complications , Tuberculosis, Pulmonary/epidemiology , Vietnam/epidemiologyABSTRACT
SETTING: Reported tuberculosis (TB) cure rates are high in Vietnam with the 8-month short-course chemotherapy regimen. However, long-term treatment outcomes are unknown. OBJECTIVE: To assess survival and relapse rates among patients successfully treated for new smear-positive pulmonary tuberculosis (PTB). METHODS: A cohort of patients treated in 32 randomly selected districts in northern Vietnam were followed up 12-24 months after reported cure or treatment success for survival and bacteriologically confirmed relapse. Measurements included sputum smear examination, culture and interview for recent treatment history. RESULTS: Of 304 patients included in the study, no information was available for 31 (10%) and 19 (6%) had died. Bacteriology results were available for 244 (80%). The median interval between treatment completion and follow-up was 19 months. Relapse was recorded in 21/244 (8.6%, 95%CI 5.4-13), including 9 (4%) with positive sputum smears, 3 (1%) with negative smears but positive culture and 9 (4%) who had started TB retreatment. Four of 12 culture-positive relapse cases (33%) had multidrug-resistant strains. If the definition of relapse was extended to include death, reportedly due to TB, the relapse proportion was 26/263 (9.9%, 95%CI 6.6-14). CONCLUSION: A substantial proportion of patients (15%) had died or relapsed after being successfully treated for TB in northern Vietnam.
Subject(s)
Tuberculosis/drug therapy , Tuberculosis/epidemiology , Adolescent , Adult , Female , Humans , Male , Middle Aged , Recurrence , Treatment Outcome , Tuberculosis/mortality , Tuberculosis, Multidrug-Resistant/epidemiology , Vietnam/epidemiologyABSTRACT
SETTING: Six provinces in Vietnam where the DOTS strategy was introduced in 1989. OBJECTIVE: To assess the impact of improved tuberculosis (TB) control on TB epidemiology in Vietnam. METHODS: Data from the surveillance system in the period 1990-2003 were analysed to assess trends of notification rates and the mean ages of notified cases. Data from repeated tuberculin surveys in the period 1986-2002 were estimated to assess the prevalence of TB infection, the annual risk of infection and its trend using various cut-off points in those with and without bacille Calmette-Guérin (BCG) scar. RESULTS: Age-standardised notification rates in the period 1996-2003 declined significantly, by 2.6% to 5.9% per year, in five provinces. However, in four provinces notification rates in the age group 15-24 years increased significantly, by 4.5% to 13.6% per year, during this period. The mean age of newly diagnosed patients with smear-positive TB increased up to 1995 but decreased thereafter. The annual risk of TB infection showed a significant annual decrease (4.9% per year) in one province in surveys performed between 1986 and 1997, and in two provinces (6.6% and 4.7%) in surveys conducted between 1993 and 2002. CONCLUSION: These data suggest limited impact to date of the DOTS strategy in Vietnam.
Subject(s)
Directly Observed Therapy , Tuberculosis, Pulmonary/drug therapy , Tuberculosis, Pulmonary/epidemiology , Adolescent , Adult , Aged , Child , Humans , Middle Aged , Vietnam/epidemiologyABSTRACT
OBJECTIVE: To assess the yield of sputum smear microscopy and sex differences in the National Tuberculosis Control Programme in the north of Vietnam. METHODS: Review of registers of 30 randomly selected laboratories (26 district, 4 provincial level). RESULTS: The average daily workload per technician was 4.4 examinations in district and 5.3 examinations in provincial laboratories. To find one smear-positive case, 9.7 suspects were examined and 29.3 smears done. The smear-positive rate (mean 10.3%) was higher among men (11.6%) than among women (8.4%, P < 0.001). There were more men than women among tuberculosis (TB) suspects (male:female ratio 1.36, 95%CI 1.19-1.54), but even more so among smear-positive patients (1.89, 95%CI 1.64-2.14), irrespective of specimen quality and number of smears examined. Three smears were examined for 18,055 suspects (61.7%). The incremental gain was 33.5% and 4.9% for the second and third smear examination, respectively; 186 (95%CI 160-221) smears needed to be examined to find one additional case of TB with a third serial examination. CONCLUSION: The diagnostic process seemed generally efficient. The male:female ratios suggest higher TB incidence in men rather than lower access to TB facilities for women. The third smear examination could be omitted.
Subject(s)
Communicable Disease Control/methods , Mycobacterium tuberculosis/isolation & purification , Program Evaluation , Sputum/microbiology , Tuberculosis, Pulmonary/diagnosis , Adolescent , Adult , Aged , Child , Child, Preschool , Female , Humans , Incidence , Infant , Infant, Newborn , Male , Microscopy/methods , Middle Aged , Retrospective Studies , Tuberculosis, Pulmonary/epidemiology , Tuberculosis, Pulmonary/prevention & control , Vietnam/epidemiologyABSTRACT
OBJECTIVE: To describe the establishment and development of the National Tuberculosis Control Programme (NTP) of Vietnam. METHODS: Data were obtained from the surveillance system established by the new NTP in 1986 and based on the principles now described as the WHO DOTS strategy. RESULTS: The proportion of districts covered by the NTP increased from 40% in 1986 to almost 100% in 2000. The proportion of communes applying NTP guidelines increased from 18% in 1986 to 99.8% in 2000. The total number of tuberculosis cases notified increased from 8737 in 1986 to 89 792 in 2000. Most of these are new smear-positive cases. Based on WHO estimations of the incidence rate, the proportion of new smear-positive cases detected and put on short-course treatment has been over 70% since 1996. Reported cure rates with short-course chemotherapy are consistently over 85%. CONCLUSIONS: DOTS is feasible in a low-income, high-burden country. The main reasons for success were political commitment, a well-functioning health network, integration of tuberculosis control into the general health service at district level, a continuous supply of drugs and effective external support. Major challenges are long-term financial support, expansion to remote areas and vulnerable groups, definition of the role of the private sector, and future developments of the HIV epidemic and multidrug resistance.
Subject(s)
National Health Programs , Tuberculosis/prevention & control , Humans , National Health Programs/organization & administration , Tuberculosis/epidemiology , Vietnam/epidemiologyABSTRACT
OBJECTIVE: To characterise the time course of stress relaxation and recovery from stress relaxation in human ankles. DESIGN: Two experiments were conducted. The first used a randomised within-subjects design, and the second used a randomised between-subjects regression design. BACKGROUND: Several studies have described the time course of stress relaxation in human joints, but most have looked only at the effects of short durations of stretch. The time course of recovery from stretch in human ankles has not been documented. METHODS: In the first experiment, one ankle of each of eight subjects was stretched to a fixed dorsiflexion angle for 20 min. The ankle was then released for 2 min (during which time subjects either remained relaxed or performed isometric contractions), then stretched again. In a second experiment, on 24 subjects, the ankle was stretched for 20 min, then released between 0 and 20 min, then stretched again. In both experiments, subjects remain relaxed and ankle torque was measured continuously. RESULTS: When a constant-angle stretch was applied to the ankle, torque declined bi-exponentially towards an asymptote that was 58% of the initial torque. Nearly 5 min of stretch were required to obtain half of the maximal possible stress relaxation. Torque had recovered by 43% within 2 min of the release of stretch, but the degree of recovery did not appear to depend on whether subjects remained relaxed or performed isometric contractions. The time course of recovery was similar to the time course of stress relaxation. CONCLUSIONS: Long duration stretches are required to produce a large proportion of the maximal possible stress relaxation. Recovery is initially rapid when the stretch is released. RELEVANCE: These data provide a description of the time course of the effects of stretch, and of the subsequent relief of stretch, on mechanical properties of human ankles.
Subject(s)
Ankle/physiology , Adult , Biomechanical Phenomena , Equipment Design , Female , Humans , Male , Muscle Contraction , Muscle, Skeletal/physiology , Regression Analysis , Stress, Mechanical , Time Factors , TorqueABSTRACT
The flavonoid family of phytochemicals, particularly those derived from soy, has received attention regarding their estrogenic activity as well as their effects on human health and disease. In addition to these flavonoids other phytochemicals, including phytostilbene, enterolactone, and lignans, possess endocrine activity. The types and amounts of these compounds in soy and other plants are controlled by both constitutive expression and stress-induced biosynthesis. The health benefits of soy-based foods may, therefore, be dependent upon the amounts of the various hormonally active phytochemicals within these foods. The aim was to identify unique soy phytochemicals that had not been previously assessed for estrogenic or antiestrogenic activity. Here we describe increased biosynthesis of the isoflavonoid phytoalexin compounds, glyceollins, in soy plants grown under stressed conditions. In contrast to the observed estrogenic effects of coumestrol, daidzein, and genistein, we observed a marked antiestrogenic effect of glyceollins on ER signaling, which correlated with a comparable suppression of 17 beta-estradiol-induced proliferation in MCF-7 cells. Further evaluation revealed greater antagonism toward ER alpha than ER beta in transiently transfected HEK 293 cells. Competition binding assays revealed a greater affinity of glyceollins for ER alpha vs. ER beta, which correlated to greater suppression of ER alpha signaling with higher concentrations of glyceollins. In conclusion, we describe the phytoalexin compounds known as glyceollins, which exhibit unique antagonistic effects on ER in both HEK 293 and MCF-7 cells. The glyceollins as well as other phytoalexin compounds may represent an important component of the health effects of soy-based foods.
Subject(s)
Benzopyrans/pharmacology , Glycine max/chemistry , Hormone Antagonists/pharmacology , Plant Extracts/pharmacology , Receptors, Estrogen/physiology , Benzopyrans/metabolism , Binding, Competitive , Cell Division/drug effects , Cell Line/cytology , Cell Line/drug effects , Estradiol/pharmacology , Estrogen Receptor alpha , Estrogen Receptor beta , Humans , Osmolar Concentration , Pterocarpans , Receptors, Estrogen/metabolism , Signal Transduction/drug effectsABSTRACT
Adaptive changes in gene expression are thought to contribute to dependence, addiction and other behavioral responses to chronic ethanol abuse. DNA array studies provide a nonbiased detection of networks of gene expression changes, allowing insight into functional consequences and mechanisms of such molecular responses. We used oligonucleotide arrays to study nearly 6000 genes in human SH-SY5Y neuroblastoma cells exposed to chronic ethanol. A set of 42 genes had consistently increased or decreased mRNA abundance after 3 days of ethanol treatment. Groups of genes related to norepinephrine production, glutathione metabolism, and protection against apoptosis were identified. Genes involved in catecholamine metabolism are of special interest because of the role of this pathway in mediating ethanol withdrawal symptoms (physical dependence). Ethanol treatment elevated dopamine beta-hydroxylase (DBH, EC 1.14.17.1) mRNA and protein levels and increased releasable norepinephrine in SH-SY5Y cultures. Acute ethanol also increased DBH mRNA levels in mouse adrenal gland, suggesting in vivo functional consequences for ethanol regulation of DBH. In SH-SY5Y cells, ethanol also decreased mRNA and secreted protein levels for monocyte chemotactic protein 1, an effect that could contribute to the protective role of moderate ethanol consumption in atherosclerotic vascular disease. Finally, we identified a subset of genes similarly regulated by both ethanol and dibutyryl-cAMP treatment in SH-SY5Y cells. This suggests that ethanol and cAMP signaling share mechanistic features in regulating a subset of ethanol-responsive genes. Our findings offer new insights regarding possible molecular mechanisms underlying behavioral responses or medical consequences of ethanol consumption and alcoholism.
Subject(s)
Ethanol/pharmacology , Gene Expression Regulation/drug effects , Neurons/drug effects , Symporters , Animals , Bucladesine/pharmacology , Carrier Proteins/biosynthesis , Central Nervous System Depressants/pharmacology , Dopamine beta-Hydroxylase/biosynthesis , Drug Interactions , Female , Gene Expression Profiling , Humans , Intracellular Signaling Peptides and Proteins , Membrane Proteins/biosynthesis , Mice , Mice, Inbred DBA , Monocyte Chemoattractant Proteins/biosynthesis , Neurons/physiology , Norepinephrine Plasma Membrane Transport Proteins , Tumor Cells, CulturedABSTRACT
To understand the mechanism of T cell help for IgG production in systemic lupus erythematosus (SLE) we investigated the response of CD4- and CD8-negative (double-negative (DN)) T cells because 1) DN T cells are present at unusually high frequency in patients with SLE and can induce pathogenic autoantibodies; 2) the DN T cell repertoire includes cells restricted by CD1 Ag-presenting molecules; and 3) CD1c is expressed on a population of circulating B cells. We derived DN T cell lines from SLE patients and healthy individuals. In the presence of CD1(+) APCs, DN T cell lines from SLE patients produced both IL-4 and IFN-gamma, whereas DN T cells from healthy donors produced IFN-gamma, but no IL-4. In general, cells from patients with highly active disease produced high levels of IFN-gamma; cells from those with little activity produced high IL-4. Coculture of CD1c-directly reactive T cells from healthy donors with CD1c(+) B cells elicited IgM Abs, but little or no IgG. In contrast, CD1c-directly reactive T cells from SLE patients induced isotype switching, with a striking increase in IgG production. Neutralizing Abs to CD1c inhibited the ability of DN T cells to induce IgG production from CD1c(+) B cells, further indicating that CD1c mediated the T and B cell interaction. IgG production was also inhibited by neutralizing Abs to IL-4, correlating with the cytokine pattern of DN T cells derived from these patients. The data suggest that CD1c-restricted T cells from SLE patients can provide help to CD1c(+) B cells for IgG production and could therefore promote pathogenic autoantibody responses in SLE.
Subject(s)
Antigens, CD1/immunology , Immunoglobulin G/biosynthesis , Lupus Erythematosus, Systemic/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocytes, Helper-Inducer/immunology , Adolescent , Adult , Aged , Antigen Presentation , Antigens, CD1/metabolism , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Cell Line , Cells, Cultured , Dendritic Cells/immunology , Female , Fetal Blood/cytology , Fetal Blood/immunology , Fetal Blood/metabolism , Humans , Interleukin-4/biosynthesis , Lupus Erythematosus, Systemic/metabolism , Lymphocyte Cooperation , Male , Middle Aged , Protein Isoforms/immunology , Protein Isoforms/metabolismABSTRACT
We found that in MCF-7 breast carcinoma cells, PI3K and Akt suppressed a dose-dependent induction of apoptosis by tumor necrosis factor alpha (TNF). PI3K and Akt stimulated NF-kappaB activation in a dose-dependent manner, suggesting a common link between these two pathways. TNF has been shown to activate both an apoptotic cascade, as well as a cell survival signal through NF-kappaB. PI3K and AKT cell survival signaling were correlated with increased TNF-stimulated NF-kappaB activity in MCF-7 cells. We demonstrate that while both TNFR1 and NIK are partially involved in Akt-induced NF-kappaB stimulation, a dominant negative IkappaBalpha completely blocked Akt-NF-kappaB cross-talk. PI3K-Akt signaling activated NF-kappaB through both TNFR signaling-dependent and -independent mechanisms, potentially representing a mechanism by which Akt functions to suppress apoptosis in cancer.
Subject(s)
Apoptosis , NF-kappa B/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins , Tumor Necrosis Factor-alpha/pharmacology , Cell Line , Dose-Response Relationship, Drug , Humans , Luciferases/metabolism , Plasmids/metabolism , Proto-Oncogene Proteins c-akt , Recombinant Proteins/metabolism , Signal Transduction , Transfection , Tumor Cells, CulturedABSTRACT
Members of the flavonoid class of phytochemicals have previously been demonstrated to possess estrogenic activity in a number of hormonally responsive systems. We have performed the present study to characterize the estrogenic and antiestrogenic activity of flavonoids in the estrogen receptor (ER)-positive MCF-7 human breast cancer cell line. Using an ER-dependent reporter gene assay and an ER competition binding assay, we have identified phytochemicals possessing estrogenic and antiestrogenic activities, which appeared to correlate directly with their capacity to displace [3H]estradiol from ER. Several flavonoids, including kaempferide, apigenin, and flavone, were distinct, in that their antiestrogenic activity did not appear to correlate with binding to ER, and therefore their suppression of estrogen-mediated gene transactivation and proliferation may occur independent of direct antagonism of the receptor. Further examination in HEK-293 cells transfected with ERalpha or ERbeta demonstrated potent antagonism with kaempferide and apigenin, while flavone was weakly antagonistic only toward ERP. These results suggest that the receptor binding-independent antiestrogenic chemicals may function through alternate signaling pathways as indirect ER modulators in a receptor- and cell type-specific manner. We conclude that antiestrogenic activities of flavonoid phytochemicals may occur through ER binding-dependent and -independent mechanisms and that the binding-independent antiestrogen activity of certain flavonoids is biologically significant in regulation of breast cancer cell proliferation.
Subject(s)
Breast Neoplasms/metabolism , Estrogens, Non-Steroidal/pharmacology , Flavonoids/pharmacology , Isoflavones , Neoplasms, Hormone-Dependent/metabolism , Receptors, Estrogen/metabolism , Binding, Competitive , Breast Neoplasms/prevention & control , Cell Division/drug effects , Cell Transformation, Neoplastic/drug effects , Dose-Response Relationship, Drug , Estradiol/metabolism , Estrogen Antagonists/classification , Estrogen Antagonists/metabolism , Estrogen Antagonists/pharmacology , Estrogens, Non-Steroidal/classification , Estrogens, Non-Steroidal/metabolism , Female , Flavonoids/classification , Flavonoids/metabolism , Humans , Luciferases , Neoplasms, Hormone-Dependent/prevention & control , Phytoestrogens , Plant Preparations , Receptors, Estrogen/agonists , Receptors, Estrogen/antagonists & inhibitors , Tumor Cells, CulturedABSTRACT
A clinical and haematological study of 75 patients with beta-thalassemia/haemoglobin E (HbE) in Vietnam is described. The clinical picture is similar to thalassemia major. Anemia is often severe, haemoglobin was 5.0 +/- 1.6 g/dl. Splenomegaly was almost consistently detected. Haemochromatosis was clear. Both red cell indices and morphology showed hypochromicity and microcytosis, the MCH was 23.3 +/- 2.9 pg, the MCV was 81.5 +/- 11 fl; anisocytosis, poiklocytosis, tear drop cells, leptocytosis, target cells, and polychromasia were always observed. The osmotic fragility of erythrocytes was increased. The erythrocytic lifespan was shortened, about 7-15 days and the erythrocytes were destroyed in the spleen in 63 per cent of cases. Depending on whether it was beta(+)-thalassemia/HbE or beta(0)-thalassemia/HbE, HbF ranged from 22.8 +/- 7.2 to 57 +/- 12.7 per cent; HbE from 30.1 +/- 12.2 to 42.7 +/- 13 per cent; and HbA1 was decreased down to from only 46.8 +/- 13.5 to 0 per cent.