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1.
J Magn Magn Mater ; 401: 495-505, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-27041794

RESUMO

Detailed EPR investigations on as-grown and annealed TiO2 nanoparticles in the anatase and rutile phases were carried out at X-band (9.6 GHz) at 77, 120-300 K and at 236 GHz at 292 K. The analysis of EPR data for as-grown and annealed anatase and rutile samples revealed the presence of several paramagnetic centers: Ti3+, O-, adsorbed oxygen (O2-) and oxygen vacancies. On the other hand, in as-grown rutile samples, there were observed EPR lines due to adsorbed oxygen (O2-) and the Fe3+ ions in both Ti4+ substitutional positions, with and without coupling to an oxygen vacancy in the near neighborhood. Anatase nanoparticles were completely converted to rutile phase when annealed at 1000° C, exhibiting EPR spectra similar to those exhibited by the as-grown rutile nanoparticles. The high-frequency (236 GHz) EPR data on anatase and rutile samples, recorded in the region about g = 2.0 exhibit resolved EPR lines, due to O- and O2- ions enabling determination of their g-values with higher precision, as well as observation of hyperfine sextets due to Mn2+ and Mn4+ ions in anatase.

2.
J Infect ; 67(5): 378-84, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23876330

RESUMO

OBJECTIVES: Evaluate data available from a national voluntary reporting system and describe the data processing necessary to enable the development and application of outbreak detection methods in healthcare settings. METHODS: Evaluation was performed on an extract of data reported between March 2007 and May 2012. Reporting delays were calculated and analysed at the trust, regional and national levels. Negative binomial regression analysis was performed to detect any changes in laboratory reporting within this time. RESULTS: 167 hospital laboratories have reported to the voluntary reporting system. 1,705,126 reports were made in the five-year study period. There is large variation in how laboratories report to the system. Under half (44.9%) report in a timely manner, with >90% of infections reported within three weeks of the specimen date. Overall, there was a significant increase of 17.5% in reporting after October 2010 (95% CI 13.8-21.4%, p < 0.001) and an improvement in reporting delay, when new statutory reporting regulations were introduced. CONCLUSIONS: The outbreak detection algorithm used at the national and regional level requires further modification to optimise outbreak detection for individual hospitals. For any prospective outbreak detection system to perform optimally it is imperative that laboratories ensure that the data they submit is complete, consistent and timely.


Assuntos
Doenças Transmissíveis/diagnóstico , Notificação de Doenças/métodos , Surtos de Doenças , Vigilância da População/métodos , Doenças Transmissíveis/tratamento farmacológico , Doenças Transmissíveis/epidemiologia , Doenças Transmissíveis/microbiologia , Sistemas de Gerenciamento de Base de Dados , Notificação de Doenças/estatística & dados numéricos , Farmacorresistência Bacteriana , Humanos , Laboratórios Hospitalares
3.
J Safety Res ; 43(3): 187-94, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22974684

RESUMO

INTRODUCTION: Light-vehicle driver education programs that contain content about sharing the road with heavy vehicles may be helpful in reducing future light-vehicle/heavy-vehicle interactions. However, the extent of curricula in the United States including such content is unclear. METHOD: Researchers developed an online survey targeted at instructors/administrators of state driver education programs to identify curricula addressing heavy vehicles and to determine perceived effectiveness. RESULTS: Ninety-one percent of respondents indicated that the light-vehicle driver education curriculum they teach/administer included a component covering how to safely share the road with heavy vehicles (82% perceived this component to be effective). DISCUSSION: Although a large proportion of these programs included a component on how to safely share the road with heavy vehicles, participants indicated there may be room for improvement. IMPACT ON INDUSTRY: Participants recommended that future improvements to driver education programs include updated materials and student hands-on experience with heavy vehicles.


Assuntos
Condução de Veículo/educação , Currículo , Veículos Automotores/classificação , Segurança , Coleta de Dados , Humanos , Estados Unidos
4.
Bone Marrow Transplant ; 47(12): 1489-98, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22179556

RESUMO

Sickle cell disease (SCD) is an autosomal recessive inherited hematological disorder characterized by chronic hemolysis and vaso-occlusion, resulting in multiorgan dysfunction and premature death. The only known curative therapy for patients with severe SCD is myeloablative conditioning and allo-SCT from HLA-matched sibling donors. In this state of the art review, we discuss current and future considerations including patient selection/eligibility, intensity of conditioning regimens, allogeneic graft sources, graft manipulation, mixed donor chimerism, organ function and stability and autologous gene correction stem cell strategies. Recent novel approaches to promote mixed donor chimerism have included the use of matched unrelated adult donors, umbilical cord blood donors, haploidentical familial donors and the utilization of nonmyeloablative, such as reduced intensity and reduced toxicity conditioning regimens. Future strategies will include gene therapy and autologous gene correction stem cell designs. Prospects are bright for novel stem and cellular approaches for patients with severe SCD, and we are currently at the end of the beginning for utilizing cellular therapeutics for the curative treatment of this chronic and debilitating condition.


Assuntos
Anemia Falciforme/cirurgia , Transplante de Células-Tronco/métodos , Humanos , Transplante Autólogo , Transplante Homólogo
5.
Nanosci Nanotechnol Lett ; 3(4): 561-567, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21984955

RESUMO

We report on electron-spin resonance microscopy (ESRM) providing sub-micron resolution (~700nm) with a high spin concentration sample, i.e. lithium phthalocyanine (LiPc) crystal. For biomedical applications of our ESRM, we have imaged samples containing rat basophilic leukemia (RBL) cells as well as cancerous tissue samples with a resolution of several microns using a water soluble spin probe, Trityl_OX063_d24. Phantom samples with the nitroxide spin label, (15)N PDT, were also imaged to demonstrate that nitroxides, which are commonly used as spin labels, may also be used for ESRM applications. ESRM tissue imaging would therefore be valuable for diagnostic or therapeutic purposes. Also, ESRM can be used to study the motility or the metabolism of cells in various environments. With further modification and/or improvement of imaging probe and spectrometer instrumentation sub-micron biological images should be obtainable, thereby providing a useful tool for various biomedical applications.

6.
J Chem Phys ; 134(2): 024508, 2011 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-21241121

RESUMO

The "Swedish slow motion theory" [Nilsson and Kowalewski, J. Magn. Reson. 146, 345 (2000)] applied so far to Nuclear Magnetic Relaxation Dispersion (NMRD) profiles for solutions of transition metal ion complexes has been extended to ESR spectral analysis, including in addition g-tensor anisotropy effects. The extended theory has been applied to interpret in a consistent way (within one set of parameters) NMRD profiles and ESR spectra at 95 and 237 GHz for two Gd(III) complexes denoted as P760 and P792 (hydrophilic derivatives of DOTA-Gd, with molecular masses of 5.6 and 6.5 kDa, respectively). The goal is to verify the applicability of the commonly used pseudorotational model of the transient zero field splitting (ZFS). According to this model the transient ZFS is described by a tensor of a constant amplitude, defined in its own principal axes system, which changes its orientation with respect to the laboratory frame according to the isotropic diffusion equation with a characteristic time constant (correlation time) reflecting the time scale of the distortional motion. This unified interpretation of the ESR and NMRD leads to reasonable agreement with the experimental data, indicating that the pseudorotational model indeed captures the essential features of the electron spin dynamics.


Assuntos
Compostos Heterocíclicos/química , Compostos Organometálicos/química , Teoria Quântica , Espectroscopia de Ressonância de Spin Eletrônica , Espectroscopia de Ressonância Magnética
7.
Appl Magn Reson ; 37(1-4): 819-832, 2010 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-20458356

RESUMO

The sensitivity of a high frequency electron spin resonance (ESR) spectrometer depends strongly on the structure used to couple the incident millimeter wave to the sample that generates the ESR signal. Subsequent coupling of the ESR signal to the detection arm of the spectrometer is also a crucial consideration for achieving high spectrometer sensitivity. In previous work, we found that a means for continuously varying the coupling was necessary for attaining high sensitivity reliably and reproducibly. We report here on a novel asymmetric mesh structure that achieves continuously variable coupling by rotating the mesh in its own plane about the millimeter wave transmission line optical axis. We quantify the performance of this device with nitroxide spin-label spectra in both a lossy aqueous solution and a low loss solid state system. These two systems have very different coupling requirements and are representative of the range of coupling achievable with this technique. Lossy systems in particular are a demanding test of the achievable sensitivity and allow us to assess the suitability of this approach for applying high frequency ESR to the study of biological systems at physiological conditions, for example. The variable coupling technique reported on here allows us to readily achieve a factor of ca. 7 improvement in signal to noise at 170 GHz and a factor of ca. 5 at 95 GHz over what has previously been reported for lossy samples.

8.
Appl Magn Reson ; 36(2): 291-295, 2009 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-20161547

RESUMO

High frequency (236 GHz) electron paramagnetic resonance (EPR) studies of Fe(3+) ions at 255 K are reported in a Sn(1-x)Fe(x)O(2) powder with x = 0.005 which is a ferromagnetic semiconductor at room temperature. The observed EPR spectrum can be simulated reasonably well as overlap of spectra due to four magnetically inequivalent high-spin (HS) Fe(3+) ions (S = 5/2). The spectrum intensity is calculated, using the overlap I(BL) + (I(HS1)+I(HS2)+I(HS3)+I(HS4))×e(-0.00001×B), where B is the magnetic field intensity in Gauss, I represents the intensity of an EPR line (HS1, HS2, HS3, HS4), and BL stands for the base line. (The exponential factor, as found by fitting to the experimental spectrum, is related to the Boltzmann population distribution of energy levels at 255 K, which is the temperature of the sample in the spectrometer.) These high-frequency EPR results are significantly different from those at X-band. The large values of the zero-field splitting parameter (D) observed here for the four centers at the high frequency of 236 GHz are beyond the capability of X-band, which can only record spectra of ions only with much smaller D values than those reported here.

9.
Biopharm Drug Dispos ; 26(9): 379-85, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16130176

RESUMO

The purpose of this study was to evaluate the safety and pharmacokinetics of nemifitide, a synthetic antidepressant pentapeptide, following its subcutaneous (s.c.) administration by standard needle injection or by a needle-free (Biojecttrade mark) injection and to compare these two routes of administration for systemic exposure. This small-scale, randomized, single-dose, parallel design, open-label pilot study consisted of three treatment groups of four subjects each dosed as follows: group 1: 40 mg of nemifitide administered by standard needle/syringe and groups 2 and 3: 40 and 80 mg nemifitide, respectively, administered by using a needle-free (Bioject injection delivery system. Plasma concentrations of nemifitide were determined by LC/MS/MS in blood samples collected at 10 min and 0.5, 1, 2, 4, 6 and 24 h after dosing. PK parameters, including observed C(max), T(max) and AUC(0-24), were calculated and statistical analysis of the data was conducted. Safety assessments (dosing site evaluations) were done at 0.5, 1, 5 and 24 h after dosing. Vital signs and clinical laboratory tests were taken on day 1 prior to dosing and at 24 h post-dose. Adverse experiences in all subjects were observed only as drug-related local reactions at the injection sites. All were considered mild in severity and transient (resolved by 24 h after dosing). T(max) was observed at 10 min after dose and was the same in all subjects. In the three dosing groups, 1 (40 mg), 2 (40 mg) and 3 (80 mg), observed C(max) values were 226, 245 and 440 ng/ml, respectively, and AUC(0-24) values were 108, 106 and 205 ng.h/ml, respectively. Ratios of AUC(0-24) and observed C(max) for nemifitide in plasma between groups 1 and 2 were within the 80%-125% range, indicating that the two modes of drug administration resulted in similar systemic exposure to nemifitide. Pharmacokinetic parameters (AUC(0-24) and C(max)) indicate dose-proportionality between the doses of 40 and 80 mg.


Assuntos
Antidepressivos/farmacocinética , Oligopeptídeos/farmacocinética , Adulto , Idoso , Antidepressivos/administração & dosagem , Antidepressivos/sangue , Área Sob a Curva , Feminino , Humanos , Injeções Subcutâneas/métodos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Oligopeptídeos/administração & dosagem , Oligopeptídeos/sangue , Projetos Piloto
10.
Z Orthop Ihre Grenzgeb ; 141(2): 223-6, 2003.
Artigo em Alemão | MEDLINE | ID: mdl-12695961

RESUMO

AIM: In urology, single cases of lethal pulmonary embolism following extracorporeal shock wave application to renal concrements have been reported. Therefore, lungs of rabbits were histopathologically investigated following extracorporeal shock wave application to the femur. METHOD: In 8 mature Chinchilla-Bastard rabbits, shock wave application to one distal femur was performed with energy flux density of 0.9 mJ/mm2. In another 6 rabbits, sham-treatment (0 mJ/mm2) to one distal femur was performed. 6 weeks later, the animals were sacrificed and their lungs were blindly investigated by an independent pathologist. RESULTS: In 7 out of the 8 treated animals (0.9 mJ/mm2) but in none of the sham-treated controls, patchy discolorations of the surface of the lung were observed. Furthermore, in 6 out of the 8 treated animals but in none of the sham-treated controls, bony fragments with signs of resorption were observed in lung vessels. CONCLUSION: Application of extracorporeal shock waves with energy flux densities higher than 0.9 mJ/mm2 has been recommended in the literature for the treatment of aseptic non-unions. In this procedure, the possibility of the occurrence of bone fragments in the lung with the potential risk of pulmonary embolism should be regarded.


Assuntos
Fêmur/patologia , Migração de Corpo Estranho/patologia , Ondas de Choque de Alta Energia/efeitos adversos , Lesão Pulmonar , Embolia Pulmonar/patologia , Animais , Feminino , Pulmão/patologia , Alvéolos Pulmonares/patologia , Coelhos
11.
Qual Life Res ; 11(1): 57-70, 2002 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12003056

RESUMO

BACKGROUND: The impact of oral health on HIV patients has not been sufficiently documented. OBJECTIVE: To estimate the associations between measures of oral and generic health-related quality of life in persons receiving medical care for HIV. DESIGN: This is a longitudinal study of interview data collected in a probability sample of adults with HIV receiving health care in the US. The data were collected at three points in time. PATIENTS: Two thousand eight hundred and sixty-four HIV-infected adults using medical care. MEASUREMENTS: Physical and mental health were assessed using 28 items and oral health was assessed using seven items on oral-related pain and discomfort, worry, appearance, and function. Clinical measures included CD4 count, oral symptoms, physical symptoms, and stage of HIV. Physical functioning and emotional well-being were measured on a 0-100 scale with higher scores indicating better health. Oral health was measured using seven items with a five point scale. RESULTS: In multivariate analyses, oral symptoms had the strongest association with oral health-related quality of life. Each additional oral symptom was associated with an average decrease in oral health (0-100 possible range) of 3.97 points (p = 0.000). In addition, oral health was significantly associated with both physical and mental health. A one-point increase in oral health was associated with a 0.05 (p = 0.000) increase in mental health and 0.02 increase in physical health (p = 0.031). CONCLUSIONS: Oral health is strongly associated with physical and mental health but provides noteworthy unique information in persons with HIV infection. Thus, physical and mental health measures of HIV patients should incorporate indicators of oral functioning and well-being.


Assuntos
Infecções por HIV/psicologia , Saúde Mental , Saúde Bucal , Qualidade de Vida , Adulto , Idoso , Feminino , Infecções por HIV/terapia , Indicadores Básicos de Saúde , Humanos , Entrevistas como Assunto , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Estados Unidos
12.
Xenobiotica ; 32(3): 221-33, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11958561

RESUMO

1. SB-242235 (1-(4-piperidinyl)-4-(4-fluorophenyl)-5-(2-methoxy-4-pyrimidinyl) imidazole) is a potent and selective p38 MAP kinase inhibitor that may be an effective therapy for cytokine-mediated diseases such as autoimmune or inflammatory diseases. The present studies were conducted to evaluate the pharmacokinetics of SB-242235 in several preclinical species, including rat, dog and monkey. 2. SB-242235 demonstrates generally favourable pharmacokinetic properties in all species examined. Systemic plasma clearance was high in rat, but in the non-rodent species SB-242235 demonstrated low to moderate clearance with plasma half-lives > 4h. Oral bioavailability in each preclinical species was high. In rat and monkey, SB-242235 demonstrated non-linear elimination kinetics that manifested as a decrease in clearance with increasing dose and apparent oral bioavailability > 100% at high oral doses. Furthermore, SB-242235 displayed concentration-dependent plasma protein binding over a concentration range of 1000-10,000 ng ml(-1). 3. In conclusion, SB-242235 demonstrates high oral bioavailability across the major preclinical species, and may thus be a useful tool compound for investigation of the role of p38 inhibition in various disease states. However, the observations of non-linear protein binding and disposition also suggest the need for caution in the design of and data interpretation from such studies.


Assuntos
Inibidores Enzimáticos/farmacocinética , Imidazóis/farmacocinética , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Piridinas/farmacocinética , Animais , Área Sob a Curva , Disponibilidade Biológica , Proteínas Sanguíneas/metabolismo , Difusão , Cães , Meia-Vida , Humanos , Macaca fascicularis , Masculino , Ligação Proteica , Ratos , Especificidade da Espécie , Proteínas Quinases p38 Ativadas por Mitógeno
13.
Tsitologiia ; 44(11): 1058-67, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12561726

RESUMO

Polyploidization of the extravillous trophoblast (EVT) cells at different stages of differentiation and invasion into the uterine wall in human placenta has been studied. An increase in the ploidy level of EVT cells in the course of their differentiation within cell columns (CC) was shown. Stem cells were mainly diploid (86.2%); incidence of polyploid nuclei of highly proliferative cells of the proximal part of CC increased progressively. In the distal part of CC, where EVT cells did not divide mitotically, polyploid cells prevailed, with 58.0 and 3.5% nuclei being 4c and 8c, respectively. The highest percentage of polyploid cells was found in the population of EVT cells attached directly to the surface of the decidualized endometrium: percentage of tetraploid cells turned out to be 74.7% and the share of octaploid nuclei rose up to 4.9%; however, there appeared a few (0.3%) 16c cells. The majority of EVT cells invading the decidualized endometrium were polyploid, the share of octaploid and hexadecaploid cells rose up to 9.7 and 1.4%, respectively. On the other hand, the percentage of diploid cells also increased up to 29.2% as compared to EVT cells attached to decidua (20.0%). The same tendency proved to be even stronger in myometrium: the share of diploid EVT cells increased up to 46.0%, a prominent amount of tetraploid (45.1%) and highly polyploid (8c and 16c) cells retained in the EVT cell population (7.4 and 1.1%, respectively). Immunohistochemical staining of Ki-67 protein (MIB1), which labels cells held in the cell cycle, showed a high incidence of MIB1-positive stem cells (93.7%) and the EVT cells of the proximal part of CC (85.5%) characterized by high mitotic activity. A lower MIB1-positivity (43.2%) was found in the distal part of CC, whereas invasive EVT cells showed no MIB1-labeling. The presence of MIB1-positive nuclei in the distal part of CCs in the absence of mitoses, taken together with data on polyploidization of these cells, indicates their switch to the endoreduplication cycle. As a whole, the data obtained evidence that differentiation of EVT cells of the invasive pathway is accompanied by polyploidization. However, in a population of trophoblast cells capable of most profound invasion (up to myometrium), the proportion of diploid cells rose. These results suggest that the human cytotrophoblast invasion into the uterine wall requires an optimum, not the highest, ploidy level, whereas highly polyploid cells may form a subpopulation at the border between the maternal and fetal parts of placenta.


Assuntos
Placenta/fisiologia , Poliploidia , Trofoblastos/fisiologia , Contagem de Células , Ciclo Celular , Núcleo Celular/química , Citofotometria , DNA/análise , Endométrio/citologia , Feminino , Humanos , Queratinas/análise , Antígeno Ki-67/análise , Miométrio/citologia , Placenta/citologia , Placentação , Gravidez , Primeiro Trimestre da Gravidez , Trofoblastos/química , Trofoblastos/classificação
14.
Artigo em Inglês | MEDLINE | ID: mdl-11740480

RESUMO

OBJECTIVES: We sought to analyze the relationship between self-reported oral dryness and the demographic, enabling, behavioral, clinical, and treatment characteristics among human immunodeficiency virus (HIV)-positive patients in medical care. STUDY DESIGN: The study group consisted of the HIV Cost and Services Utilization Study cohort, a nationally representative probability sample of HIV-infected adults receiving medical care in the contiguous United States. RESULTS: It was estimated that 29% of adults (64,947 individuals) with HIV infection receiving medical care in the United States have a complaint of dry mouth. A multivariate logistic analysis was carried out to explore the association between several covariates and dry mouth. It was shown that compared with whites, individuals of Hispanic ethnic origin were 61% more likely to report dry mouth (OR, 1.61; 95% CI, 1.04-2.50; P =.04). Those who were unemployed were 55% more likely to report the symptom of dry mouth than were subjects who were employed (OR, 1.55; 95% CI, 1.22-1.98; P =.001). In comparison with nonsmokers, current smokers were 36% more likely to report dry mouth (OR, 1.36; 95% CI, 1.04-1.79;P =.03). The use of antidepressant drugs and antituberculosis/anti-Mycobacterium avium (anti-TB/anti-MAC) medications had the strongest association with dry mouth complaint. Those taking antidepressants were 55% more likely to report dry mouth (OR, 1.55; 95% CI, 1.23-1.97; P =.0001); compared with nonusers, patients receiving anti-TB/MAC drugs were 46% more likely to report dry mouth (OR, 1.46; 95% CI, 1.03-2.06; P =.04]. In comparison with those with undetectable viral load, individuals with a viral load of more than 100,000/mm(3) were 151% more likely to report dry mouth (OR, 2.51; 95% CI,1.58-3.96; P =.0001). CONCLUSIONS: Our findings suggest that optimizing viral suppression, smoking cessation, and tailoring antidepressant and anti-TB/MAC medications may be promising interventions to decrease dry-mouth symptoms among HIV-infected individuals.


Assuntos
Infecções por HIV/complicações , Xerostomia/etiologia , Adjuvantes Imunológicos/efeitos adversos , Adolescente , Adulto , Análise de Variância , Antidepressivos/efeitos adversos , Antituberculosos/efeitos adversos , Relação CD4-CD8 , Estudos de Coortes , Feminino , Infecções por HIV/tratamento farmacológico , Hispânico ou Latino/estatística & dados numéricos , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Autoavaliação (Psicologia) , Fumar , Estados Unidos/epidemiologia , Carga Viral , Xerostomia/epidemiologia
15.
Pharm Res ; 18(9): 1336-44, 2001 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11683250

RESUMO

PURPOSE: A series of studies was conducted to evaluate the preclinical pharmacokinetics of SB-239063 (trans-1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl)-5-[(2-methoxy)pyrimidin-4-yl] imidazole), a potent and selective p38 MAP kinase inhibitor. METHODS: SB-239063 was administered both i.v. and p.o. in the rat, dog, cynomolgus monkey, and rhesus monkey, with standard pharmacokinetic parameters generated from the concentration vs. time data. RESULTS: Initial rat studies suggested possible nonlinear disposition, however, assay refinement revealed an in vivo trans-cis isomerization of SB-239063 to a metabolite with nearly identical chromatographic and mass spectral properties. SB-239063 exhibited low to moderate clearance and good bioavailability in the rat and dog, but poor bioavailability in the cynomolgus monkey. Substantial in vivo trans-cis isomerization occurred in the rat and cynomolgus monkey, but occurred to a far lesser extent in the dog. The isomerization reaction was reversible, with a recycled fraction of 0.20 and 0.0003 in the rat and cynomolgus monkey, respectively. In the rhesus monkey, bioavailability was also poor. but no in vivo isomerization was observed. Conclusions. These studies demonstrate the necessity of exercising vigilance in conducting high-throughput analytical method development, and the importance of using a variety of preclinical species when evaluating the disposition of new drug candidates.


Assuntos
Inibidores Enzimáticos/farmacocinética , Imidazóis/farmacocinética , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Pirimidinas/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Cães , Inibidores Enzimáticos/administração & dosagem , Imidazóis/administração & dosagem , Injeções Intravenosas , Isomerismo , Macaca fascicularis , Macaca mulatta , Masculino , Pirimidinas/administração & dosagem , Ratos , Especificidade da Espécie , Especificidade por Substrato , Proteínas Quinases p38 Ativadas por Mitógeno
17.
J Am Chem Soc ; 123(13): 3055-63, 2001 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-11457016

RESUMO

The two-body Slowly Relaxing Local Structure (SRLS) model was applied to (15)N NMR spin relaxation in proteins and compared with the commonly used original and extended model-free (MF) approaches. In MF, the dynamic modes are assumed to be decoupled, local ordering at the N-H sites is represented by generalized order parameters, and internal motions are described by effective correlation times. SRLS accounts for dynamical coupling between the global diffusion of the protein and the internal motion of the N-H bond vector. The local ordering associated with the coupling potential and the internal N-H diffusion are tensors with orientations that may be tilted relative to the global diffusion and magnetic frames. SRLS generates spectral density functions that differ from the MF formulas. The MF spectral densities can be regarded as limiting cases of the SRLS spectral density. SRLS-based model-fitting and model-selection schemes similar to the currently used MF-based ones were devised, and a correspondence between analogous SRLS and model-free parameters was established. It was found that experimental NMR data are sensitive to the presence of mixed modes. Our results showed that MF can significantly overestimate order parameters and underestimate local motion correlation times in proteins. The extent of these digressions in the derived microdynamic parameters is estimated in the various parameter ranges, and correlated with the time scale separation between local and global motions. The SRLS-based analysis was tested extensively on (15)N relaxation data from several isotropically tumbling proteins. The results of SRLS-based fitting are illustrated with RNase H from E. coli, a protein extensively studied previously with MF.


Assuntos
Ressonância Magnética Nuclear Biomolecular/métodos , Proteínas/química , Difusão , Isótopos de Nitrogênio , Termodinâmica
18.
Biophys J ; 81(2): 994-1005, 2001 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-11463641

RESUMO

The effects of binding of myristoylated ADP ribosylation factor 6 (myr-ARF6), an activator of phospholipase D (PLD), to a model membrane were investigated using an electron spin resonance (ESR) labeling technique. Initial studies were conducted in vesicles composed of 1-palmitoyl-2-oleoyl phosphatidylethanolamine, dipalmitoylphosphatidylcholine, phosphatidylinositol 4,5-biphosphate (PIP(2)), and cholesterol. Recombinant ARF6 binding significantly enhances defects in both the headgroup and acyl-chain regions of the membrane, which are revealed by the emergence of sharp components in the spectra from a headgroup label, 1,2-dipalmitoylphosphatidyl-2,2,6,6-tetramethyl-1-piperidinyloxy-choline (DPPTC), and a chain label, 10PC, after myr-ARF6 binding. Binding of non-myristoylated ARF6 (non-ARF6) shows markedly reduced effects. Interestingly, no change in spectra from DPPTC was observed upon myr-ARF6 binding when PIP(2) in the vesicles was replaced by other negatively charged lipids, including phosphatidylinositol, phosphatidylserine, and phosphatidylglycerol, even when normalized for charge. The production of the sharp peak appears to be a specific event, because another GTP binding protein, CDC42, which binds PIP(2) and activates PLD, fails to induce changes in vesicle structure. These results suggest a previously unappreciated role for ARF in mediating a protein/lipid interaction that produces defects in lipid bilayers. This function may serve as an initial event in destabilizing membrane structure for subsequent membrane fusion or biogenesis of vesicles.


Assuntos
Fatores de Ribosilação do ADP/metabolismo , Espectroscopia de Ressonância de Spin Eletrônica , Bicamadas Lipídicas/química , Bicamadas Lipídicas/metabolismo , Lipossomos/química , Lipossomos/metabolismo , Fosfatidilinositol 4,5-Difosfato/metabolismo , Fator 6 de Ribosilação do ADP , Humanos , Espectroscopia de Ressonância Magnética , Modelos Biológicos , Fosfatidilcolinas/metabolismo , Ligação Proteica , Marcadores de Spin
19.
J Org Chem ; 66(3): 839-52, 2001 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-11430103

RESUMO

This paper presents reactions in which the putative cationic intermediate in the Morin rearrangement is trapped by aromatic carbon nucleophiles (indoles and furans). For example, reaction of sulfoxide 27 with trifluoroacetic acid in chloroform provides, among other products, indole 29 and indoline 30. The indoline was shown to be in equilibrium with the nine-membered ring bridged indole 31. Other examples of Morin rearrangement-trapping reactions are presented, and mechanisms for these transformations are proposed.


Assuntos
Carbono/química , Furanos/química , Indóis/química , Cátions , Espectroscopia de Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray
20.
J Public Health Dent ; 61(1): 14-21, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11317599

RESUMO

OBJECTIVE: Oral health conditions associated with HIV disease are frequently more severe than those of the general population, making access to both dental and medical care important. Using the domains specified in the Behavioral Model of Health Services Use, this paper examines the correlates of unmet needs for dental and medical care in a nationally representative sample of patients with HIV. METHODS: This investigation is a cross-sectional study using baseline data from the HIV Cost and Services Utilization Study (HCSUS), the first nationally representative study of persons in care for HIV. Using probability-based techniques, 4,042 people were randomly selected in January 1996, and 2,864 (71%) completed a structured interview that included questions on unmet needs for dental and medical care. Regression analysis was used to identify variables associated with having unmet needs for dental care only, medical care only, and both medical and dental care. RESULTS: Of the estimated 230,900 people in treatment for HIV in the United States, approximately 58,000 had unmet medical or dental needs based on self-reported data. Unmet dental needs were more than twice as prevalent as unmet medical needs (32,900 vs 14,300), and 11,600 people were estimated to have both types of unmet needs. Multinomial logit regression showed that persons with low income had increased odds of reporting unmet needs for both dental and medical care. The uninsured and those insured by Medicaid without dental benefits had more than three times the odds of having unmet needs for both types of care than did the privately insured. CONCLUSIONS: To serve both the dental and medical needs of diverse populations affected by HIV disease, greater coordination of services is needed. In addition, state insurance programs for people with HIV should consider the feasibility of expanding their benefit structure to include dental care benefits.


Assuntos
Assistência Odontológica para Doentes Crônicos , Infecções por HIV , Necessidades e Demandas de Serviços de Saúde , Serviços de Saúde , Adulto , Fatores Etários , Contagem de Linfócito CD4 , Intervalos de Confiança , Estudos Transversais , Etnicidade , Feminino , Infecções por HIV/terapia , Acessibilidade aos Serviços de Saúde , Humanos , Renda , Seguro Saúde , Entrevistas como Assunto , Modelos Logísticos , Masculino , Medicaid , Área Carente de Assistência Médica , Pessoas sem Cobertura de Seguro de Saúde , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Análise de Regressão , Serviços de Saúde Rural , Fatores Sexuais , Estados Unidos , Serviços Urbanos de Saúde
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