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1.
Crit Care Med ; 52(5): 729-742, 2024 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-38165776

RESUMO

OBJECTIVES: Systemic thrombolysis improves outcomes in patients with pulmonary embolism (PE) but is associated with the risk of hemorrhage. The data on efficacy and safety of reduced-dose alteplase are limited. The study objective was to compare the characteristics, outcomes, and complications of patients with PE treated with full- or reduced-dose alteplase regimens. DESIGN: Multicenter retrospective observational study. SETTING: Tertiary care hospital and 15 community and academic centers of a large healthcare system. PATIENTS: Hospitalized patients with PE treated with systemic alteplase. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Pre- and post-alteplase hemodynamic and respiratory variables, patient outcomes, and complications were compared. Propensity score (PS) weighting was used to adjust for imbalances of baseline characteristics between reduced- and full-dose patients. Separate analyses were performed using the unweighted and weighted cohorts. Ninety-eight patients were treated with full-dose (100 mg) and 186 with reduced-dose (50 mg) regimens. Following alteplase, significant improvements in shock index, blood pressure, heart rate, respiratory rate, and supplemental oxygen requirements were observed in both groups. Hemorrhagic complications were lower with the reduced-dose compared with the full-dose regimen (13% vs. 24.5%, p = 0.014), and most were minor. Major extracranial hemorrhage occurred in 1.1% versus 6.1%, respectively ( p = 0.022). Complications were associated with supratherapeutic levels of heparin anticoagulation in 37.5% of cases and invasive procedures in 31.3% of cases. The differences in complications persisted after PS weighting (15.4% vs. 24.7%, p = 0.12 and 1.3% vs. 7.1%, p = 0.067), but did not reach statistical significance. There were no significant differences in mortality, discharge destination, ICU or hospital length of stay, or readmission after PS weighting. CONCLUSIONS: In a retrospective, PS-weighted observational study, when compared with the full-dose, reduced-dose alteplase results in similar outcomes but fewer hemorrhagic complications. Avoidance of excessive levels of anticoagulation or invasive procedures should be considered to further reduce complications.


Assuntos
Embolia Pulmonar , Ativador de Plasminogênio Tecidual , Humanos , Ativador de Plasminogênio Tecidual/efeitos adversos , Estudos Retrospectivos , Embolia Pulmonar/complicações , Terapia Trombolítica/efeitos adversos , Terapia Trombolítica/métodos , Hemorragia/complicações , Doença Aguda , Anticoagulantes/uso terapêutico , Fibrinolíticos/efeitos adversos , Resultado do Tratamento
2.
Inorg Chem ; 62(39): 15952-15962, 2023 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-37725578

RESUMO

A comprehensive field- and temperature-dependent examination of nuclear magnetic resonance paramagnetic relaxation enhancements (PREs) for the constitutive protons of [Co(Tpm)2][BF4]2 is presented. Data for an apically substituted derivative clearly establish that bis-Tpm complexes of Co(II) undergo Jahn-Teller dynamics about the molecular threefold axis. PREs from the parent Tpm complex were used to numerically extract the electron relaxation times (T1e). The Tpm complex showed field-dependent behavior, with an approximately 40% higher activation barrier than the related trispyrazolylborate (Tp) complex, based on fits to the T1e vs T, B0 data. Analysis of the field-dependent line widths revealed a surprisingly large contribution from susceptibility (Curie) relaxation (20-35% at the highest field), and a molecular radius (9.5 Å) that is consistent with a tightly associated counterion slowing rotation in solution. Density functional theory showed a shared vibration that is consistent with the Jahn-Teller and appears proportionately higher in energy in [Co(Tpm)2]2+. Complete active-space self-consistent field calculations support ascribing electron relaxation to enhanced mixing of the two Eg orbital sets that accompanies the tetragonal distortion and the differences in electron correlation times to the higher Jahn-Teller activation barrier in [Co(Tpm)2]2+.

3.
J Couns Psychol ; 70(2): 133-145, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36633995

RESUMO

Sexual minorities report more psychological distress, unmet mental health needs, and barriers to mental health care compared with heterosexuals, yet little is known about their barriers to seeking out mental health care. The present study reports the factors that influence intentions to seek out mental health care of a national survey of 398 sexual minorities. Structural equation modeling identified structural barriers, such as cost, time, and knowing how to access services, as the strongest predictor of sexual minorities' help-seeking intentions. Latent moderators indicated sexual minorities' help-seeking intentions varied depending upon their degree of psychological distress. This revealed a pattern where the most vulnerable participants (i.e., those with high structural barriers and negative help-seeking attitudes) were willing to pursue mental health care only when they were experiencing significant distress. Furthermore, nearly 40% of participants reported unmet mental health needs, and structural barriers were the primary reasons for this deficit. Findings from this study contrast with previous mental health help-seeking research by emphasizing the importance of structural vulnerability, which refers to the external forces that frame and constrain choices, thereby impeding decision-making and limiting life options for those who are in systemically disadvantaged social positions. These findings are discussed in terms of counseling psychology training, practice, social justice advocacy, and future health care research. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Assuntos
Serviços de Saúde Mental , Minorias Sexuais e de Gênero , Humanos , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Aconselhamento , Saúde Mental
4.
J Thromb Thrombolysis ; 54(4): 605-615, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35320471

RESUMO

BACKGROUND: Alteplase treatment can cause a systemic coagulopathy although the incidence and contributory factors are unknown in pulmonary embolism (PE). Fixed-dosing of alteplase for PE may lead to interpatient variability in drug exposure and influence post-thrombolytic coagulopathy (PTC). While changes in fibrinogen and INR have been used to describe PTC, no universal PTC definition is available. OBJECTIVES: Evaluate the incidence of PTC after alteplase treatment for PE, the effect of patient weight and blood/plasma volume and the association with bleeding complications. METHODS: We conducted a retrospective cohort study of patients treated with alteplase for massive or high-risk submassive PE. Demographics, alteplase dosing, laboratory assessment of coagulopathy, and bleeding events were collected. The primary endpoint was incidence of PTC defined as an international normalized ratio (INR) > 1.5 or fibrinogen < 170 mg/dL. Secondary outcomes included correlation between coagulopathies and alteplase dose normalized to actual body weight (ABW), ideal body weight (IBW), plasma volume (PV), and estimated blood volume (EBV). Bleeding events in patients with and without PTC were compared. RESULTS: 125 patients met criteria for inclusion in the study. PTC occurred in 35.3% of patients, with INR >1.5 in 21.8% and fibrinogen <170 mg/dL in 26%. Alteplase dose >50 mg was associated with increased odds of PTC (OR 6.5, CI 2.1-19.9). Dose normalized to ABW and EBV correlated weakly with absolute increase in post-alteplase INR (r =0.20, p =0.06 and r =0.21, p =0.057 respectively) and to percent change in INR (r =0.20, p = 0.058 and r =0.21, p =0.048 respectively). Dose/ABW, dose/PV, and dose/EBV each correlated moderately with absolute decrease in fibrinogen (r =-0.53, -0.49, and -0.47 respectively, p <0.001 for each) and percent change in fibrinogen (r = -0.55, -0.49, and -0.49 respectively, p < 0.001 for each). Dose/IBW correlated weakly with absolute and percent decrease in fibrinogen (r = -0.32, p =0.013 and r =-0.33, p =0.011). Patients with bleeding were more likely to have PTC (58.3% vs. 28.6%, p= 0.05) and a bleeding event was predictive of PTC (OR 5.33, 1.32-23.99). CONCLUSIONS: PTC is prevalent in patients with PE. PTC is influenced by alteplase dose and exposure parameters (ABW, IBW, PV, EBV) and may contribute to the bleeding risk.


Assuntos
Transtornos da Coagulação Sanguínea , Embolia Pulmonar , Humanos , Ativador de Plasminogênio Tecidual/uso terapêutico , Estudos Retrospectivos , Fibrinolíticos/uso terapêutico , Transtornos da Coagulação Sanguínea/tratamento farmacológico , Hemorragia/etiologia , Fibrinogênio/uso terapêutico , Terapia Trombolítica/efeitos adversos , Resultado do Tratamento
5.
J Ultrasound Med ; 41(1): 33-40, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33797767

RESUMO

Point-of-care ultrasound (POCUS) is becoming an essential skill for internists. To date, there are no professional guidelines for how POCUS skills should be taught to medical students. A panel of POCUS experts from seven academic medical centers in the United States was convened to describe the components of independently developed IM clerkship POCUS training programs, identify areas of similarity and difference, and propose recommendations for alignment.


Assuntos
Sistemas Automatizados de Assistência Junto ao Leito , Humanos
6.
J Ultrasound Med ; 41(5): 1069-1076, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-34272888

RESUMO

OBJECTIVES: The physical exam component of a periodic health visit in the elderly has not been considered useful. Standard Medicare Wellness visits require no physical exam beyond blood pressure and most physicians perform limited exams during these visits. The objective of this study was to test the feasibility, potential benefit, and costs of performing a screening ultrasound (US) exam during Medicare Wellness visits. METHODS: A physician examiner at an academic internal medicine primary care clinic performed a screening US exam targeting important abnormalities of patients 65-85 years old during a Medicare Wellness visit. The primary care physician (PCP) recorded the follow-up items for each abnormality identified by the US examiner and assessed the benefit of each abnormality for the participant. Abnormality benefit, net exam benefit per participant, follow-up items and costs, participant survey results, and exam duration were assessed. RESULTS: Participants numbered 108. Total abnormalities numbered 283 and new diagnoses were 172. Positive benefit scores were assigned to 38.8%, neutral (zero) scores to 59.4%, and negative benefit scores to 1.8% of abnormalities. Net benefit scores per participant were positive in 63.9%, 0 in 34.3%, and negative in 1.8%. Follow-up items were infrequent resulting in 76% of participants without follow-up cost. Participant survey showed excellent acceptance of the exam. CONCLUSIONS: The US screening exam identified frequent abnormalities in Medicare Wellness patients. The assessed benefits were rarely negative and often mild to moderately positive, with important new chronic conditions identified. Follow-up costs were low when the PCPs were also US experts.


Assuntos
Programas de Rastreamento , Medicare , Idoso , Idoso de 80 Anos ou mais , Humanos , Medicina Interna , Exame Físico/métodos , Ultrassonografia , Estados Unidos
7.
J Org Chem ; 86(21): 15085-15095, 2021 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-34641678

RESUMO

1H NMR spectroscopy is a powerful tool for the conformational analysis of ortho-phenylene foldamers in solution. However, as o-phenylenes are integrated into ever more complex systems, we are reaching the limits of what can be analyzed by 1H- and 13C-based NMR techniques. Here, we explore fluorine labeling of o-phenylene oligomers for analysis by 19F NMR spectroscopy. Two series of fluorinated oligomers have been synthesized. Optimization of monomers for Suzuki coupling enables an efficient stepwise oligomer synthesis. The oligomers all adopt well-folded geometries in solution, as determined by 1H NMR spectroscopy and X-ray crystallography. 19F NMR experiments complement these methods well. The resolved singlets of one-dimensional 19F{1H} spectra are very useful for determining relative conformer populations. The additional information from two-dimensional 19F NMR spectra is also clearly valuable when making 1H assignments. The comparison of 19F isotropic shielding predictions to experimental chemical shifts is not, however, currently sufficient by itself to establish o-phenylene geometries.


Assuntos
Fluoretos , Flúor , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Conformação Molecular
8.
Bioorg Med Chem ; 40: 116183, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33965839

RESUMO

In an effort to probe the biophysical mechanisms of inhibition for ten previously-reported inhibitors of metallo-ß-lactamases (MBL) with MBL IMP-1, equilibrium dialysis, metal analyses coupled with atomic absorption spectroscopy (AAS), native state mass spectrometry (native MS), and ultraviolet-visible spectrophotometry (UV-VIS) were used. 6-(1H-tetrazol-5-yl) picolinic acid (1T5PA), ANT431, D/l-captopril, thiorphan, and tiopronin were shown to form IMP-1/Zn(II)/inhibitor ternary complexes, while dipicolinic acid (DPA) and 4-(3-aminophenyl)pyridine-2,6-dicarboxylic acid (3AP-DPA) stripped some metal from the active site of IMP but also formed ternary complexes. DPA and 3AP-DPA stripped less metal from IMP-1 than from VIM-2 but stripped more metal from IMP-1 than from NDM-1. In contrast to a previous report, pterostilbene does not appear to bind to IMP-1 under our conditions. These results, along with previous studies, demonstrate similar mechanisms of inhibition toward different MBLs for different MBL inhibitors.


Assuntos
Ácidos Dicarboxílicos/farmacologia , Inibidores Enzimáticos/farmacologia , Compostos de Sulfidrila/farmacologia , Sulfetos/farmacologia , beta-Lactamases/metabolismo , Ácidos Dicarboxílicos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Espectrometria de Massas , Estrutura Molecular , Pseudomonas aeruginosa/enzimologia , Serratia marcescens/enzimologia , Espectrofotometria Atômica , Espectrofotometria Ultravioleta , Relação Estrutura-Atividade , Compostos de Sulfidrila/química , Sulfetos/química
9.
J Clin Ultrasound ; 49(1): 56-58, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32935863

RESUMO

We report the case of a 71-year-old male with Crohn's disease, shortness of breath, and chest pain that highlights cardiac involvement in inflammatory bowel disease and the role of point-of-care ultrasonography using an alternate cardiac ultrasound window in making the diagnosis of Crohn's pericarditis. The role of ultrasonography in diagnosis and management of inflammatory bowel disease focuses primarily on intestinal pathology. Cardiac involvement is a rare but clinically impactful extraintestinal manifestation, the diagnosis of which benefits from ultrasonography if the clinician performing and interpreting the exam is aware of the possibility and understands the potential value of whole-body ultrasonography as part of a physical exam.


Assuntos
Doença de Crohn/diagnóstico , Ecocardiografia/métodos , Pericardite/diagnóstico , Sistemas Automatizados de Assistência Junto ao Leito , Idoso , Doença de Crohn/complicações , Humanos , Masculino , Pericardite/etiologia
10.
Crit Care Med ; 48(2): 151-157, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31939782

RESUMO

OBJECTIVES: The study goal was to concurrently evaluate agreement of a 9-point pulmonary ultrasound protocol and portable chest radiograph with chest CT for localization of pathology to the correct lung and also to specific anatomic lobes among a diverse group of intubated patients with acute respiratory failure. DESIGN: Prospective cohort study. SETTING: Medical, surgical, and neurologic ICUs at a 670-bed urban teaching hospital. PATIENTS: Intubated adults with acute respiratory failure having chest CT and portable chest radiograph performed within 24 hours of intubation. INTERVENTIONS: A 9-point pulmonary ultrasound examination performed at the time of intubation. MEASUREMENTS AND MAIN RESULTS: Sixty-seven patients had pulmonary ultrasound, portable chest radiograph, and chest CT performed within 24 hours of intubation. Overall agreement of pulmonary ultrasound and portable chest radiograph findings with correlating lobe ("lobe-specific" agreement) on CT was 87% versus 62% (p < 0.001), respectively. Relaxing the agreement definition to a matching CT finding being present anywhere within the correct lung ("lung-specific" agreement), not necessarily the specific mapped lobe, showed improved agreement for both pulmonary ultrasound and portable chest radiograph respectively (right lung: 92.5% vs 65.7%; p < 0.001 and left lung: 83.6% vs 71.6%; p = 0.097). The highest lobe-specific agreement was for the finding of atelectasis/consolidation for both pulmonary ultrasound and portable chest radiograph (96% and 73%, respectively). The lowest lobe-specific agreement for pulmonary ultrasound was normal lung (79%) and interstitial process for portable chest radiograph (29%). Lobe-specific agreement differed most between pulmonary ultrasound and portable chest radiograph for interstitial findings (86% vs 29%, respectively). Pulmonary ultrasound had the lowest agreement with CT for findings in the left lower lobe (82.1%). Pleural effusion agreement also differed between pulmonary ultrasound and portable chest radiograph (right: 99% vs 87%; p = 0.009 and left: 99% vs 85%; p = 0.004). CONCLUSIONS: A clinical, 9-point pulmonary ultrasound protocol strongly agreed with specific CT findings when analyzed by both lung- and lobe-specific location among a diverse population of mechanically ventilated patients with acute respiratory failure; in this regard, pulmonary ultrasound significantly outperformed portable chest radiograph.


Assuntos
Pulmão/diagnóstico por imagem , Pulmão/patologia , Síndrome do Desconforto Respiratório/diagnóstico por imagem , Síndrome do Desconforto Respiratório/patologia , Idoso , Idoso de 80 Anos ou mais , Estado Terminal , Feminino , Hospitais de Ensino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Radiografia Torácica/métodos , Radiografia Torácica/normas , Respiração Artificial , Síndrome do Desconforto Respiratório/mortalidade , Tomografia Computadorizada por Raios X/métodos , Tomografia Computadorizada por Raios X/normas , Ultrassonografia/métodos , Ultrassonografia/normas
11.
J Biol Inorg Chem ; 25(5): 717-727, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32500360

RESUMO

Due to the rapid proliferation of antibiotic-resistant pathogenic bacteria, known as carbapenem-resistant enterobacteriaceae, the efficacy of ß-lactam antibiotics is threatened. ß-lactam antibiotics constitute over 50% of the available antibiotic arsenal. Recent efforts have been focused on developing inhibitors to these enzymes. In an effort to understand the mechanism of inhibition(s) of four FDA-approved thiol-containing drugs that were previously reported to be inhibitors of New Delhi metallo-ß-lactamase (NDM-1), various biochemical and spectroscopic techniques were used. Isothermal titration calorimetry demonstrated the binding affinity to NDM-1 corresponds to the reported IC50 values of the inhibitors. Equilibrium dialyses and metal analyses demonstrated that all of these inhibitors formed ternary complexes with ZnZn-NDM-1. Spectroscopic studies on CoCo-NDM-1 revealed two distinct binding modes for the thiol-containing compounds. These findings validate the need to further investigate the mechanism of inhibition of MBL inhibitors. Further research to identify inhibition capabilities beyond reported IC50 values is necessary for understanding the binding modes of these identified compounds and to provide the necessary foundation for developing clinically relevant MBL inhibitors.


Assuntos
Compostos de Sulfidrila/farmacologia , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Compostos de Sulfidrila/química , Inibidores de beta-Lactamases/química , beta-Lactamases/genética
12.
J Biol Chem ; 293(32): 12606-12618, 2018 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-29909397

RESUMO

Infections by carbapenem-resistant Enterobacteriaceae are difficult to manage owing to broad antibiotic resistance profiles and because of the inability of clinically used ß-lactamase inhibitors to counter the activity of metallo-ß-lactamases often harbored by these pathogens. Of particular importance is New Delhi metallo-ß-lactamase (NDM), which requires a di-nuclear zinc ion cluster for catalytic activity. Here, we compare the structures and functions of clinical NDM variants 1-17. The impact of NDM variants on structure is probed by comparing melting temperature and refolding efficiency and also by spectroscopy (UV-visible, 1H NMR, and EPR) of di-cobalt metalloforms. The impact of NDM variants on function is probed by determining the minimum inhibitory concentrations of various antibiotics, pre-steady-state and steady-state kinetics, inhibitor binding, and zinc dependence of resistance and activity. We observed only minor differences among the fully loaded di-zinc enzymes, but most NDM variants had more distinguishable selective advantages in experiments that mimicked zinc scarcity imposed by typical host defenses. Most NDM variants exhibited improved thermostability (up to ∼10 °C increased Tm ) and improved zinc affinity (up to ∼10-fold decreased Kd, Zn2). We also provide first evidence that some NDM variants have evolved the ability to function as mono-zinc enzymes with high catalytic efficiency (NDM-15, ampicillin: kcat/Km = 5 × 106 m-1 s-1). These findings reveal the molecular mechanisms that NDM variants have evolved to overcome the combined selective pressures of ß-lactam antibiotics and zinc deprivation.


Assuntos
Mutação , Zinco/farmacologia , beta-Lactamases/química , beta-Lactamases/metabolismo , Antibacterianos/metabolismo , Cristalografia por Raios X , Estabilidade Enzimática , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Proteica , Inibidores de beta-Lactamases/metabolismo , beta-Lactamases/genética , beta-Lactamases/isolamento & purificação
13.
J Am Chem Soc ; 141(7): 3153-3159, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30678456

RESUMO

Carbon-carbon bond-forming reductive elimination from elusive organocopper(III) complexes has been considered the key step in many copper-catalyzed and organocuprate reactions. However, organocopper(III) complexes with well-defined structures that can undergo reductive elimination are extremely rare, especially for the formation of Csp3-Csp3 bonds. We report herein a general method for the synthesis of a series of [alkyl-CuIII-(CF3)3]- complexes, the structures of which have been unequivocally characterized by NMR spectroscopy, mass spectrometry, and X-ray crystal diffraction. At elevated temperature, these complexes undergo reductive elimination following first-order kinetics, forming alkyl-CF3 products with good yields (up to 91%). Both kinetic studies and DFT calculations indicate that the reductive elimination to form Csp3-CF3 bonds proceeds through a concerted transition state, with a Δ H⧧ = 20 kcal/mol barrier.

14.
J Biol Inorg Chem ; 24(1): 31-37, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30353442

RESUMO

Co(II) substitution into the copper amine oxidases (CAOs) has been an effective tool for evaluating the mechanism of oxygen reduction in these enzymes. However, formation of hydrogen peroxide during turnover raises questions about the relevant oxidation state of the cobalt in these enzymes and, therefore, the interpretation of the activity of the metal-substituted enzyme with respect to its mechanism of action. In this study, Co(II) was incorporated into the CAO from Hansenula polymorpha (HPAO). The effect of hydrogen peroxide on the catalytic activity of cobalt-substituted HPAO was evaluated. Hydrogen peroxide, either generated during turnover or added exogenously, caused a decrease in the activity of the enzyme but did not oxidize Co(II) to Co(III). These results are in strong contrast with results from the CAO from Arthrobacter globiformis (AGAO), where hydrogen peroxide causes an increase in the activity of the enzyme as the Co(II) is oxidized to Co(III). The results of this study with HPAO support previous reports that have shown that this enzyme acts by transferring an electron directly from the reduced TPQ cofactor to dioxygen rather than passing the electron through the bound metal ion. Furthermore, these results provide additional evidence to support the idea that different CAOs use different mechanisms for catalysis.


Assuntos
Amina Oxidase (contendo Cobre)/metabolismo , Cobalto/metabolismo , Proteínas Fúngicas/metabolismo , Pichia/metabolismo , Cobre/metabolismo , Cinética , Oxirredução , Oxigênio/metabolismo , Pichia/enzimologia
15.
Chemistry ; 25(45): 10625-10632, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31066934

RESUMO

The single-molecule magnet (SMM) properties of a series of ferrocenium complexes, [Fe(η5 -C5 R5 )2 ]+ (R=Me, Bn), are reported. In the presence of an applied dc field, the slow dynamics of the magnetization in [Fe(η5 -C5 Me5 )2 ]BArF are revealed. Multireference quantum mechanical calculations show a large energy difference between the ground and first excited states, excluding the commonly invoked, thermally activated (Orbach-like) mechanism of relaxation. In contrast, a detailed analysis of the relaxation time highlights that both direct and Raman processes are responsible for the SMM properties. Similarly, the bulky ferrocenium complexes, [Fe(η5 -C5 Bn5 )2 ]BF4 and [Fe(η5 -C5 Bn5 )2 ]PF6 , also exhibit magnetization slow dynamics, however an additional relaxation process is clearly detected for these analogous systems.

16.
Biochemistry ; 57(35): 5218-5229, 2018 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-30106565

RESUMO

In an effort to evaluate whether a recently reported putative metallo-ß-lactamase (MßL) contains a novel MßL active site, SPS-1 from Sediminispirochaeta smaragdinae was overexpressed, purified, and characterized using spectroscopic and crystallographic studies. Metal analyses demonstrate that recombinant SPS-1 binds nearly 2 equiv of Zn(II), and steady-state kinetic studies show that the enzyme hydrolyzes carbapenems and certain cephalosporins but not ß-lactam substrates with bulky substituents at the 6/7 position. Spectroscopic studies of Co(II)-substituted SPS-1 suggest a novel metal center in SPS-1, with a reduced level of spin coupling between the metal ions and a novel Zn1 metal binding site. This site was confirmed with a crystal structure of the enzyme. The structure shows a Zn2 site that is similar to that in NDM-1 and other subclass B1 MßLs; however, the Zn1 metal ion is coordinated by two histidine residues and a water molecule, which is held in position by a hydrogen bond network. The Zn1 metal is displaced nearly 1 Å from the position reported in other MßLs. The structure also shows extended helices above the active site, which create a binding pocket that precludes the binding of substrates with large, bulky substituents at the 6/7 position of ß-lactam antibiotics. This study reveals a novel metal binding site in MßLs and suggests that the targeting of metal binding sites in MßLs with inhibitors is now more challenging with the identification of this new MßL.


Assuntos
Spirochaeta/enzimologia , Zinco/metabolismo , beta-Lactamases/metabolismo , beta-Lactamas/metabolismo , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Cinética , Modelos Moleculares , Filogenia , Conformação Proteica , Zinco/química , beta-Lactamases/química , beta-Lactamas/química
17.
Chemistry ; 24(45): 11559-11563, 2018 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-29905985

RESUMO

Trifluoromethyl-containing compounds play a significant role in medicinal chemistry, materials and fine chemistry. Although direct C-H trifluoromethylation has been achieved on Csp2 -H bonds, direct conversion of Csp3 -H bonds to Csp3 -CF3 remains challenging. We report herein an efficient protocol for the selective trifluoromethylation of benzylic C-H bonds. This process is mediated by a combination CuIII -CF3 species and persulfate salts. A wide range of methylarenes can be selectively trifluoromethylated at the benzylic positions. A combination of experimental and theoretical mechanistic studies suggests that the reaction involves a radical intermediate and a CuIII -CF3 species as the CF3 transfer reagent.

18.
Inorg Chem ; 57(1): 187-203, 2018 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-29235857

RESUMO

Herein, we report the synthesis and characterization of two dinuclear FeIIIZnII complexes [FeIIIZnIILP1] (1) and [FeIIIZnIILP2] (2), in which LP1 and LP2 are conjugated systems containing one and two pyrene groups, respectively, connected via the diamine -HN(CH2)4NH- spacer to the well-known N5O2-donor H2L ligand (H2L = 2-bis{[(2-pyridylmethyl)aminomethyl]-6-[(2-hydroxybenzyl)(2-pyridylmethyl)]aminomethyl}-4-methylphenol). The complex [FeIIIZnIIL1] (3), in which H2L was modified to H2L1, with a carbonyl group attached to the terminal phenol group, was included in this study for comparison purposes.1 Both complexes 1 and 2 were satisfactorily characterized in the solid state and in solution. Extended X-ray absorption fine structure data for 1 and 3 in an acetonitrile solution show that the multiply bridged structure seen in the solid state of 3 is retained in solution. Potentiometric and UV-vis titration of 1 and 2 show that electrostatic interaction between the protonated amino groups and coordinated water molecules significantly decreases the pKa of the iron(III)-bound water compared to those of 3. On the other hand, catalytic activity studies using 1 and 2 in the hydrolysis of the activated substrate bis(2,4-dinitrophenyl)phosphate (BDNPP) resulted in a significant increase in the association of the substrate (Kass ≅ 1/KM) compared to that of 3 because of electrostatic and hydrophobic interactions between BDNPP and the side-chain diaminopyrene of the ligands H2LP1 and H2LP2. In addition, the introduction of the pyrene motifs in 1 and 2 enhanced their activity toward DNA and as effective antitumor drugs, although the biochemical mechanism of the latter effect is currently under investigation. These complexes represent interesting examples of how to promote an increase in the activity of traditional artificial metal nucleases by introducing second-coordination-sphere effects.


Assuntos
Antineoplásicos/farmacologia , Biomimética , DNA/efeitos dos fármacos , Compostos Férricos/farmacologia , Hidrolases/metabolismo , Compostos Organometálicos/farmacologia , Zinco/farmacologia , Antineoplásicos/química , Antineoplásicos/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Clivagem do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Férricos/química , Compostos Férricos/metabolismo , Humanos , Hidrolases/química , Ligantes , Modelos Moleculares , Conformação Molecular , Compostos Organometálicos/química , Compostos Organometálicos/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Zinco/química , Zinco/metabolismo
20.
South Med J ; 111(7): 411-417, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29978226

RESUMO

Outpatient diagnosis of acute bacterial sinusitis, using only traditional physical examination and clinical criteria, results in the overuse of antibiotics in patients with upper respiratory complaints. Point-of-care maxillary sinus ultrasound is easy to learn and quick to perform in a primary care clinic. The technique can reduce antibiotic prescribing by reassuring both patients and providers of the absence of fluid in the sinus, the hallmark of maxillary sinusitis. A review of the literature, description of technique, and results of sinus ultrasound implementation in a large internal medicine clinic are included.


Assuntos
Seio Maxilar/diagnóstico por imagem , Sinusite Maxilar/diagnóstico por imagem , Sistemas Automatizados de Assistência Junto ao Leito , Ultrassonografia/métodos , Humanos , Medicina Interna , Tomografia Computadorizada por Raios X
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