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1.
Anaesthesia ; 77(4): 449-455, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35166373

RESUMO

High gastric residual volume and low pH are associated with increased mortality following pulmonary aspiration in animal studies. The use of pre-operative oral paracetamol has not been investigated in younger children and infants in the context of a prescriptive 1-h clear fluid fast aimed at reducing the risk of pulmonary aspiration while improving patient experience. Children aged 1 month up to a weight of 25 kg and scheduled for elective surgery were randomly allocated to receive a prescribed 3.6 ml.kg-1 drink of water alone (water group) or 3 ml.kg-1 water and oral Infant Calpol® syrup (24 mg.ml-1 concentration, equivalent volume 0.6 ml.kg-1 , paracetamol group) 1 h before the induction of anaesthesia. Following induction, a nasogastric tube was used to aspirate gastric contents and the volume and pH were recorded. Ninety-seven children, median (IQR [range]) age 24 (12-45 [1-96]) months and weight 12.4 (9.7-16.0 [2.9-27.0]) kg, were analysed. Median time from drink to induction was 54 (45-60 [21-113]) min. There was no significant difference in gastric residual volume (p = 1) or pH (p = 0.99) between the water and the paracetamol groups. Sub-group analysis revealed no significant difference in gastric residual volume or pH for 29 children who weighed < 10 kg compared with > 10 kg. Using a prescriptive fluid regime of 3 ml.kg-1 of water, the addition of oral paracetamol syrup did not significantly alter gastric residual volume or pH in the context of a 1-h fast in infants and young children.


Assuntos
Acetaminofen , Jejum , Pré-Escolar , Humanos , Concentração de Íons de Hidrogênio , Volume Residual , Água
2.
Hum Reprod ; 36(2): 367-380, 2021 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-33355349

RESUMO

STUDY QUESTION: Are there phase-specific changes in the early secretory (ES) phase human tubal lavage proteome that can inform and potentially optimize IVF culture media? SUMMARY ANSWER: The human tubal lavage proteome during the ES phase relative to the menstrual phase reveals substantial differential protein abundance in pathways such as glycolysis, redox homeostasis and activation of 14-3-3 zeta-mediated signaling. WHAT IS KNOWN ALREADY: The Fallopian tube is uniquely suited to the development of the preimplantation embryo as it transits the tube during the ES phase of the menstrual cycle. Euploid cleavage-stage embryo arrest may reflect incomplete recapitulation of in-vivo conditions by current media formulations. STUDY DESIGN, SIZE, DURATION: Proteome-wide analysis of distal tubal lavage specimens collected from 26 healthy women undergoing open microtubal anastomosis surgery from January 2013 to January 2018 was performed. Specimens were grouped by menstrual cycle phase in order to analyze phase-specific differences in protein abundance. For the murine embryo assay, single-cell embryos (N = 482) were collected from superovulated wild type C57BL/6 female mice and cultured in microdrops over 5 days for the assessment of blastocyst development. PARTICIPANTS/MATERIALS, SETTING, METHODS: Human tubal lavage specimens were processed for label-free mass spectrometry. Reported menstrual cycle day was confirmed by measuring serum hormones. Key protein targets in the ES phase were validated via immunoblot. The ES phase-specific increase in 14-3-3 zeta protein was confirmed via ELISA of conditioned media obtained from primary human Fallopian tube epithelial cell culture. A murine embryo assay was performed to investigate the impact of graduated concentrations of 14-3-3 zeta on the blastocyst development rate. MAIN RESULTS AND THE ROLE OF CHANCE: Comparison of the ES and menstrual phase human tubal lavage proteomes revealed 74 differentially expressed proteins with enrichment of pathways and biological processes involved in the regulation of carbohydrate metabolism, oxidative stress and cell survival. The adapter-regulator protein 14-3-3 zeta was among the most significantly increased in the ES phase. Supplementation of embryo culture media with 14-3-3 zeta at concentrations tested did not significantly improve the murine blastocyst development. LIMITATIONS, REASONS FOR CAUTION: Although select associations were recapitulated in the conditioned media from sex steroid exposed primary human tubal epithelial cells, cell culture represents an in-vitro approximation. Changes to embryo culture media, such as protein supplementation, must undergo rigorous preclinical safety testing prior to adoption for human use. WIDER IMPLICATIONS OF THE FINDINGS: This study represents the first description of the human Fallopian tube lavage proteome across the menstrual cycle, revealing a unique proteomic signature during the ES phase. Although supplementation of culture media with 14-3-3 zeta at appropriate concentrations showed no significant impact on the murine blastocyst development rate, other biologically plausible candidate proteins for individual or high throughput testing strategies are identified. STUDY FUNDING/COMPETING INTEREST(S): This work was funded in part by an Army Medical Department Advanced Medical Technology Initiative grant from the United States Army Medical Research and Materiel Command's Telemedicine and Advanced Technology Research Center. There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.


Assuntos
Tubas Uterinas , Proteoma , Animais , Blastocisto , Técnicas de Cultura Embrionária , Feminino , Fertilização in vitro , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Proteômica , Irrigação Terapêutica
3.
J Nanosci Nanotechnol ; 12(11): 8431-6, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23421226

RESUMO

Targeted drug delivery has been one of the most important biomedical applications for magnetic particles. Such applications require magnetic particles to have functionalized surfaces/surface coatings that facilitate their incorporation into a polymer matrix to produce a polymer composite. In this paper, nanocrystalline nickel ferrite particles with an oleic acid surface coating were synthesized using a non-hydrolytic sol-gel method and incorporated into a biodegradable polymer matrix, poly(D,L-lactide) PLA prepared using a double emulsion method. As-synthesized nickel ferrite particles had a multi-crystalline structure with chemically adsorbed oleic acid on their surface. After forming the PLA composite, nickel ferrite particles were encapsulated in PLA microspheres. At low nickel ferrite concentrations, composites showed very similar surface charges to that of PLA. The composites were magnetically responsive and increasing the nickel ferrite concentration was found to increase magnetization of the composite.


Assuntos
Implantes Absorvíveis , Biopolímeros/química , Cristalização/métodos , Compostos Férricos/síntese química , Separação Imunomagnética/métodos , Nanocápsulas/química , Poliésteres/química , Hidrólise , Substâncias Macromoleculares/química , Teste de Materiais , Conformação Molecular , Nanocápsulas/ultraestrutura , Níquel , Tamanho da Partícula , Transição de Fase , Propriedades de Superfície
4.
J Nanosci Nanotechnol ; 11(3): 2607-10, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21449436

RESUMO

In this work, effects of exchange coupling of soft magnetic layer on switching field and magnetization reversal behaviour of CoPt-SiO2(soft)/CoPt-SiO2(hard) exchange coupled media were investigated. With increasing the thickness of the soft layer, both the coercivity and magnetization squareness of composite media decreased. Soft layer thickness 4 nm and below was more effective to significantly reduce the switching field than that above 4 nm. More incoherent switching behavior was observed with increasing soft layer thickness.


Assuntos
Cobalto/química , Magnetismo , Nanoestruturas/química , Nanoestruturas/ultraestrutura , Platina/química , Teste de Materiais , Tamanho da Partícula
5.
AJNR Am J Neuroradiol ; 42(6): 1144-1150, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33832956

RESUMO

BACKGROUND AND PURPOSE: SWI hypointense cerebral lesions have been reported in adults with the inherited cerebellar neurodegenerative disorder ataxia telangiectasia. This study aims to establish the prevalence, age-dependency, and spatial distribution of these lesions in children and young people with ataxia telangiectasia. MATERIALS AND METHODS: Participants with classic ataxia telangiectasia and matched controls underwent SWI acquisition at 3T at 1 or 2 time points. SWI hypointense lesions were manually labeled according to the Microbleed Anatomical Rating Scale. Differences in prevalence of lesion number between groups with ataxia telangiectasia and without ataxia telangiectasia were tested with the Fisher exact test, and differences in age between participants with ataxia telangiectasia with and without lesions were tested using independent samples Mann-Whitney U test. The relationship between age and lesion number was modeled as an exponential function. RESULTS: Analyzable SWI datasets from 17 participants with ataxia telangiectasia (with median age at first scan of 12.4 years; range, 4.6-20.2 years; 8 [47%] were female) and 22 matched healthy controls showed prevalence of SWI hypointense lesions in 41% of participants with ataxia telangiectasia and 0% in controls (P = .001, Fisher exact test). Lesions were exclusively supratentorial and predominantly lobar. Participants with ataxia telangiectasia with SWI hypointense lesions were older than those without (median age 5.2 years versus 9.3 years, U = 10.5, P = .014). An exponential curve described the relationship between age and lesion number (R 2 = 0.67). CONCLUSIONS: SWI hypointense lesions are common in children and young people with ataxia telangiectasia, accumulating from 12 years of age onward. In contrast to cerebellar-dominant neurodegeneration in ataxia telangiectasia, SWI hypointense lesions were exclusively supratentorial. Further investigation is needed to establish the clinical relevance of these imaging-detected lesions.


Assuntos
Ataxia Telangiectasia , Ataxia Telangiectasia/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Criança , Pré-Escolar , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino
6.
Science ; 235(4786): 295-9, 1987 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-17750384

RESUMO

Before 1978 in China, the economic institutions for agriculture and industry operated essentially under a centrally planned system. The reasons for a change toward a more market-oriented economy and the key elements of economic reform are discussed. Today the major issues being deliberated by the leading economic officials include reform of the price system, the administrative structure of state-owned enterprises, the banking system and macroeconomic control mechanisms, and foreign trade and investment.

7.
Science ; 251(5001): 1590-2, 1991 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-17793142

RESUMO

An unusual distribution of particle sizes has been observed following the formation of molybdenum particles by argon ion sputtering. Many of the molybdenum particles produced by sputtering at the threshold pressure for particle formation in the vapor appear to be single crystalline cubes. There are two prominent peaks in the edge length distribution of the cubes, one centered at 4.8 nanometers with a halfwidth of approximately 1.3 nanometers and the other at 17.5 nanometers. The peak for the larger cubes is approximately square and has a total width of 7.0 nanometers. Evidence is presented that the larger cubes are formed by a 3 by 3 by 3 self-arrangement of the smaller cubes, which contain approximately 7000 atoms. Self-arrangement in inorganic structures is normally only observed when the building blocks are atoms, molecules, or clusters of less than 100 atoms.

8.
Nat Commun ; 9(1): 3319, 2018 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-30127419

RESUMO

Out-of-plane ferroelectricity with a high transition temperature in nanometer-scale films is required to miniaturize electronic devices. Direct visualization of stable ferroelectric polarization and its switching behavior in atomically thick films is critical for achieving this goal. Here, ferroelectric order at room temperature in the two-dimensional limit is demonstrated in tetragonal BiFeO3 ultrathin films. Using aberration-corrected scanning transmission electron microscopy, we directly observed robust out-of-plane spontaneous polarization in one-unit-cell-thick BiFeO3 films. High-resolution piezoresponse force microscopy measurements show that the polarization is stable and switchable, whereas a tunneling electroresistance effect of up to 370% is achieved in BiFeO3 films. Based on first-principles calculations and Kelvin probe force microscopy measurements, we explain the mechanism of polarization stabilization by the ionic displacements in oxide electrode and the surface charges. Our results indicate that critical thickness for ferroelectricity in the BiFeO3 film is virtually absent, making it a promising candidate for high-density nonvolatile memories.

9.
J Nanosci Nanotechnol ; 7(8): 2790-4, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17685299

RESUMO

This paper reports the synthesis of high quality LiYF4, BaYF5, and NaLaF4 nanocrystals by high-temperature co-decomposition of precursors in organic solvents. Their bulk counterparts have long been used as efficient luminescent hosts for various applications including lasers, upconversion fluorescence, and quantum cutters. The particles were characterized using TEM, XRD, dynamic light scattering (DLS), and fluorescence spectrometry. Trifluoroacetic acid (CF3COOH) and the reaction temperature were crucial for the formation of NaLaF4 and LiYF4 nanoparticles. NaLaF4 was not formed without using CF3COOH, only LaF3 and NaF mixture was formed. NaLaF4 nanoparticles were obtained only when CF3COOH was added in the reaction solution and the temperature was > or =330 degrees C. For the synthesis of LiYF4,, in the absence of CF3COOH in the reaction, a mixture of YOF and LiYF4 nanoparticles was formed. Pure LiYF4 particles were obtained only until CF3COOH was added in the reaction at 340 degrees C or above. The nanoparticles were easily dispersed in organic solvents include hexane, toluene, and chloroform and formed transparent colloidal solutions. The ease of doping of these as-synthesized host nanoparticles for designed optical properties was assessed. The LiYF4, BaYF5, and NaLaF4 nanoparticles, co-doped with 20% Ytterbium (Yb) and 2% Erbium (Er), showed bright upconversion fluorescence upon 980 nm NIR excitation, confirming the high quality of as-synthesized nanoparticles. These nanoparticles are potential candidates for nano-optical devices, thin films, telecommunication, and bio-probes.


Assuntos
Nanotecnologia/métodos , Compostos de Bário/química , Química Orgânica/métodos , Cristalização , Eletroquímica/métodos , Fluoretos/química , Lantânio/química , Compostos de Lítio/química , Nanopartículas Metálicas/química , Microscopia Eletrônica de Transmissão , Modelos Químicos , Nanopartículas/química , Sódio/química , Solventes/química , Temperatura , Difração de Raios X
10.
Ann Urol (Paris) ; 41(1): 31-6, 2007 Feb.
Artigo em Francês | MEDLINE | ID: mdl-17338498

RESUMO

Transabdominal sacrocolpopexy offers an excellent definitive treatment option for patients with high grade vaginal vault prolapse with long-term success rates ranging from 93-99%. However, because it is a transabdominal procedure it is associated with increased morbidity compared with vaginal repairs. We describe a novel minimally invasive technique of vaginal vault prolapse repair and present out initial experience. The surgical technique involves placement of five laparoscopic ports: three for the Da Vinci robot and two for the assistant. A polypropylene mesh is then attached to the sacral promontory and to the vaginal apex using Gortex sutures. At the end of the case, the mesh material is the covered by the peritoneum. We also present our initial experience with this technique in 18 consecutive patients. The analysis focused on complications, urinary continence, patient satisfaction, and morbidity. Follow-up was conducted by provider-patient interview. Twenty-five patients underwent a robotic-assisted laparoscopic sacrocolpopexy at our institution in the past 24 months for severe symptomatic vaginal vault prolapse. 10/25 (40%) underwent a concomitant anti-incontinence procedure. Mean follow-up was 5. (1-12) months and mean age was 66 (47-82) years. Mean total operative time was 3.2 (2.25-4.75) hours. One patient had to be converted to an open procedure secondary to unfavorable anatomy. All but one patient were discharged from the hospital after an overnight stay; one patient left on postoperative day #2. Complications were limited to mild port site infections in two patients, which resolved with oral antibiotic therapy. One patient developed recurrent grade 3 rectocele, but had no evidence of cystocele or enterocele. We present a novel technique for vaginal vault prolapse repair that combines the advantages of open sacrocolpopexy with the decreased morbidity and improved cosmesis of laparoscopic surgery. It is associated with decreased hospital stay, low complication and conversion rates, and high patient satisfaction. While our early experience is encouraging, long-term data is needed to confirm these findings and establish longevity of the repair.


Assuntos
Colposcopia/métodos , Laparoscopia/métodos , Cirurgia Assistida por Computador , Prolapso Uterino/cirurgia , Feminino , Humanos , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Minimamente Invasivos , Robótica , Técnicas de Sutura
11.
J Nanosci Nanotechnol ; 6(7): 2135-40, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17025138

RESUMO

Monodisperse magnetic nanoparticles are of great scientific and technical interests. This paper reports a single-step synthesis of monodisperse magnetite nanoparticles with particle size of 8 nm. Iron/maghaemite core/shell nanoparticles with particle size of 11 nm were obtained by reducing the concentration of oleylamine. TEM and in-situ FTIR results suggested that iron-oleylamine intermediate was generated in-situ and decomposed at higher temperature. Oleylamine was also found on the surface of nanoparticles, indicating its role as capping agent which provided steric protection of as-synthesized nanoparticles from agglomeration. Both magnetite and iron/maghaemite core/shell nanoparticles were superparamagnetic at room temperature with a blocking temperature at 80 K and 67 K, respectively.


Assuntos
Aminas/química , Cristalização/métodos , Compostos Férricos/química , Ferro/química , Magnetismo , Nanoestruturas/química , Nanoestruturas/ultraestrutura , Adsorção , Substâncias Macromoleculares/química , Teste de Materiais , Conformação Molecular , Nanotecnologia/métodos , Tamanho da Partícula , Propriedades de Superfície
12.
J Nanosci Nanotechnol ; 6(4): 1024-30, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16736761

RESUMO

The nanostructured FeNi thin films were deposited on a polycrystalline Cu substrate by reducing constituent metal salts in refluxing ethylene glycol. The effect of substrate position was investigated. During deposition, the substrate was subject to one of the following processes: (a) complete immersion in solution, (b) repeated immersion followed by suspension above solution (denoted as quenching), and (c) suspension above the solution. Compared to the conventional polyol synthesis of FeNi where Fe concentration could not exceed 30 at%, the quenching process dramatically increased Fe at% to above 40%. Complete suspension of substrate above the solution resulted in Fe-rich films where Fe at% >90%. The microhardness, adhesion, and magnetic properties of deposited films showed a strong dependence on the long-range and short-range order of the film, which, in turn, depended on the substrate position. Quenched films with ordered local Ni environment and higher crystallinity had the highest Vickers hardness, best adhesion to substrate, and largest saturation magnetization compared to those deposited on substrates placed in other positions. The oxidation of Fe occurring in the vapor deposition significantly affected the film properties.


Assuntos
Coloides/química , Cristalização/métodos , Compostos de Ferro/química , Nanoestruturas/química , Nanoestruturas/ultraestrutura , Níquel/química , Polímeros/química , Eletrólise , Teste de Materiais , Membranas Artificiais , Conformação Molecular , Tamanho da Partícula , Propriedades de Superfície
13.
Sci Rep ; 6: 34637, 2016 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-27686046

RESUMO

The microstructure and magnetic properties of the FePt films grown on large mismatched ZrN (15.7%) intermediate layer were investigated. With using ZrN intermediate layer, FePt 10 nm films exhibited (001) texture except for some weaker FePt (110) texture. Good epitaxial relationships of FePt (001) <100>//ZrN (001) <100>//TiN (001) <100> among FePt and ZrN/TiN were revealed from the transmission electron microscopy (TEM) results. As compared with TiN intermediate layer, although FePt-SiO2-C films grown on ZrN/TiN intermediate layer showed isotropic magnetic properties, the large interfacial energy and lattice mismatch between FePt and ZrN would lead to form columnar structural FePt films with smaller grain size and improved isolation. By doping ZrN into the TiN layer, solid solution of ZrTiN was formed and the lattice constant is increased comparing with TiN and decreased comparing with ZrN. Moreover, FePt-SiO2-C films grown on TiN 2 nm-20 vol.% ZrN/TiN 3 nm intermediate layer showed an improved perpendicular magnetic anisotropy. Simultaneously, columnar structure with smaller grain size retained.

14.
Biomaterials ; 26(29): 5818-26, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15949547

RESUMO

The safety and toxicity of nanoparticles are of growing concern despite their significant scientific interests and promising potentials in many applications. The properties of nanoparticles depend not only on the size but also the structure, microstructure and surface coating. These in turn are controlled by the synthesis and processing conditions. The dependence of cytotoxicity on particle size and on the presence of oleic acid as surfactant on nickel ferrite particles were investigated in vitro using the Neuro-2A cell line as a model. For nickel ferrite particles without oleic acid prepared by ball milling, cytotoxicity was independent of particle size within the given mass concentrations and surface areas accessible to the cells. For nickel ferrite particles coated with oleic acid prepared by the polyol method, the cytotoxicity significantly increased when one or two layers of oleic acid were deposited. Large particles (150+/-50 nm diameter) showed a higher cytotoxicity than smaller particles (10+/-3 nm diameter).


Assuntos
Materiais Biocompatíveis/química , Materiais Revestidos Biocompatíveis/química , Compostos Férricos/química , Nanotecnologia/métodos , Níquel/química , Animais , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Relação Dose-Resposta a Droga , Teste de Materiais , Camundongos , Micelas , Microscopia Eletrônica de Transmissão , Ácido Oleico/química , Tamanho da Partícula , Propriedades de Superfície , Difração de Raios X
15.
Minerva Urol Nefrol ; 57(1): 17-22, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15944518

RESUMO

Ureteroscopic treatment of upper urinary tract calculi is continuously evolving. Initial reports were limited to the treatment of distal ureteral stones. These cases had mixed success, and compared to modern ureteroscopy, had significant associated morbidity. The entire urinary tract can now be safely accessed via ureteroscopy almost always. Improvements in ureteroscope technology have certainly made this possible. These advances include smaller steerable scopes and sharper optics and video. The enhanced view of the upper urinary tract in combination with advances in lithotripsy, in particular, the holmium laser, has resulted in increased treatment success and reduced procedure related morbidity. This review describes the advances in ureteroscopic technology and provides data regarding treatment success and associated complications.


Assuntos
Cálculos Renais/terapia , Cálculos Ureterais/terapia , Ureteroscopia , Humanos
16.
Arch Neurol ; 41(10): 1084-5, 1984 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-6477217

RESUMO

We created "bloody taps" by adding homologous blood to acellular samples of CSF and counted the RBCs and WBCs at specific time intervals. After two hours at room temperature (22 degrees C), 40% of the WBCs in the traumatic tap had lysed. At 4 degrees C, 15% of the cells lysed in the same period of time. After five hours at 22 degrees C, 53% of the WBCs had lysed, while refrigeration reduced this figure to 31%. The clinical implications of these data are clear. If a sample of CSF is not promptly refrigerated and analyzed, WBC lysis will result in a false impression of the number of WBCs that are present. This lysis of WBCs reduces the reliability of the corrective formula that uses CSF and blood RBC and WBC counts to estimate the number of WBCs in CSF that are attributable to contamination with blood.


Assuntos
Líquido Cefalorraquidiano/análise , Contagem de Eritrócitos , Contagem de Leucócitos , Punção Espinal , Sobrevivência Celular , Humanos , Temperatura
17.
J Med Chem ; 35(26): 4795-808, 1992 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-1479581

RESUMO

A series of tripeptides which contain alpha,alpha-difluorostatone residues at P1-P1' and span the S3-S1' subsites have been shown to be potent inhibitors of human leukocyte elastase (HLE). The tripeptides described contain the nonproteinogenic achiral residue N-(2,3-dihydro-1H-inden-2-yl)glycine at the P2-position. This redidue has previously been shown in the case of HLE to be a good bioisosteric replacement for L-proline. Of the peptides prepared, those which contain the alpha,alpha-difluoromethylene keton derivative of L-valine (difluorostatone) are the preferred residue at the P1-primary specificity position. Substitution at P1 by the corresponding alpha,alpha-difluoromethylene ketones of L-leucine and L-phenylalanine gives inactive compounds. Of the tripeptides described the most potent in vitro compound is ethyl N-[N-CBZ-L-valyl-N-(2,3-dihydro-1H-inden-2-yl)glycyl]- 4(S)-amino-2,2-difluoro-3-oxo-5-methylhexanoate (17B) (IC50 = 0.635 microM). It is presumed that the inhibitor 17b interacts with the S3-S1' binding regions of HLE. Additionally extended binding inhibitors were prepared which interact with the S3-S3' binding subsites of HLE. In order to effect interaction with the S1'-S3' subsites of HLE, the leaving group side of cleaved peptides, spacers based upon Gly-Gly, and those linked via the N epsilon of L-lysine were utilized. One of the most potent extended compounds (P3-P3') in vitro is methyl N6-[4(S)-[[N-[N-CBZ-L-valyl-N- (2,3-dihydro-1H-inden-2-yl)glycyl]amino]-2,2-difluoro-3-oxo-5- methylhexanoyl]-2(S)-(acetylamino)-6-aminohexanoate (24b) (IC50 = 0.057 microM). The described in vitro active inhibitors were also evaluated in hamsters in an elastase-induced pulmonary hemorrhage (EPH) model. In this model, intratracheal (it.) administration of 22c, 5 min prior to HLE challenge (10 micrograms, it.) effectively inhibited hemorrhage (94.6%) in a dose-dependent manner. The described alpha,alpha-difluoromethylene ketone inhibitors are assumed to act as transition-state analogs. The inhibition process presumably acts via hemiketal formation with the active site Ser195 of HLE, and is facilitated by the strongly electron withdrawing effect of the alpha,alpha-difluoromethylene functionality.


Assuntos
Hidrocarbonetos Fluorados/síntese química , Oligopeptídeos/síntese química , Elastase Pancreática/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Sítios de Ligação/efeitos dos fármacos , Cricetinae , Humanos , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/farmacologia , Elastase de Leucócito , Masculino , Mesocricetus , Modelos Moleculares , Dados de Sequência Molecular , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Relação Estrutura-Atividade , Perus
18.
J Med Chem ; 35(4): 641-62, 1992 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-1542092

RESUMO

A series of tripeptides possessing trifluoromethyl or aryl ketone residues at P1 were prepared and evaluated both in vitro and in vivo as potential inhibitors of human leukocyte elastase (HLE). Tripeptides containing non naturally occurring N-substituted glycine residues at the P2-position have been demonstrated to be potent in vitro inhibitors of HLE, with IC50 values in the submicromolar range. Sterically demanding substituents on the P2-nitrogen have no detrimental effect on in vitro potency. The inhibition process presumably acts via hemiketal formation with the active site Ser195 of HLE, and is facilitated by the strongly electron withdrawing trifluoromethyl functionality. Deletion of the amino acid at the P3-subsite region affords inactive compounds. Valine is the preferred residue at the P1-position, whereas the corresponding glycine, alanine, alpha,alpha-dimethylglycine, or phenylalanine analogues are all inactive. The compounds described herein all confer a high degree of in vitro specificity when tested against representative cysteine, aspartyl, metallo, and other serine proteases. One of the most potent in vitro inhibitors is (3RS)-N-[4-[[[(4-chlorophenyl)sulfonyl]amino]carbonyl]phenyl] oxomethyl]-L-valyl-N-(2,3-dihydro-1H-inden-2-yl)glycine N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]amide (20i; BI-RA-260) (IC50 = 0.084 microM). Compound 20i was also tested in hamsters in an elastase-induced pulmonary hemorrhage (EPH) model. In this model, intratracheal (it.) administration of 20i, 5 min prior to HLE challenge, effectively inhibited hemorrhage in a dose-dependent manner with an ED50 of 4.8 micrograms. The inhibitor 20i, 20 micrograms administered it. 24, 48, and 72 h prior to HLE challenge, exhibits significant inhibition against hemorrhage at all time points (97%, 64% and 49%, respectively). In a 21-day chronic model of emphysema in hamsters, 200 micrograms of HLE administered it. caused an elastase-induced emphysema in the lungs which can be quantitated histologically utilizing image analysis. In this assay, 20i significantly inhibited pulmonary lesions associated with septal destruction and increased alveolar spaces, when dosed at 20 micrograms it. 5 min prior to challenge with HLE.


Assuntos
Indenos/farmacologia , Oligopeptídeos/farmacologia , Elastase Pancreática/antagonistas & inibidores , Animais , Sítios de Ligação , Cricetinae , Enfisema/induzido quimicamente , Enfisema/prevenção & controle , Hemorragia/induzido quimicamente , Hemorragia/prevenção & controle , Humanos , Ligação de Hidrogênio , Indenos/química , Indenos/uso terapêutico , Elastase de Leucócito , Pneumopatias/induzido quimicamente , Pneumopatias/prevenção & controle , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Oligopeptídeos/síntese química , Oligopeptídeos/química , Oligopeptídeos/uso terapêutico , Elastase Pancreática/química , Relação Estrutura-Atividade , Valina/química
19.
J Med Chem ; 35(10): 1887-97, 1992 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-1375293

RESUMO

Dibenz[b,f][1,4]oxazepin-11(10H)-ones (III), pyrido[2,3-b][1,4]benzoxazepin-6(5H)-ones (IV), and pyrido[2,3-b]- [1,5]benzoxazepin-5(6H)-ones (V) were found to inhibit human immunodeficiency virus type 1 reverse transcriptase with IC50 values as low as 19 nM. A-ring substitution has a profound effect on activity, with appropriate substituents at the positions ortho and para to the lactam nitrogen providing dramatically enhanced potency. Substitution in the C-ring is generally neutral or detrimental to activity. Although a C-ring amino substituent at the position meta to the lactam carbonyl is generally beneficial to activity, it has essentially no effect when the A-ring is optimally substituted. Like the dipyridodiazepinone nevirapine, compounds III-V are specific for HIV-1 RT, exhibiting no inhibitory activity against HIV-2 RT or other virial reverse transcriptase enzymes.


Assuntos
Dibenzoxazepinas/farmacologia , HIV-1/enzimologia , Inibidores da Transcriptase Reversa , Dibenzoxazepinas/química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Proteínas Recombinantes/antagonistas & inibidores
20.
Transplantation ; 72(8): 1458-60, 2001 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-11685122

RESUMO

Laparoscopic donor nephrectomy is gaining increasing popularity because the procedure helps reduce disincentives to live kidney donation and has increased the live kidney donor pool. The left kidney of the donor is the preferred allograft because the right renal vein is shorter. Similarly, the right renal artery might be foreshortened because it hides behind the inferior vena cava during laparoscopic transperitoneal dissection. There are instances, however, in which it is not practical to take the left kidney due to vascular anomalies or asymmetric function. We describe a novel technique for obtaining greater renal arterial length utilizing laparoscopic interaortocaval dissection.


Assuntos
Transplante de Rim , Nefrectomia/métodos , Artéria Renal/cirurgia , Doadores de Tecidos , Aorta , Dissecação , Humanos , Laparoscopia , Masculino , Pessoa de Meia-Idade , Veia Cava Inferior
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