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3.
Phys Rev Lett ; 110(23): 237202, 2013 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-25167527

RESUMO

We report the discovery of a magnetic quantum critical transition in Mn[N(CN)(2)](2) that drives the system from a canted antiferromagnetic state to the fully polarized state with amplified magnetoelastic coupling as an intrinsic part of the process. The local lattice distortions, revealed through systematic phonon frequency shifts, suggest a combined MnN(6) octahedra distortion+counterrotation mechanism that reduces antiferromagnetic interactions and acts to accommodate the field-induced state. These findings deepen our understanding of magnetoelastic coupling near a magnetic quantum critical point and away from the static limit.

4.
Phys Rev Lett ; 111(4): 047202, 2013 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-23931402

RESUMO

We combined Raman and infrared vibrational spectroscopies with complementary lattice dynamics calculations and magnetization measurements to reveal the dynamic aspects of charge-lattice-spin coupling in Co[N(CN)2]2. Our work uncovers electron-phonon coupling as a magnetic field-driven avoided crossing of the low-lying Co2+ electronic excitation with two ligand phonons and a magnetoelastic effect that signals a flexible local CoN6 environment. Their simultaneous presence indicates the ease with which energy is transferred over multiple length and time scales in this system.

5.
Colorectal Dis ; 14(9): e612-7, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22413783

RESUMO

AIM: Laparoscopic colectomy for colorectal cancer is associated with definite short-term benefits, and is increasingly practised worldwide. The limitations of a pure laparoscopic approach include a relative lack of tactile feedback and long procedural time. Hand-assisted laparoscopic surgery was introduced in an attempt to facilitate operation by improving the tactile sensation. To date, there is no consensus as to which approach is better. Herein we conducted a randomized controlled trial comparing hand-assisted laparoscopic colectomy (HALC) with total laparoscopic colectomy (TLC) in the management of right-sided colonic cancer. METHODS: Adult patients with carcinoma of the caecum and ascending colon were recruited and randomized to undergo either HALC or TLC. Measured outcomes included operative time, blood loss, conversion rate, postoperative morbidities, postoperative pain, length of hospital stay, disease recurrence and patient survival. RESULTS: Sixty patients (HALC=30, TLC=30) were recruited. The two groups were comparable with regard to age, gender distribution, body mass index and final histopathological staging. No difference was observed between the groups in terms of operating time, conversion rate, operative blood loss, pain score and length of hospital stay. With a median follow-up of 27 to 33 months, no difference was observed in terms of disease recurrence, and the 5-year survival rates remained similar (83%vs 80%, P=0.923). CONCLUSION: HALC is safe and feasible, but it does not show any significant benefits over TLC in terms of operating time and conversion rate. Routine use of the hand-assisted laparoscopic technique in right hemicolectomy is therefore not recommended.


Assuntos
Colectomia/métodos , Neoplasias Colorretais/cirurgia , Laparoscopia Assistida com a Mão/métodos , Laparoscopia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Ceco/cirurgia , Colo Ascendente/cirurgia , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Dor Pós-Operatória , Resultado do Tratamento
6.
Phys Rev Lett ; 104(6): 067404, 2010 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-20366854

RESUMO

We report a study of the cyclotron resonance (CR) transitions to and from the unusual n=0 Landau level (LL) in monolayer graphene. Unexpectedly, we find the CR transition energy exhibits large (up to 10%) and nonmonotonic shifts as a function of the LL filling factor, with the energy being largest at half filling of the n=0 level. The magnitude of these shifts, and their magnetic field dependence, suggests that an interaction-enhanced energy gap opens in the n=0 level at high magnetic fields. Such interaction effects normally have a limited impact on the CR due to Kohn's theorem [W. Kohn, Phys. Rev. 123, 1242 (1961)], which does not apply in graphene as a consequence of the underlying linear band structure.

7.
BMC Gastroenterol ; 10: 114, 2010 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-20920280

RESUMO

BACKGROUND: The rate of H. pylori infection in Vietnam is reportedly high, but the spectrum of H. pylori-associated gastroduodenal diseases has not been systematically investigated. Moreover, despite the similarities of ethnicity and diet, the age-standardized incidence rate of gastric cancer in the northern city of Hanoi is higher than that in the southern city of Ho Chi Minh, but the reason for this phenomenon is unknown. The virulence of Vietnamese H. pylori has also not been investigated in detail. METHODS: Individuals undergoing esophagogastroduodenoscopy were randomly recruited. H. pylori infection status was determined based on the combined results of culture, histology, immunohistochemistry, rapid urine test and serum ELISA. Peptic ulcer (PU) and gastroesophageal reflux disease was diagnosed by endoscopy, and chronic gastritis was determined histologically. H. pylori virulence factors were investigated by PCR and sequencing. RESULTS: Among the examined patients, 65.6% were infected with H. pylori. The prevalence of infection was significantly higher in those over 40 years of age than in those aged ≤40. Chronic gastritis was present in all H. pylori-infected individuals, 83.1% of whom had active gastritis, and 85.3% and 14.7% had atrophy and intestinal metaplasia, respectively. PU was present in 21% of infected patients, whereas its incidence was very low in non-infected individuals. The prevalence of PU was significantly higher in Hanoi than in Ho Chi Minh. The prevalence of vacA m1, which has been identified as an independent risk factor for PU in Vietnam, was significantly higher among H. pylori isolates from Hanoi than among those from Ho Chi Minh. CONCLUSIONS: H. pylori infection is common in Vietnam and is strongly associated with PU, active gastritis, atrophy and intestinal metaplasia. vacA m1 is associated with an increased risk for PU and might contribute to the difference in the prevalence of PU and gastric cancer between Hanoi and Ho Chi Minh.


Assuntos
Duodenopatias/epidemiologia , Infecções por Helicobacter/epidemiologia , Helicobacter pylori/isolamento & purificação , Gastropatias/epidemiologia , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antibacterianos/análise , Estudos Transversais , DNA Bacteriano/análise , Duodenopatias/diagnóstico , Duodenopatias/microbiologia , Endoscopia Gastrointestinal , Ensaio de Imunoadsorção Enzimática , Feminino , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/microbiologia , Helicobacter pylori/genética , Helicobacter pylori/imunologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Prevalência , Fatores de Risco , Distribuição por Sexo , Gastropatias/diagnóstico , Gastropatias/microbiologia , Vietnã/epidemiologia , Adulto Jovem
8.
Data Brief ; 30: 105587, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32368600

RESUMO

Residual stresses in large offshore mooring chains have been measured for the first time and presented in this article. Two chain links with the same size and material, one only subjected to proof load and no cyclic service loads and the other exposed to service loads as well as the proof load, were selected for the experiment. Residual stresses just below the surface were measured using the hole-drilling technique and the neutron diffraction technique was employed for deeper measurements. The data can be used to investigate residual stress redistribution in the chain links because of material removal due to corrosion and cyclic service loads that the chains are exposed to during their service time. Moreover, the data can be used to validate numerical models for predicting residual stresses. A more detailed interpretation of the data presented in this article is provided in "Experimental and numerical study of mooring chain residual stresses and implications for fatigue life" [1].

9.
Phys Rev Lett ; 103(15): 157401, 2009 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-19905665

RESUMO

We investigated magnetoelastic coupling through the field-driven transition to the fully polarized magnetic state in quasi-two-dimensional [Cu(HF2)(pyz)2]BF4 by magnetoinfrared spectroscopy. This transition modifies out-of-plane ring distortion and bending vibrational modes of the pyrazine ligand. The extent of these distortions increases with the field, systematically tracking the low-temperature magnetization. These distortions weaken the antiferromagnetic spin exchange, a finding that provides important insight into magnetic transitions in other copper halides.

10.
Mol Cell Biol ; 5(12): 3429-35, 1985 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-3915776

RESUMO

The Saccharomyces cerevisiae ribosomal protein rp51 is encoded by two interchangeable genes, RP51A and RP51B. We altered the RP51 gene dose by creating deletions of the RP51A or RP51B genes or both. Deletions of both genes led to spore inviability, indicating that rp51 is an essential ribosomal protein. From single deletion studies in haploid cells, we concluded that there was no intergenic dosage compensation at the level of mRNA abundance or mRNA utilization (translational efficiency), although phenotypic analysis had previously indicated a small compensation effect on growth rate. Similarly, deletions in diploid strains indicated that no strong mechanisms exist for intragenic dosage compensation; in all cases, a decreased dose of RP51 genes was characterized by a slow growth phenotype. A decreased dose of RP51 genes also led to insufficient amounts of 40S ribosomal subunits, as evidenced by a dramatic accumulation of excess 60S ribosomal subunits. We conclude that inhibition of 40S synthesis had little or no effect on the synthesis of the 60S subunit components. Addition of extra copies of rp51 genes led to extra rp51 protein synthesis. The additional rp51 protein was rapidly degraded. We propose that rp51 and perhaps many ribosomal proteins are normally oversynthesized, but the unassembled excess is degraded, and that the apparent compensation seen in haploids, i.e., the fact that the growth rate of mutant strains is less depressed than the actual reduction in mRNA, is a consequence of this excess which is spared from proteolysis under this circumstance.


Assuntos
Genes Fúngicos , Proteínas Ribossômicas/genética , Saccharomyces cerevisiae/genética , Diploide , Amplificação de Genes , Haploidia , Mutação , Processamento de Proteína Pós-Traducional , Proteínas Ribossômicas/biossíntese , Ribossomos/metabolismo , Saccharomyces cerevisiae/metabolismo
11.
Mol Cell Biol ; 11(2): 1048-61, 1991 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-1990266

RESUMO

A protein, denoted UHF-1, was found to bind upstream of the transcriptional start site of both the early and late H4 (EH4 and LH4) histone genes of the sea urchin Strongylocentrotus purpuratus. A nuclear extract from hatching blastulae contained proteins that bind to EH4 and LH4 promoter fragments in a band shift assay and produced sharp DNase I footprints upstream of the EH4 gene (from -133 to -106) and the LH4 gene (from -94 to -66). DNase I footprinting performed in the presence of EH4 and LH4 promoter competitor DNAs indicated that UHF-1 binds more strongly to the EH4 site. A sequence match of 11 of 13 nucleotides was found within the two footprinted regions: [sequence: see text]. Methylation interference and footprinting experiments showed that UHF-1 bound to the two sites somewhat differently. DNA-protein UV cross-linking studies indicated that UHF-1 has an electrophoretic mobility on sodium dodecyl sulfate-acrylamide gels of approximately 85 kDa and suggested that additional proteins, specific to each promoter, bind to each site. In vitro and in vivo assays were used to demonstrate that the UHF-1-binding site is essential for maximal transcription of the H4 genes. Deletion of the EH4 footprinted region resulted in a 3-fold decrease in transcription in a nuclear extract and a 2.6-fold decrease in expression in morulae from templates that had been injected into eggs. In the latter case, deletion of the binding site did not grossly disrupt the temporal program of expression from the injected EH4 genes. LH4 templates containing a 10-bp deletion in the consensus region or base substitutions in the footprinted region were transcribed at 14 to 58% of the level of the wild-type LH4 template. UHF-1 is therefore essential for maximal expression of the early and late H4 genes.


Assuntos
Genes , Histonas/genética , Regiões Promotoras Genéticas , Fatores de Transcrição/metabolismo , Animais , Sequência de Bases , Sítios de Ligação , Ligação Competitiva , DNA/genética , DNA/isolamento & purificação , Desoxirribonuclease I , Humanos , Cinética , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Sondas de Oligonucleotídeos , Mapeamento por Restrição , Ouriços-do-Mar/genética , Transcrição Gênica
12.
Mol Cell Biol ; 9(4): 1476-87, 1989 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-2725512

RESUMO

Early embryonic H4 (EH4) and H2B (EH2B) and late embryonic H4 (LH4) histone genes were transcribed in vitro in a nuclear extract from hatching blastula embryos of the sea urchin Strongylocentrotus purpuratus. The extract was prepared by slight modifications of the methods of Morris et al. (G. F. Morris, D. H. Price, and W. F. Marzluff, Proc. Natl. Acad. Sci. USA 83:3674-3678, 1986) that have been used to obtain a cell-free transcription system from embryos of the sea urchin Lytechinus variegatus. Achievement of maximum levels of transcription of the EH4 and LH4 genes required a 5- to 10-min preincubation of template with extract in the absence of ribonucleoside triphosphates. This preincubation allowed the formation of a stable complex which was preferentially transcribed compared with a second EH4 or LH4 template that was added 10 min later. Although the EH4 gene inhibited both EH4 and LH4 gene transcription in this assay and although the LH4 gene inhibited both EH4 and LH4 genes, neither of these genes inhibited transcription of the EH2B gene. Preincubation with the EH2B gene had no effect on the transcription of subsequently added EH4 or LH4 genes. Using this template commitment assay, we showed that the site of binding of at least one essential factor required for transcription of both EH4 and LH4 genes was located between positions -102 and -436 relative to the 5' terminus of the EH4 mRNA. Moreover, deletion of this region resulted in a reduction in EH4 gene transcription in vitro. The sea urchin gene-specific trans-acting factors, in the analysis of the cis-acting sequences with which they interact, and in biochemical studies on the formation of stable transcription complexes.


Assuntos
Histonas/genética , Fatores de Transcrição/metabolismo , Transcrição Gênica , Animais , Sítios de Ligação , Feminino , Óvulo/metabolismo , Capuzes de RNA/metabolismo , RNA Mensageiro/metabolismo , Ouriços-do-Mar
13.
Circ Res ; 91(12): e45-54, 2002 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-12480825

RESUMO

Structural and functional cardiac anisotropy varies with the development, location, and pathophysiology in the heart. The goal of this study was to design a cell culture model system in which the degree, change in fiber direction, and discontinuity of anisotropy can be controlled over centimeter-size length scales. Neonatal rat ventricular myocytes were cultured on fibronectin on 20-mm diameter circular cover slips. Structure-function relationships were assessed using immunostaining and optical mapping. Cell culture on microabraded cover slips yielded cell elongation and coalignment in the direction of abrasion, and uniform, macroscopically continuous, elliptical propagation with point stimulation. Coarser microabrasion (wider and deeper abrasion grooves) increased longitudinal (23.5 to 37.2 cm/s; r=0.66) and decreased transverse conduction velocity (18.1 to 9.2 cm/s; r=-0.84), which resulted in increased longitudinal-to-transverse velocity anisotropy ratios (1.3 to 3.7, n=61). A thin transition zone between adjacent uniformly anisotropic areas with 45 degrees or 90 degrees difference in fiber orientation acted as a secondary source during 2x threshold field stimulus. Cell culture on cover slips micropatterned with 12- or 25- micro m wide fibronectin lines and previously coated with decreasing concentrations of background fibronectin yielded transition from continuous to discontinuous anisotropic architecture with longitudinally oriented intercellular clefts, decreased transverse velocity (16.9 to 2.6 cm/s; r=-0.95), increased velocity anisotropy ratios (1.6 to 5.6, n=70), and decreased longitudinal velocity (36.4 to 14.6 cm/s; r=-0.85) for anisotropy ratios >3.5. Cultures of cardiac myocytes with controlled degree, uniformity and continuity of structural, and functional anisotropy may enable systematic 2-dimensional in vitro studies of macroscopic structure-related mechanisms of reentrant arrhythmias. The full text of this article is available at http://www.circresaha.org.


Assuntos
Técnicas de Cultura de Células/métodos , Técnicas Eletrofisiológicas Cardíacas , Sistema de Condução Cardíaco/fisiologia , Modelos Cardiovasculares , Miocárdio/citologia , Potenciais de Ação/fisiologia , Animais , Animais Recém-Nascidos , Anisotropia , Técnicas de Cultura de Células/instrumentação , Divisão Celular/fisiologia , Polaridade Celular/fisiologia , Células Cultivadas , Estimulação Elétrica , Fibronectinas , Fluorescência , Sistema de Condução Cardíaco/citologia , Ventrículos do Coração/citologia , Óptica e Fotônica , Ratos , Ratos Sprague-Dawley
14.
Int J Tuberc Lung Dis ; 10(9): 963-9, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16964785

RESUMO

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.


Assuntos
Terapia Diretamente Observada , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/epidemiologia , Adolescente , Adulto , Idoso , Criança , Humanos , Pessoa de Meia-Idade , Vietnã/epidemiologia
15.
Cancer Res ; 54(14): 3868-77, 1994 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-8033109

RESUMO

Because progesterone antagonists are growth inhibitors, they are in Phase III clinical trials for the treatment of breast cancer. However, when cellular cAMP levels are elevated, some antiprogestins inappropriately activate transcription. We have proposed that hormone "resistance" may result from such unintended stimulation of breast cancer by antagonists. In transient expression systems, the two natural isoforms of human progesterone receptors (PR), B-receptors and truncated A-receptors, have dissimilar effects on agonist-mediated transcription. We show here that in the presence of 8-Br-cAMP, antiprogestin-occupied B-receptors but not A-receptors become transcriptional activators. Therefore, we developed new model systems to study each PR isoform independently in a breast cancer setting: (a) a stable PR-negative monoclonal subline (T47D-Y) of PR-positive T47D breast cancer cells was selected by flow cytometric PR screening. T47D-Y cells are PR-negative by immunoassays, by ligand binding assay, by growth resistance to progestins, by failure to bind a progesterone response element (PRE) in vitro, and by failure to transactivate PRE-regulated promoters; and (b) T47D-Y cells were stably transfected with expression vectors encoding one or the other PR isoform, and two monoclonal cell lines were selected that express either B-receptors (T47D-YB) or A-receptors (T47D-YA) at levels equal to those seen in natural T47D cells. The ectopically expressed receptors are properly phosphorylated, and like endogenously expressed receptors, they undergo ligand-dependent down-regulation. The expected B:B or A:A homodimers are present in cell extracts from each cell line, but A:B heterodimers are missing in both. In the presence of agonists, cAMP-dependent, transcriptional synergism of PRE-regulated promoters is seen in both cell lines. By contrast, in the presence of the antiprogestins RU486 or ZK112993, inappropriate transactivation occurs in YB cells but not in YA cells. The class of antiprogestins represented by ZK98299, which blocks PR binding to DNA, does not activate transcription in either cell line. We propose that these new cell lines are physiological models for the study of PR isoform-specific antiprogestin resistance in breast cancer.


Assuntos
Neoplasias da Mama/química , AMP Cíclico/farmacologia , Progestinas/antagonistas & inibidores , Receptores de Progesterona/análise , Sequência de Bases , Neoplasias da Mama/patologia , Feminino , Gonanos/farmacologia , Humanos , Mifepristona/análogos & derivados , Mifepristona/farmacologia , Dados de Sequência Molecular , Receptores de Progesterona/genética , Transcrição Gênica/efeitos dos fármacos , Células Tumorais Cultivadas
16.
J Phys Condens Matter ; 28(16): 165602, 2016 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-27001951

RESUMO

We studied the magneto-optical response of a canonical topological insulator Bi2Se3 with the goal of addressing a controversial issue of electron-phonon coupling. Magnetic-field induced modifications of reflectance are very pronounced in the infrared part of the spectrum, indicating strong electron-phonon coupling. This coupling causes an asymmetric line-shape of the 60 cm(-1) phonon mode, and is analyzed within the Fano formalism. The analysis reveals that the Fano asymmetry parameter (q) changes sign when the cyclotron resonance is degenerate with the phonon mode. To the best of our knowledge this is the first example of magnetic field driven q-reversal.

17.
Circulation ; 101(15): 1792-8, 2000 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-10769279

RESUMO

BACKGROUND: Estrogens have vascular effects through the activation of estrogen receptors (ERs). In addition to ERalpha, the first ER to be cloned, a second subtype called ERbeta has recently been discovered. METHODS AND RESULTS: Using a reverse-transcriptase polymerase chain reaction assay that employs the same primer pair to simultaneously amplify ERalpha and ERbeta transcripts, we found that ERbeta is the ER form that is predominantly expressed in human vascular smooth muscle, particularly in women. The transcriptional effects of the 2 ERs in transfected HeLa cells differed. In response to 17beta-estradiol, ERalpha is a stronger transactivator than ERbeta at low receptor concentrations. However, at higher receptor concentrations, ERalpha activity self-squelches, and ERbeta is a stronger transactivator. Tamoxifen has partial agonist effects with ERalpha but not with ERbeta. CONCLUSIONS: The protective effects of estrogens in the cardiovascular system of women may be due to the genomic effects of ERbeta in vascular tissue.


Assuntos
Músculo Liso Vascular/metabolismo , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Transcrição Gênica , Estradiol/análogos & derivados , Estradiol/farmacologia , Antagonistas de Estrogênios/farmacologia , Receptor alfa de Estrogênio , Receptor beta de Estrogênio , Feminino , Fulvestranto , Células HeLa , Humanos , Ligantes , Regiões Promotoras Genéticas , RNA/análise , Receptores de Estrogênio/efeitos dos fármacos , Análise de Regressão , Tamoxifeno/farmacologia
18.
Int J Tuberc Lung Dis ; 9(2): 151-6, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15732733

RESUMO

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.


Assuntos
Programas Nacionais de Saúde , Tuberculose/prevenção & controle , Humanos , Programas Nacionais de Saúde/organização & administração , Tuberculose/epidemiologia , Vietnã/epidemiologia
19.
Mol Endocrinol ; 7(10): 1256-65, 1993 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-8123133

RESUMO

When antagonist-occupied steroid receptors have agonist-like effects, the clinical consequences are grave. We present evidence that human progesterone B-receptors (hPRB) when occupied by progesterone antagonists, inappropriately activate transcription by an unusual mechanism that does not require the canonical progesterone response element (PRE). In HeLa cells cotransfected with a PRE-tk-chloramphenicol acetyltransferase reporter and a hPRB expression vector, strong transcription is seen not only when receptors are activated by the agonist R5020, but also in the presence of the three antiprogestins, RU486, ZK112993, and ZK98299. Human PRB occupied by ZK98299 do not bind to a PRE, suggesting that the transcriptional stimulation is independent of DNA binding. Indeed, a tk-chloramphenicol acetyltransferase promoter-reporter lacking the PRE loses transcriptional activation by the agonist, but retains transactivation by the three antagonists. The PRE-independent antagonist-induced transcription requires that hPRB have an intact DNA-binding domain, but hPR target gene specificity is not required, because a hPRB mutant that binds an estrogen response element still activates transcription. It appears that antagonist-occupied hPR activate transcription without binding to a PRE, perhaps by interacting with tethering proteins instead. Even a gene that is not a normal progesterone target could be aberrantly activated. Human cells contain equimolar amounts of hPRB and the N-terminally truncated natural isotype, hPRA. Unlike hPRB, hPRA are not transcriptionally activated by progesterone antagonists. We, therefore, tested the effects of antagonists when the two receptor isotypes are coexpressed and found that A-receptors can annul the inappropriate transcription by B-receptors. Thus, when both receptor forms are present, the hPRA phenotype is dominant. Moreover, pure hPRB/hPRA heterodimers, produced by fos/jun leucine zipper domain-hPR chimeras, also have the inactive transcriptional phenotype of hPRA. Our studies suggest not only that the two hPR isotypes are functionally quite different, but also that some of the agonist-like transcriptional effects of antagonist-occupied B-receptors proceed through novel mechanisms.


Assuntos
DNA/metabolismo , Progesterona/antagonistas & inibidores , Receptores de Progesterona/fisiologia , Transcrição Gênica , Sítios de Ligação , Genes Reporter , Genes fos , Genes jun , Gonanos/farmacologia , Células HeLa , Humanos , Zíper de Leucina , Mifepristona/análogos & derivados , Mifepristona/farmacologia , Fenótipo , Progesterona/farmacologia , Regiões Promotoras Genéticas , Receptores de Progesterona/antagonistas & inibidores , Receptores de Progesterona/genética , Proteínas Recombinantes de Fusão , Transfecção
20.
Mol Endocrinol ; 8(10): 1347-60, 1994 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-7854352

RESUMO

Human progesterone target tissues contain two progesterone receptors: B-receptors (hPRB), which are 933 amino acids in length, and A-receptors (hPRA), which lack the N-terminal 164 amino acids. The two isoforms differ functionally when they are occupied by agonists or antagonists. We postulated that the unique 164-amino acid, B-upstream segment (BUS) is in part responsible for the functional differences between the two isoforms and have constructed a series of hPR expression vectors encoding BUS fused to isolated down-stream functional domains of the receptors. These include the two transactivation domains: activation function-1 (AF1), located in a 90-amino acid segment just up-stream of the DNA-binding domain (DBD) and nuclear localization signal (NLS), and AF2, located in the hormone-binding domain. BUS is a highly phosphorylated domain, and contains the serine residues responsible for the hPRB triplet protein structure. The construct containing BUS-DBD-NLS binds tightly to DNA when aided by accessory nuclear factors. In HeLa cells, BUS-DBD-NLS strongly and autonomously activates transcription of chloramphenicol acetyltransferase (CAT) from a promoter containing two progesterone response elements (PRE2-TATAtk-CAT). Transcription levels with BUS-DBD-NLS are equivalent to those seen with full-length hPRB, and are higher than those seen with hPRA. BUS specifically requires an intact hPR DBD to be transcriptionally active. DBD mutants that cannot bind DNA or whose DNA binding specificity has been switched to an estrogen response element cannot cooperate in BUS transcriptional activity. The function of BUS-DBD-NLS is promoter and cell specific. It does not transactivate a CAT reporter driven by the mouse mammary tumor virus promoter in HeLa cells and poorly transactivates PRE2-TATAtk-CAT in PR-negative T47D breast cancer cells. However, in the breast cancer cells, BUS-DBD-NLS transactivation of PRE2-TATAtk-CAT can be reconstituted by either elevating cellular levels of cAMP or linking BUS and DBD to AF1 or AF2 of hPR, each of which alone is also inactive in these cells. We conclude that hPRB contains a unique third activation function (AF3) located within BUS and requiring the functional DBD of hPR. Depending on the promoter or cell tested, AF3 can activate transcription autonomously, or it can functionally synergize with AF1 or AF2. Autonomous AF3 function may explain the unexpected transactivating actions of antiprogestin-occupied hPRB, an issue of importance in hormone-resistant breast cancers and in tissue-specific agonist-like effects of hormone antagonists.


Assuntos
Fragmentos de Peptídeos/fisiologia , Receptores de Progesterona/fisiologia , Ativação Transcricional , 8-Bromo Monofosfato de Adenosina Cíclica/farmacologia , Sítios de Ligação , Cloranfenicol O-Acetiltransferase/genética , DNA/metabolismo , Sinergismo Farmacológico , Genes Reporter , Células HeLa , Humanos , Vírus do Tumor Mamário do Camundongo/genética , Fragmentos de Peptídeos/farmacologia , Fosforilação , Regiões Promotoras Genéticas , TATA Box , Transcrição Gênica
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