Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 36
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Aging Ment Health ; : 1-9, 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32067481

RESUMO

Objectives: Studies on service needs of people with young onset dementia have taken a problem-oriented approach with resulting recommendations focusing on reducing service shortcomings. This study aimed to build on 'what works' in real-life practice by exploring the nature of post-diagnostic support services that were perceived positively by younger people with dementia and carers.Method: Positive examples of support were gathered between August 2017 and September 2018, via a national survey. Inductive thematic analysis was employed to explore the nature of positively experienced services provided for younger people with dementia, including analysis of what was provided by positively experienced services.Results: Two hundred and thirty-three respondents reported 856 positive experiences of support. Data analysis yielded eight themes regarding the objectives of positive services: Specialist Advice and Information on Young Onset Dementia, Access to Age-appropriate Services, Interventions for Physical and Mental Health, Opportunities for Social Participation, Opportunities to Have a Voice, Enablement of Independence while Managing Risk, Enablement of Financial Stability, and Support Interventions for Family Relationships.Conclusion: The study findings (a) suggest that positive services may collectively create an enabling-protective circle that supports YPD to re-establish and maintain a positive identity in the face of young onset dementia, and (b) provide a basis from which future good practice can be developed.

3.
Aging Ment Health ; : 1-12, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31647324

RESUMO

Objectives: Personal experiences of receiving a diagnosis of young onset dementia (YOD) are often overlooked in a complex assessment process requiring substantial investigation. A thematic synthesis of published until November 2018 qualitative studies was completed to understand the lived experiences of younger people. This informed a Delphi study to learn how diagnostic processes could be improved, identify the strengths and weaknesses of current approaches, and help educate professionals concerning key issues. Method: Systematic searches of bibliographic databases were conducted involving self-reported experiences of diagnosis of YOD. Eight out of 47 papers identified were quality assessed using Walsh & Browne's criteria for methodological appraisal. Results: The review emphasises that delays in diagnosis can often be attributed to (1) delays in accessing help, and (2) misattribution of symptoms by the clinician. The impact of diagnosis is influenced by the clinician's use of language; and reactions to diagnosis varied from feelings of reassurance (in that their symptoms are now explained), to shock and destabilisation. Conclusion: This review suggests that improving the recognition of presenting symptoms, reducing diagnostic errors, and identifying the emotional needs arising from diagnosis are required to improve the diagnostic experience for younger adults, and to promote future engagement with services.

4.
BJPsych Open ; 5(3): e48, 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31530311

RESUMO

BACKGROUND: Routine psychiatric assessments tailored to older patients are often insufficient to identify the complexity of presentation in younger patients with dementia. Significant overlap between psychiatric disorders and neurodegenerative disease means that high rates of prior incorrect psychiatric diagnosis are common. Long delays to diagnosis, misdiagnosis and lack of knowledge from professionals are key concerns. No specific practice guidelines exist for diagnosis of young-onset dementia (YOD). AIMS: The review evaluates the current evidence about best practice in diagnosis to guide thorough assessment of the complex presentations of YOD with a view to upskilling professionals in the field. METHOD: A comprehensive search of the literature adopting a scoping review methodology was conducted regarding essential elements of diagnosis in YOD, over and above those in current diagnostic criteria for disease subtypes. This methodology was chosen because research in this area is sparse and not amenable to a traditional systematic review. RESULTS: The quality of evidence identified is variable with the majority provided from expert opinion and evidence is lacking on some topics. Evidence appears weighted towards diagnosis in frontotemporal dementia and its subtypes and young-onset Alzheimer's disease. CONCLUSIONS: The literature demonstrates that a clinically rigorous and systematic approach is necessary in order to avoid mis- or underdiagnosis for younger people. The advent of new disease-modifying treatments necessitates clinicians in the field to improve knowledge of new imaging techniques and genetics, with the goal of improving training and practice, and highlights the need for quality indicators and alignment of diagnostic procedures across clinical settings. DECLARATION OF INTEREST: None.

5.
Clin Linguist Phon ; : 1-19, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31291748

RESUMO

The number of children speaking more than one language as well as the number of languages spoken in Ireland has increased significantly posing a problem for timely identification of children with language disorder. The current study aims to profile performance of monolingual and multilingual children on language processing tasks: non-word repetition (NWR) and sentence repetition (SR). We used: (1) Crosslinguistic (CL) and English Language-Specific (LS) NWR and (2) SR in English, Polish and Russian. Children's socioeconomic status, language emergence, the age of exposure (AoE) to English and the percentage of English spoken at home were recorded. The study included 88 children age 5-8 attending a school in a disadvantaged area. CL and LS NWR yielded similar distribution of scores for monolinguals and multilinguals. The tasks identified small number of children who performed significantly lower than the mean while there were no significant differences between the groups. In English SR, monolinguals significantly outperformed multilinguals. Comparison of SR in English and Polish/Russian indicated that some children showed balanced performance in both of their languages while others showed marked differences performing better in either Polish/Russian or English depending on their AoE to English and percentage of English spoken at home. The pilot study suggests that CL-NWR is a promising screening tool for identifying monolingual and multilingual children with language disorder while SR provides more detailed information on children's language performance relative to their language exposure. SR task is recommended to be used only if comparable tasks are available in all of children's languages.

6.
ACS Med Chem Lett ; 10(3): 300-305, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30891130

RESUMO

We encountered a dilemma in the course of studying a series of antagonists of the G-protein coupled receptor CC chemokine receptor-2 (CCR2): compounds with polar C3 side chains exhibited good ion channel selectivity but poor oral bioavailability, whereas compounds with lipophilic C3 side chains exhibited good oral bioavailability in preclinical species but poor ion channel selectivity. Attempts to solve this through the direct modulation of physicochemical properties failed. However, the installation of a protonation-dependent conformational switching mechanism resolved the problem because it enabled a highly selective and relatively polar molecule to access a small population of a conformer with lower polar surface area and higher membrane permeability. Optimization of the overall properties in this series yielded the CCR2 antagonist BMS-741672 (7), which embodied properties suitable for study in human clinical trials.

7.
J Nurs Care Qual ; 33(2): 116-122, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29466260

RESUMO

The purpose of this quality improvement initiative was to improve oropharyngeal dysphagia screening and reduce aspiration pneumonia rates on 3 inpatient hospital medical units. Guided by a Plan-Do-Study-Act methodology, an interdisciplinary health team developed and implemented a systematic process for oropharyngeal dysphagia screening and management. As a result, use of the screening protocol increased, timely initiation of speech language pathology consultations increased, and aspiration pneumonia rates decreased.


Assuntos
Programas de Rastreamento/métodos , Equipe de Assistência ao Paciente , Pneumonia Aspirativa/prevenção & controle , Melhoria de Qualidade , Transtornos de Deglutição/diagnóstico , Humanos
8.
Mem Cognit ; 46(2): 274-284, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29119542

RESUMO

Research into the effects of cognitive aging on route navigation usually focuses on differences in learning performance. In contrast, we investigated age-related differences in route knowledge after successful route learning. One young and two groups of older adults categorized using different cut-off scores on the Montreal Cognitive Assessment (MoCA), were trained until they could correctly recall short routes. During the test phase, they were asked to recall the sequence in which landmarks were encountered (Landmark Sequence Task), the sequence of turns (Direction Sequence Task), the direction of turn at each landmark (Landmark Direction Task), and to identify the learned routes from a map perspective (Perspective Taking Task). Comparing the young participant group with the older group that scored high on the MoCA, we found effects of typical aging in learning performance and in the Direction Sequence Task. Comparing the two older groups, we found effects of early signs of atypical aging in the Landmark Direction and the Perspective Taking Tasks. We found no differences between groups in the Landmark Sequence Task. Given that participants were able to recall routes after training, these results suggest that typical and early signs of atypical aging result in differential memory deficits for aspects of route knowledge.


Assuntos
Envelhecimento Cognitivo/fisiologia , Disfunção Cognitiva/fisiopatologia , Aprendizagem Espacial/fisiologia , Memória Espacial/fisiologia , Navegação Espacial/fisiologia , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Adulto Jovem
9.
PeerJ ; 5: e3027, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28316882

RESUMO

BACKGROUND: International trade for luxury products, medicines, and tonics poses a threat to both terrestrial and marine wildlife. The demand for and consumption of gill plates (known as Peng Yu Sai, "Fish Gill of Mobulid Ray") from devil and manta rays (subfamily Mobulinae, collectively referred to as mobulids) poses a significant threat to these marine fishes because of their extremely low productivity. The demand for these gill plates has driven an international trade supplied by largely unmonitored and unregulated catches from target and incidental fisheries around the world. Scientific research, conservation campaigns, and legal protections for devil rays have lagged behind those for manta rays despite similar threats across all mobulids. METHODS: To investigate the difference in attention given to devil rays and manta rays, we examined trends in the scientific literature and updated species distribution maps for all mobulids. Using available information on target and incidental fisheries, and gathering information on fishing and trade regulations (at international, national, and territorial levels), we examined how threats and protective measures overlap with species distribution. We then used a species conservation planning approach to develop the Global Devil and Manta Ray Conservation Strategy, specifying a vision, goals, objectives, and actions to advance the knowledge and protection of both devil and manta rays. RESULTS AND DISCUSSION: Our literature review revealed that there had been nearly 2.5-times more "manta"-titled publications, than "mobula" or "devil ray"-titled publications over the past 4.5 years (January 2012-June 2016). The majority of these recent publications were reports on occurrence of mobulid species. These publications contributed to updated Area of Occupancy and Extent of Occurrence maps which showed expanded distributions for most mobulid species and overlap between the two genera. While several international protections have recently expanded to include all mobulids, there remains a greater number of national, state, and territory-level protections for manta rays compared to devil rays. We hypothesize that there are fewer scientific publications and regulatory protections for devil rays due primarily to perceptions of charisma that favour manta rays. We suggest that the well-established species conservation framework used here offers an objective solution to close this gap. To advance the goals of the conservation strategy we highlight opportunities for parity in protection and suggest solutions to help reduce target and bycatch fisheries.

10.
Dementia (London) ; 16(3): 315-328, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26112167

RESUMO

Alzheimer's disease results in marked declines in navigation skills that are particularly pronounced in unfamiliar environments. However, many people with Alzheimer's disease eventually face the challenge of having to learn their way around unfamiliar environments when moving into assisted living or care-homes. People with Alzheimer's disease would have an easier transition moving to new residences if these larger, and often more institutional, environments were designed to compensate for decreasing orientation skills. However, few existing dementia friendly design guidelines specifically address orientation and wayfinding. Those that do are often based on custom, practice or intuition and not well integrated with psychological and neuroscientific knowledge or navigation research, therefore often remaining unspecific. This paper discusses current dementia friendly design guidelines, reports findings from psychological and neuropsychological experiments on navigation and evaluates their potential for informing design guidelines that decrease spatial disorientation for people with dementia.


Assuntos
Confusão/prevenção & controle , Demência/complicações , Demência/psicologia , Ambiente de Instituições de Saúde , Instituições Residenciais , Navegação Espacial , Confusão/complicações , Planejamento Ambiental , Humanos
11.
Front Psychol ; 6: 1936, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26733921

RESUMO

We present two experiments investigating how navigators deal with ambiguous landmark information when learning unfamiliar routes. In the experiments we presented landmark objects repeatedly along a route, which allowed us to manipulate how informative single landmarks were (1) about the navigators' location along the route and (2) about the action navigators had to take at that location. Experiment 1 demonstrated that reducing location informativeness alone did not affect route learning performance. While reducing both location and action informativeness led to decreased route learning performance, participants still performed well above chance level. This demonstrates that they used other information than just the identity of landmark objects at their current position to disambiguate their location along the route. To investigate how navigators distinguish between visually identical intersections, we systematically manipulated the identity of landmark objects and the actions required at preceding intersections in Experiment 2. Results suggest that the direction of turn at the preceding intersections was sufficient to tell two otherwise identical intersections apart. Together, results from Experiments 1 and 2 suggest that route knowledge is more complex than simple stimulus-response associations and that neighboring places are tightly linked. These links not only encompass sequence information but also directional information which is used to identify the correct direction of travel at subsequent locations, but can also be used for self-localization.

12.
Bioorg Med Chem Lett ; 24(5): 1294-8, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24513044

RESUMO

Spiropiperidine indoline-substituted diaryl ureas had been identified as antagonists of the P2Y1 receptor. Enhancements in potency were realized through the introduction of a 7-hydroxyl substitution on the spiropiperidinylindoline chemotype. SAR studies were conducted to improve PK and potency, resulting in the identification of compound 3e, a potent, orally bioavailable P2Y1 antagonist with a suitable PK profile in preclinical species. Compound 3e demonstrated a robust antithrombotic effect in vivo and improved bleeding risk profile compared to the P2Y12 antagonist clopidogrel in rat efficacy/bleeding models.


Assuntos
Compostos de Fenilureia/química , Inibidores da Agregação de Plaquetas/química , Antagonistas do Receptor Purinérgico P2Y/química , Receptores Purinérgicos P2Y1/química , Tiazóis/química , Ureia/análogos & derivados , Administração Oral , Animais , Cães , Meia-Vida , Macaca fascicularis , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacocinética , Inibidores da Agregação de Plaquetas/farmacologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Ratos , Receptores Purinérgicos P2Y1/metabolismo , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/farmacologia , Tiazóis/uso terapêutico , Trombose/tratamento farmacológico , Ureia/farmacocinética , Ureia/farmacologia , Ureia/uso terapêutico
13.
Bioorg Med Chem Lett ; 23(19): 5442-7, 2013 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-23953070

RESUMO

Modification of a phenolic lead structure based on lessons learned from increasing the potency of steroidal glucocorticoid agonists lead to the discovery of exceptionally potent, nonsteroidal, indazole GR agonists. SAR was developed to achieve good selectivity against other nuclear hormone receptors with the ultimate goal of achieving a dissociated GR agonist as measured by human in vitro assays. The specific interactions by which this class of compounds inhibits GR was elucidated by solving an X-ray co-crystal structure.


Assuntos
Amidas/química , Amidas/farmacologia , Descoberta de Drogas , Receptores de Glucocorticoides/agonistas , Sítios de Ligação , Cristalografia por Raios X , Humanos , Indazóis/química , Indazóis/farmacologia , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Esteroides/química , Esteroides/farmacologia , Relação Estrutura-Atividade
14.
PLoS One ; 8(5): e65051, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23741450

RESUMO

As manta rays face increased threats from targeted and bycatch fisheries, manta ray watching tourism, if managed properly, may present an attractive economic alternative to consumptive use of these species. Both species in the genus Manta (Manta alfredi and Manta birostris) are classified by the International Union for the Conservation of Nature Red List as species Vulnerable to extinction in the wild, and are considered unsustainable as fisheries resources due to their conservative life history characteristics, which considerably reduce their ability to recover population numbers when depleted. Utilising dive operator surveys, Internet research, and a literature review, this study provides the first global estimate of the direct economic impact of manta ray watching tourism and examines the potential socio-economic benefits of non-consumptive manta ray watching operations relative to consumptive use of manta rays as a fishery resource. In the 23 countries in which manta ray watching operations meeting our criteria were identified, we estimated direct revenue to dive operators from manta ray dives and snorkels at over US$73 million annually and direct economic impact, including associated tourism expenditures, of US$140 million annually. Ten countries account for almost 93% of the global revenue estimate, specifically Japan, Indonesia, the Maldives, Mozambique, Thailand, Australia, Mexico, United States, Federated States of Micronesia and Palau. In many of the areas where directed fisheries for manta rays are known to occur, these activities overlap with manta ray tourism sites or the migratory range of the mantas on which these sites depend, and are likely to be unsustainable and detrimental to manta ray watching tourism.


Assuntos
Atividades Humanas/economia , Animais , Custos e Análise de Custo , Geografia , Inquéritos e Questionários
15.
Bioorg Med Chem Lett ; 23(10): 3028-33, 2013 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-23578688

RESUMO

A series of carbamoylmethylene linked prodrugs of 1 (BMS-582949), a clinical p38α inhibitor, were synthesized and evaluated. Though the phosphoryloxymethylene carbamates (3, 4, and 5) and α-aminoacyloxymethylene carbamates (22, 23, and 26) were found unstable at neutral pH values, fumaric acid derived acyloxymethylene carbamates (2, 28, and 31) were highly stable under both acidic and neutral conditions. Prodrugs 2 and 31 were also highly soluble at both acidic and neutral pH values. At a solution dose of 14.2mpk (equivalent to 10mpk of 1), 2 gave essentially the same exposure of 1 compared to dosing 10mpk of 1 itself. At a suspension dose of 142mpk (equivalent to 100mpk of 1), 2 demonstrated that it could overcome the solubility issue associated with 1 and provide a much higher exposure of 1. To our knowledge, the unique type of prodrugs like 2, 28, and 31 was not reported in the past and could represent a novel prodrug approach for secondary amides, a class of molecules frequently identified as drug candidates.


Assuntos
Dacarbazina/análogos & derivados , Pró-Fármacos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirróis/farmacologia , Triazinas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Cristalografia por Raios X , Dacarbazina/química , Relação Dose-Resposta a Droga , Concentração de Íons de Hidrogênio , Modelos Moleculares , Estrutura Molecular , Pró-Fármacos/administração & dosagem , Pró-Fármacos/síntese química , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/síntese química , Pirróis/administração & dosagem , Pirróis/síntese química , Ratos , Solubilidade , Relação Estrutura-Atividade , Temperatura Ambiente , Triazinas/administração & dosagem , Triazinas/síntese química , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
16.
Sleep Breath ; 16(3): 881-6, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21948101

RESUMO

PURPOSE: Adverse surgical outcomes may occur more frequently in patients with sleep-disordered breathing (SDB). Despite this concern, there have been no prospective studies using objective measures of postoperative SDB to determine the scope of the problem. We designed a prospective study to determine the feasibility of identifying SDB in elective postoperative patients by the use of a type IV portable monitor (PM). METHODS: Patients >18 years old who presented for elective surgery with at least one postoperative hospital night on a non-monitored unit were enrolled and wore a type IV device that measured nasal flow, heart rate, and oxygen saturation on their first postoperative night. Respiratory disturbance index (RDI) and oxygen desaturation index (ODI) were generated for each patient. RESULTS: Data sufficient for interpretation were collected on 100/116 patients enrolled. SDB (RDI ≥5) was observed in 51% of the study group, and 17% had a RDI >15. An elevated ODI ≥5 was seen in 42%, while 17% had an ODI ≥15. Device malfunction occurred in 16% of the study participants. CONCLUSION: A type IV PM can be employed in the postoperative setting to detect and gauge the severity of SDB.


Assuntos
Procedimentos Cirúrgicos Eletivos , Sistemas Automatizados de Assistência Junto ao Leito , Polissonografia/instrumentação , Complicações Pós-Operatórias/diagnóstico , Apneia Obstrutiva do Sono/diagnóstico , Adulto , Idoso , Comorbidade , Desenho de Equipamento , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxigenoterapia , Complicações Pós-Operatórias/terapia , Estudos Prospectivos , Apneia Obstrutiva do Sono/terapia
17.
Eur J Pharmacol ; 651(1-3): 9-17, 2011 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-21044623

RESUMO

The cannabinoid CB(1) G protein-coupled receptor has been shown to be a regulator of food consumption and has been studied extensively as a drug target for the treatment of obesity. To advance understanding of the receptor's three-dimensional structure, we performed mutagenesis studies at human cannabinoid CB(1) receptor residues F200 and S383 and measured changes in activity and binding affinity of compounds from two recently discovered active chemotypes, arylsulfonamide agonists and tetrahydroquinoline-based inverse agonists, as well as literature compounds. Our results add support to previous findings that both agonists and inverse agonists show varied patterns of binding at the two mutated residue sites, suggesting multiple subsites for binding to the cannabinoid CB(1) receptor for both functional types of ligands. We additionally find that an F200L mutation in the receptor largely restores binding affinity to ligands and significantly decreases constitutive activity when compared to F200A, resulting in a receptor phenotype that is closer to the wild-type receptor. The results downplay the importance of aromatic stacking interactions at F200 and suggest that a bulky hydrophobic contact is largely sufficient to provide significant receptor function and binding affinity to cannabinoid CB(1) receptor ligands.


Assuntos
Mutagênese , Fenilalanina , Receptor CB1 de Canabinoide/química , Receptor CB1 de Canabinoide/metabolismo , Serina , Animais , Benzoatos/metabolismo , Benzoatos/farmacologia , Células CHO , Cricetinae , Cricetulus , Agonismo Inverso de Drogas , Humanos , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Fenilalanina/genética , Fenilalanina/metabolismo , Ligação Proteica , Proteínas Proto-Oncogênicas c-myc/metabolismo , Quinolinas/metabolismo , Quinolinas/farmacologia , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/genética , Serina/genética , Serina/metabolismo , Sulfonamidas/metabolismo , Sulfonamidas/farmacologia
18.
Chest ; 138(6): 1475-9, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21138883

RESUMO

Patients who survive the acute phase of respiratory failure often are transferred to units with specialized expertise. These patients have a high risk of being readmitted to the acute care hospital. We conducted this study to determine whether supplementing a written report with a verbal telephone report reduces readmission rates within the first 72 h after discharge and decreases hospital costs. The study design was observational with a historical control group that included patients admitted to our respiratory acute care unit between November 2003 and October 2005. In November 2005, we implemented a strategy in which a written report at discharge was supplemented with a telephone report by the physician or nurse practitioner, nurse, and respiratory therapist. The intervention group began in November 2005 and continued through October 2007. The primary end point was readmission to Massachusetts General Hospital within 72 h of discharge. We also determined the cost related to readmission. The study included 362 patients. The OR for readmission if the handoff included a verbal report was 0.42 (95% CI, 0.17-1.04). The total hospital cost was significantly lower in the group where verbal report was used ($111,723 vs $148,574; P = .002). Supplementing a written report with a verbal telephone report was associated with a significant reduction in cost and an average savings of ∼ $184,000 for every 100 patients discharged, representing added value in delivered care.


Assuntos
Comunicação , Equipe de Assistência ao Paciente/organização & administração , Readmissão do Paciente/economia , Insuficiência Respiratória/terapia , Gestão de Riscos/métodos , Adulto , Idoso , Análise de Variância , Estudos de Casos e Controles , Cuidados Críticos , Feminino , Custos Hospitalares , Hospitais Gerais , Humanos , Unidades de Terapia Intensiva , Relações Interprofissionais , Tempo de Internação , Modelos Logísticos , Masculino , Massachusetts , Registros Médicos Orientados a Problemas , Pessoa de Meia-Idade , Análise Multivariada , Alta do Paciente , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/economia , Medição de Risco , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Telefone
19.
Bioorg Med Chem Lett ; 20(19): 5864-8, 2010 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-20732813

RESUMO

The design, synthesis, and structure-activity relationships (SAR) of a series of 2-aminothiazol-5-yl-pyrimidines as novel p38α MAP kinase inhibitors are described. These efforts led to the identification of 41 as a potent p38α inhibitor that utilizes a unique nitrogen-sulfur intramolecular nonbonding interaction to stabilize the conformation required for binding to the p38α active site. X-ray crystallographic studies that confirm the proposed binding mode of this class of inhibitors in p38 α and provide evidence for the proposed intramolecular nitrogen-sulfur interaction are discussed.


Assuntos
Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Nitrogênio/química , Inibidores de Proteínas Quinases/síntese química , Pirimidinas/química , Enxofre/química , Tiazóis/química , Sítios de Ligação , Cristalografia por Raios X , Desenho de Drogas , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Estrutura Terciária de Proteína , Pirimidinas/síntese química , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacologia
20.
J Med Chem ; 53(3): 1270-80, 2010 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-20047280

RESUMO

The first stereoselective synthesis of the hexahydroimidazo[1,5b]isoquinoline (HHII) scaffold as a surrogate for the steroidal A-B ring system is described. The structure-activity relationships of the analogs derived from this scaffold show that the basic imidazole moiety is tolerated by the glucocorticoid receptor (GR) in terms of binding affinity, although the partial agonist activity in the transrepressive assays depends on the substitution pattern on the B-ring. More importantly, most compounds in the HHII series bearing a tertiary alcohol moiety on the B-ring are either inactive or significantly less active in inducing GR-mediated transactivation, thus displaying a "dissociated" pharmacology in vitro.


Assuntos
Isoquinolinas/síntese química , Isoquinolinas/farmacologia , Receptores de Glucocorticoides/agonistas , Dexametasona/farmacologia , Selectina E/genética , Selectina E/metabolismo , Genes Reporter , Células HeLa , Humanos , Isoquinolinas/química , Pulmão/citologia , Pulmão/efeitos dos fármacos , Estrutura Molecular , Regiões Promotoras Genéticas , Relação Estrutura-Atividade , Transcrição Genética , Ativação Transcricional
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA