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1.
Chirality ; 31(4): 301-311, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30753745

RESUMO

Luminescent lanthanide (III) ions have been exploited for circularly polarized luminescence (CPL) for decades. However, very few of these studies have involved chiral samarium (III) complexes. Complexes are prepared by mixing axial chiral ligands (R/S))-2,2'-bis(diphenylphosphoryl)-1,1'-binaphthyl (BINAPO) with europium and samarium Tris (trifluoromethane sulfonate) (Eu (OTf)3 and Sm (OTf)3 ). Luminescence-based titration shows that the complex formed is Ln((R/S)-BINAPO)2 (OTf)3 , where Ln = Eu or Sm. The CPL spectra are reported for Eu((R/S)-BINAPO)2 (OTf)3 and Sm((R/S)-BINAPO)2 (OTf)3 . The sign of the dissymmetry factors, gem , was dependent upon the chirality of the BINAPO ligand, and the magnitudes were relatively large. Of all of the complexes in this study, Sm((S)-BINAPO)2 (OTf)3 has the largest gem  = 0.272, which is one of the largest recorded for a chiral Sm3+ complex. A theoretical three-dimensional structural model of the complex that is consistent with the experimental observations is developed and refined. This report also shows that (R/S)-BINAPO are the only reported ligands where gem (Sm3+ ) > gem (Eu3+ ).

2.
J Biol Chem ; 290(33): 20044-59, 2015 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-26085101

RESUMO

Insulin-degrading enzyme (IDE, insulysin) is the best characterized catabolic enzyme implicated in proteolysis of insulin. Recently, a peptide inhibitor of IDE has been shown to affect levels of insulin, amylin, and glucagon in vivo. However, IDE(-/-) mice display variable phenotypes relating to fasting plasma insulin levels, glucose tolerance, and insulin sensitivity depending on the cohort and age of animals. Here, we interrogated the importance of IDE-mediated catabolism on insulin clearance in vivo. Using a structure-based design, we linked two newly identified ligands binding at unique IDE exosites together to construct a potent series of novel inhibitors. These compounds do not interact with the catalytic zinc of the protease. Because one of these inhibitors (NTE-1) was determined to have pharmacokinetic properties sufficient to sustain plasma levels >50 times its IDE IC50 value, studies in rodents were conducted. In oral glucose tolerance tests with diet-induced obese mice, NTE-1 treatment improved the glucose excursion. Yet in insulin tolerance tests and euglycemic clamp experiments, NTE-1 did not enhance insulin action or increase plasma insulin levels. Importantly, IDE inhibition with NTE-1 did result in elevated plasma amylin levels, suggesting the in vivo role of IDE action on amylin may be more significant than an effect on insulin. Furthermore, using the inhibitors described in this report, we demonstrate that in HEK cells IDE has little impact on insulin clearance. In total, evidence from our studies supports a minimal role for IDE in insulin metabolism in vivo and suggests IDE may be more important in helping regulate amylin clearance.


Assuntos
Inibidores Enzimáticos/farmacologia , Insulina/metabolismo , Insulisina/antagonistas & inibidores , Animais , Sítios de Ligação , Cristalografia por Raios X , Inibidores Enzimáticos/farmacocinética , Células HEK293 , Humanos , Insulisina/química , Modelos Moleculares , Proteólise
3.
Support Care Cancer ; 24(7): 3085-93, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26894485

RESUMO

PURPOSE: Bone pain is a common side effect of pegfilgrastim and can interfere with quality of life and treatment adherence. This study investigated the impact of antihistamine prophylaxis on pegfilgrastim-induced bone pain. METHODS: This is a two-stage enrichment trial design. Patients receiving an initial dose of pegfilgrastim after chemotherapy were enrolled into the observation (OBS) stage. Those who developed significant back or leg bone pain (SP) were enrolled into the treatment (TRT) stage and randomized to daily loratadine 10 mg or placebo for 7 days. SP was defined by Brief Pain Inventory as back or leg pain score ≥5 and a 2-point increase after pegfilgrastim. The primary end point of TRT was reduction of worst back or leg bone pain with loratadine, defined as a 2-point decrease after treatment compared to OBS. RESULTS: Two hundred thirteen patients were included in the final analysis. Incidence of SP was 30.5 %. The SP subset had a worse overall Functional Assessment of Cancer Therapy-Bone Pain score (33.9 vs. 51.7, p < 0.001) and a higher mean white blood cell count (15.4 vs. 8.4 K/cm(3), p = 0.013) following pegfilgrastim than those without SP. Forty-six patients were randomized in the TRT. Benefit was 77.3 % with loratadine and 62.5 % with placebo (p = 0.35). Baseline NSAID use was documented in four patients (18.2 %) in loratadine arm and two patients (8.3 %) in placebo arm, with baseline non-NSAID use documented in five (22.7 %) and six (25 %) patients, respectively. Eight additional patients used NSAIDS by day 8 compared to day 1 (six in the loratadine and two in the placebo arm). A total of six additional patients used non-NSAIDS by day 8 compared to day 1 (four in the loratadine and two in the placebo arm). CONCLUSIONS: Administration of prophylactic loratadine does not decrease the incidence of severe bone pain or improve quality of life in a high-risk patient population. ClinicalTrials.gov identifier: NCT01311336.


Assuntos
Doenças Ósseas/prevenção & controle , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Antagonistas não Sedativos dos Receptores H1 da Histamina/uso terapêutico , Loratadina/uso terapêutico , Manejo da Dor/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Ósseas/induzido quimicamente , Feminino , Filgrastim , Humanos , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis , Qualidade de Vida , Proteínas Recombinantes/efeitos adversos , Adulto Jovem
4.
Oral Dis ; 22 Suppl 1: 87-97, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27109277

RESUMO

OBJECTIVE: The aim of this study was to determine active periodontal disease status in HIV and to determine the impact of periodontal disease resolution on HIV status. METHODS: In this longitudinal cohort study, 73 HIV-positive subjects received comprehensive dental care. AAP, CDC/AAP, and BGI case definitions determined periodontal classification. Likelihood and frequency of moderate/severe periodontal disease were assessed based on demographic variables. The influence of periodontal intervention was assessed at baseline, 12, and 24 months. IL-6 was measured in a subset of subjects. RESULTS: Of the periodontal classifications, BGI demonstrated the highest percentage category improvement with the intervention (>50%). Moderate/severe periodontitis was positively associated with HIV regardless of race, smoking status, gender, income level, and age, and was associated with increased IL-6. At baseline, the majority of subjects had severe periodontal disease regardless of ART status. Subjects with suppressed viral load at baseline demonstrated a significant improvement in BGI classification (P = 0.026), increased CD4 counts (P = 0.027), and decreased IL-6 levels (P = 0.03). CONCLUSIONS: Periodontal inflammation was prevalent regardless of ART status. In virologically suppressed subjects, the intervention decreased periodontitis with a concomitant IL-6 decrease and CD4 increase. These findings suggest a relationship between periodontal inflammation, oral microbial translocation, and HIV status.


Assuntos
Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Doenças Periodontais/terapia , Adulto , Antirretrovirais/uso terapêutico , Contagem de Linfócito CD4 , Feminino , Infecções por HIV/complicações , Infecções por HIV/metabolismo , Humanos , Inflamação/metabolismo , Interleucina-6/metabolismo , Estudos Longitudinais , Masculino , Doenças Periodontais/complicações , Doenças Periodontais/metabolismo , Estudos Prospectivos , Saliva/metabolismo , Índice de Gravidade de Doença , Carga Viral
5.
Bioorg Med Chem ; 23(13): 3260-8, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-26001341

RESUMO

The BACE1 enzyme is a key target for Alzheimer's disease. During our BACE1 research efforts, fragment screening revealed that bicyclic thiazine 3 had low millimolar activity against BACE1. Analysis of the co-crystal structure of 3 suggested that potency could be increased through extension toward the S3 pocket and through conformational constraint of the thiazine core. Pursuit of S3-binding groups produced low micromolar inhibitor 6, which informed the S3-design for constrained analogs 7 and 8, themselves prepared via independent, multi-step synthetic routes. Biological characterization of BACE inhibitors 6-8 is described.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Compostos Bicíclicos com Pontes/síntese química , Inibidores de Proteases/síntese química , Tiazinas/síntese química , Secretases da Proteína Precursora do Amiloide/química , Secretases da Proteína Precursora do Amiloide/isolamento & purificação , Animais , Ácido Aspártico Endopeptidases/química , Ácido Aspártico Endopeptidases/isolamento & purificação , Química Encefálica , Compostos Bicíclicos com Pontes/química , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Camundongos , Conformação Molecular , Simulação de Acoplamento Molecular , Inibidores de Proteases/química , Estereoisomerismo , Tiazinas/química
6.
Sci Total Environ ; 926: 171850, 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38521255

RESUMO

Agriculture is expanding rapidly across the tropics. While cultivation can boost socioeconomic conditions and food security, it also threatens native ecosystems. Oil palm (Elaeis guineensis), which is grown pantropically, is the most productive vegetable oil crop worldwide. The impacts of oil palm cultivation have been studied extensively in Southeast Asia and - to a lesser extent - in Latin America but, in comparison, very little is known about its impacts in Africa: oil palm's native range, and where cultivation is expanding rapidly. In this paper, we introduce a large-scale research programme - the Sustainable Oil Palm in West Africa (SOPWA) Project - that is evaluating the relative ecological impacts of oil palm cultivation under traditional (i.e., by local people) and industrial (i.e., by a large-scale corporation) management in Liberia. Our paper is twofold in focus. First, we use systematic mapping to appraise the literature on oil palm research in an African context, assessing the geographic and disciplinary focus of existing research. We found 757 publications occurring in 36 African countries. Studies tended to focus on the impacts of palm oil consumption on human health and wellbeing. We found no research that has evaluated the whole-ecosystem (i.e., multiple taxa and ecosystem functions) impacts of oil palm cultivation in Africa, a knowledge gap which the SOPWA Project directly addresses. Second, we describe the SOPWA Project's study design and-using canopy cover, ground vegetation cover, and soil temperature data as a case study-demonstrate its utility for assessing differences between areas of rainforest and oil palm agriculture. We outline the socioecological data collected by the SOPWA Project to date and describe the potential for future research, to encourage new collaborations and additional similar projects of its kind in West Africa. Increased research in Africa is needed urgently to understand the combined ecological and sociocultural impacts of oil palm and other agriculture in this unique region. This will help to ensure long-term sustainability of the oil palm industry-and, indeed, all tropical agricultural activity-in Africa.


Assuntos
Conservação dos Recursos Naturais , Ecossistema , Humanos , Óleos de Plantas , Agricultura , África Ocidental
7.
J Comput Chem ; 33(21): 1740-7, 2012 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-22610824

RESUMO

Mechanism-based inhibition (MBI) of cytochrome P450 (CYP) can lead to drug-drug interactions and often to toxicity. Some aliphatic and aromatic amines can undergo biotransformation reactions to form reactive metabolites such as nitrosoalkanes, leading to MBI of CYPs. It has been proposed that the nitrosoalkanes coordinate with the heme iron, forming metabolic-intermediate complex (MIC), resulting in the quasi-irreversible inhibition of CYPs. Limited mechanistic details regarding the formation of reactive nitroso intermediate and its coordination with heme-iron have been reported. A quantum chemical analysis was performed to elucidate potential reaction pathways for the generation of nitroso intermediate and the formation of MIC. Elucidation of the energy profile along the reaction path, identification of three-dimensional structures of reactive intermediates and transition states, as well as charge and spin density analyses, were performed using the density functional B3LYP method. The study was performed using Cpd I [iron (IV-oxo] heme porphine with SH(-) as the axial ligand) to represent the catalytic domain of CYP, simulating the biotransformation process. Three pathways: (i) N-oxidation followed by proton shuttle, (ii) N-oxidation followed by 1,2-H shift, and (iii) H-abstraction followed by rebound mechanism, were studied. It was observed that the proton shuttle pathway was more favorable over the whole reaction leading to reactive nitroso intermediate. This study revealed that the MIC formation from a primary amine is a favorable exothermic process, involving eight different steps and preferably takes place on the doublet spin surface of Cpd I. The rate-determining step was identified to be the first N-oxidation of primary amine.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Compostos Nitrosos/metabolismo , Teoria Quântica , Aminas/química , Aminas/metabolismo , Biotransformação , Compostos Nitrosos/química , Oxirredução
8.
Dev Neurorehabil ; 25(2): 101-114, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34241555

RESUMO

AIM: To report prospective longitudinal data of early vocaliszations of infants identified "at-risk" of cerebral palsy (CP) for early identification of communication impairment. METHOD: This case-control longitudinal prospective cohort study reports on the assessment of 36 infants, 18 identified as at-risk of CP at the time of enrolment and 18 typically developing (TD) children, at three time points: 6 months, 9 months and 12 months of age, Data were obtained through criterion and norm referenced assessments of vocaliszation behaviors. RESULTS: Early vocal behaviors of infants identified as at-risk of CP did not differ from their age matched peers at 6 months of age, however, significant group differences emerged at 9 and 12 months when pre-canonical and canonical babble typically emerge. Generalized linear mixed models analysis showed that the rate of development of early language ability and more complex speech-related vocal behaviors was slower for infants at risk of CP when compared to TD infants, with over 75% of infants with CP showing below normal vocal production and impaired language by 12 months of age. INTERPRETATION: Our data suggest characteristics of infant vocalizations associated with pre-canonical and canonical babbling provide a strong evidence base for predicting communication outcomes in infants at risk of CP.


Assuntos
Paralisia Cerebral , Transtornos da Comunicação , Estudos de Casos e Controles , Criança , Humanos , Lactente , Estudos Prospectivos , Fala
9.
Biochem Res Int ; 2022: 6536826, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35865720

RESUMO

Objective: Food proteins provide amino acids (AAs) and serve as building blocks of all vital organs, muscles, hormones, and biological fluids such as blood. Eggs are known as a good source of protein. This study compared the protein quality of bird eggs (raw and boiled), using their AA scores since some individuals consume raw eggs for various reasons. Research Methods. Eggs studied were exotic chicken, local chicken, turkey, quail, and guinea fowl eggs. The eggs were shelled and their contents (boiled and raw) lyophilized. The standard AOAC method (Kjeldahl) was used to determine protein content, while the amino acid composition was measured using an AA analyzer. The total AA scores were calculated based on the whole hen's egg AA profiles. Statistical significance was accepted at p < 0.05. Results: The Guinea fowl egg had the highest total amino acid score (TAAS) of 0.92. The other scores ranged as follows: 0.82 (quail) >0.81 (turkey) >0.75 (exotic chicken), and the lowest score was 0.65 (local chicken). The least scores were phenylalanine: 0.34 (exotic chicken), phenylalanine and serine: 0.36 (local chicken), leucine and aspartic acid: 0.41 (turkey), methionine: 0.31 (quail), and glutamic acid: 0.33 (guinea fowl). Also, guinea fowl egg had the highest total essential amino acid (TEAA) (49.6 g/100 g protein), i.e., % TEAA (55.1%), while exotic chicken egg had the lowest (41.1%), but the highest % NEAA (58.9%). Conclusion: Guinea fowl eggs had the highest EAA and TAA content. Its consumption should particularly be encouraged for children as this can significantly reduce the risk of protein-energy malnutrition and prevent protein deficiencies.

10.
J Educ Health Promot ; 11(1): 395, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36824399

RESUMO

BACKGROUND: Few researchers have examined the effectiveness of cognitive behavioral therapy in treating aggressive behaviors among individuals with dual diagnosis (intellectual disability and mental health conditions) due to the relatively recent interest in the field of psychopathology in intellectual disability. This study investigated the effectiveness of cognitive behavioral therapy in treating aggressive behaviors among clients with dual diagnoses in a community rehabilitation center, Ibadan, Oyo state, and the moderating effects of parenting style and socioeconomic status in the associations. MATERIALS AND METHOD: A 2 × 2 × 2 pre-test post-test factorial design was used. Parenting style and socioeconomic status at two levels each moderated the associations. A sample of 22 participants purposively selected was exposed to treatment using cognitive behavioral therapy, while the other five were exposed to placebo treatment all for 8 weeks. Data collected were analyzed using Line Chart and Analysis of Covariance (ANCOVA). RESULTS: Improvements were found in the post-treatment scores obtained on the Aggressive Scale for Youths. A reduction in the Aggressive Incidents chart was recorded for each participant in the treatment group when compared with the control group, using a line chart and Analysis of Covariance (ANCOVA). Evidence also demonstrated that parenting style (authoritarian and authoritative), F (1,14) = 0.75, P <.05, η2 =0.05), and socioeconomic status (high and low), F (1,14) = 0.01, P =0.020, η2 =.00), moderated the associations. CONCLUSION: Cognitive behavioral therapy is seen as a treatment intervention for individuals with intellectual disability co-existing with mental health manifesting aggressive behaviors in the community or other settings. This should be used to improve the client's quality of life under these conditions.

11.
F1000Res ; 11: 652, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36071708

RESUMO

Background: The National Youth Service Corps programme is, among other targets, aimed at promoting national inclusiveness and tolerance in a culturally heterogeneous society. Despite the importance of this programme, little has been done to evaluate its degree of success. Where evaluations are done, they are never made public. There is a need for the NYSC programme, just like all other public programmes, to be evaluated for transparency, accountability and decision-making. From an evaluation of the three measurable objectives of the NYSC programme, this dataset bridges this gap . Methods: This dataset was collected from Nigerian graduates that completed their national service between 2012 and 2021. The data was collected through an electronic survey posted to various online platforms hosting National Youth Service Corps (NYSC) members of the various sets and batches. The data collection aimed to evaluate the three cardinal objectives of the programme. After three years of data collection (from 2019 to 2021), responses were obtained from 19,278 participants that met the eligibility criteria. The data is an Excel (.xlsx) document with 19,278 cases and 95 variables. Descriptive statistics such as frequency counts and simple percentages were used to summarise the data. However, charts are further used to illustrate the demographic attributes of the respondents. The dataset is broad and covers all the 36 states in Nigeria plus the Federal Capital Territory. Results: The data set has many reuse potentials because it contains information on camp activities (such as parades, military drills, redeployment, quality of food, and facilities, among others), primary assignments and community service engagements of corps members. Conclusions: The data can offer a complete evaluation of how the (NYSC) has attained three of its four cardinal objectives. A series of relationships can further be determined and tested using inferential statistics among the variables included in the dataset.


Assuntos
Organizações , Adolescente , Humanos , Nigéria , Inquéritos e Questionários
12.
Heliyon ; 8(4): e09334, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35520624

RESUMO

This study used a latent variable structural equation modelling to quantify how staff motivation, placement and retraining partially and grossly affect teachers' job commitment across three areas. The research was quantitative, and the design adopted was the ex-post facto. This study included 500 school managers from 204 public secondary schools in Cross River State, Nigeria. Data were gathered using the "staff placement, retraining and motivation questionnaire" (SPRMQ) and the "job commitment questionnaire (JCQ)." Both instruments were assessed for face and content validity using domain and psychometric experts. The instruments' construct validity was determined using exploratory and confirmatory factor analyses based on the Maximum Likelihood (ML) estimation technique. Acceptable indices were obtained for the test of sampling adequacy and Bartlett's test of sphericity. Loadings of items for each latent factor in the study varied from .55 to .98. The reliability for internal consistency was also established using Cronbach's alpha with coefficients ranging from .93 to .97. Our findings indicate that retraining is an essential predictor of staff affective commitment (AC), normative commitment (NC) and continuance commitment (CC). However, placement and motivation did not significantly contribute to employees' job commitment across the AC, CC, and NC aspects. Cumulatively, the three upstream variables explained less than 15% of the variance in the three dimensions of job commitment, respectively. Based on these results, discussions were made with implications for research, theory, and practice.

13.
Drug Metab Dispos ; 39(5): 740-9, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21346003

RESUMO

2-Methylalanyl-N-{1-[(1R)-1-(4-fluorophenyl)-1-methyl-2-oxo-2-pyrrolidin-1-ylethyl]-1H-imidazol-4-yl}-5-phenyl-D-norvalinamide (LY654322) was rapidly cleared in rats and dogs by renal excretion of parent and metabolism (oxidative and hydrolytic). Among the metabolites identified in the urine of rats and dogs was M25, which was structurally unusual. Indeed, the characterization of M25 and investigation into its disposition relied on the convergence of diverse analytical methodologies. M25 eluted after the parent on reverse-phase chromatography with an MH(+) at m/z 598 (parent + 35 Da). Given its increased lipophilicity and its mass difference compared with the parent, it was evident that M25 was not a phase 2 conjugate. Subsequent liquid chromatography with multiple-stage tandem mass spectrometry and accurate mass experiments identified the structure of M25 as having two replicates of the 1-(4-fluorophenyl)-1-methyl-2-oxo-2-pyrrolidinyl substructure flanking a central aromatic core of composition C(7)H(3)N(5) that was refractory to fragmentation. Compared with the UV spectrum of the parent (λ(max) = 213 nm), M25 displayed a bathochromic shift (λ(max) = 311 nm), which substantiated extensive conjugation within the central core. Subsequent NMR analysis of M25 isolated from dog urine coupled with molecular modeling revealed the structure to be consistent with a diimidazopyridine core with two symmetrically substituted 1-(4-fluorophenyl)-1-methyl-2-oxo-2-pyrrolidinyl moieties. Using a structural analog with a chromophore similar to M25, LC-UV was used to quantitate M25 and determine its urinary disposition. The formation of M25 appears consistent with hydrolysis of LY654322 to an aminoimidazole, dimerization of the latter with the loss of NH(3), C-formylation, and subsequent ring closure and aromatization with loss of H(2)O.


Assuntos
Dipeptídeos/química , Dipeptídeos/metabolismo , Compostos Heterocíclicos com 3 Anéis/análise , Compostos Heterocíclicos com 3 Anéis/química , Imidazóis/química , Imidazóis/metabolismo , Piridinas/análise , Piridinas/química , Receptores de Grelina/agonistas , Animais , Dipeptídeos/sangue , Dipeptídeos/farmacocinética , Dipeptídeos/farmacologia , Cães , Feminino , Hormônio do Crescimento Humano/metabolismo , Imidazóis/sangue , Imidazóis/farmacocinética , Imidazóis/farmacologia , Masculino , Ratos , Ratos Endogâmicos F344 , Receptores de Grelina/metabolismo
14.
J Natl Med Assoc ; 102(6): 469-75, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20575211

RESUMO

OBJECTIVE: To describe weight loss methods used and interactions with health care professionals on the issue of weight among African Americans and Hispanics. METHODS: Five hundred thirty-seven African American and 526 Hispanic adults who self-described as being overweight participated in a telephone interview. RESULTS: Exercise and healthy eating were the 2 most commonly used weight loss methods among both groups; prescription medications were the least-utilized weight loss aid. Forty-one percent of African Americans and 35% of Hispanics reported having been advised to lose weight by a health care professional. CONCLUSIONS: Do-it-yourself approaches to weight loss predominate among African Americans and Hispanics; formal assistance is rarely used. Physician advice on weight loss is suboptimal.


Assuntos
Negro ou Afro-Americano , Hispânico ou Latino , Sobrepeso/prevenção & controle , Educação de Pacientes como Assunto/métodos , Redução de Peso , Adolescente , Adulto , Idoso , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Sobrepeso/etnologia , Estudos Retrospectivos , Estados Unidos/epidemiologia , Adulto Jovem
15.
Gut ; 58(10): 1354-62, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19505878

RESUMO

OBJECTIVE: Although treatment with corticosteroids induces remission in Crohn's disease, prolonged exposure to corticosteroids is undesirable. This randomised clinical trial evaluated the efficacy of recombinant human granulocyte-macrophage colony-stimulating factor (sargramostim), an activator of innate immunity, in corticosteroid-dependent patients with Crohn's disease. DESIGN: Patients were randomised in a 2:1 ratio, to sargramostim 6 microg/kg subcutaneously once daily or placebo for up to 22 weeks. The study consisted of (1) an adjunctive phase (weeks 1-4) in which patients received study drug plus corticosteroid therapy; (2) a forced corticosteroid tapering phase (weeks 4-14); and (3) an observation phase (4 weeks) in which patients received study drug plus prednisone < or =7.5 mg. The primary endpoint was corticosteroid-free remission (Crohn's Disease Activity Index (CDAI) < or =150) 4 weeks after corticosteroid elimination. Secondary endpoints were corticosteroid-free response (CDAI decreased by > or =100) and induction of remission in patients who reduced the dose of corticosteroid to 2.5-7.5 mg. RESULTS: Eighty-seven patients were randomised to sargramostim and 42 to placebo. Significantly more sargramostim-treated patients than placebo patients achieved corticosteroid-free remission (18.6% vs 4.9%; p = 0.03). Similar differences were seen for corticosteroid-free response and in patients who tapered corticosteroids to 2.5-7.5 mg/day. Sargramostim treatment was also associated with significant improvements in health-related quality of life. Patients who received sargramostim were more likely to experience musculoskeletal pain, injection site reactions and dyspnoea. CONCLUSIONS: Sargramostim was more effective than placebo for inducing corticosteroid-free remission in patients with Crohn's disease with corticosteroid dependence. Sargramostim may provide significant benefit in this population if these findings are confirmed.


Assuntos
Corticosteroides/administração & dosagem , Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Corticosteroides/efeitos adversos , Adulto , Idoso , Doença de Crohn/psicologia , Método Duplo-Cego , Esquema de Medicação , Feminino , Fármacos Gastrointestinais/efeitos adversos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida/psicologia , Proteínas Recombinantes , Indução de Remissão , Resultado do Tratamento , Adulto Jovem
16.
Genet Med ; 11(12): 843-9, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20010362

RESUMO

The collection of genetic variants that cause inherited disease (causative mutation) has occurred for decades albeit in an ad hoc way, for research and clinical purposes. More recently, the access to collections of mutations causing specific diseases has become essential for appropriate genetic health care. Because information has accumulated, it has become apparent that there are many gaps in our ability to correctly annotate all the changes that are being identified at ever increasing rates. The Human Variome Project (www.humanvariomeproject.org) was initiated to facilitate integrated and systematic collection and access to this data. This manuscript discusses how collection of such data may be facilitated through new software and strategies in the clinical genetics and diagnostic laboratory communities.


Assuntos
Pesquisa Biomédica/métodos , Bases de Dados Genéticas , Predisposição Genética para Doença/genética , Mutação , Variação Genética , Genética Médica/métodos , Genética Médica/organização & administração , Genética Médica/estatística & dados numéricos , Humanos , Cooperação Internacional
17.
J Cell Biol ; 137(7): 1581-8, 1997 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-9199172

RESUMO

We expressed the human anti-apoptotic protein, Bcl-2, in Saccharomyces cerevisiae to investigate its effects on antioxidant protection and stationary phase survival. Yeast lacking copper-zinc superoxide dismutase (sod1Delta) show a profound defect in entry into and survival during stationary phase even under conditions optimal for survival of wild-type strains (incubation in water after stationary phase is reached). Expression of Bcl-2 in the sod1Delta strain caused a large improvement in viability at entry into stationary phase, as well as increased resistance to 100% oxygen and increased catalase activity. In addition, Bcl-2 expression reduced mutation frequency in both wild-type and sod1Delta strains. In another set of experiments, wild-type yeast incubated in expired minimal medium instead of water lost viability quickly; expression of Bcl-2 significantly delayed this stationary phase death. Our results demonstrate that Bcl-2 has activities in yeast that are similar to activities it is known to possess in mammalian cells: (a) stimulation of antioxidant protection and (b) delay of processes leading to cell death.


Assuntos
Regulação Fúngica da Expressão Gênica , Proteínas Proto-Oncogênicas c-bcl-2/genética , Saccharomyces cerevisiae/genética , Superóxido Dismutase/genética , Técnicas de Transferência de Genes , Humanos , Mutação , Estresse Oxidativo , Saccharomyces cerevisiae/crescimento & desenvolvimento
18.
Science ; 169(3942): 277-8, 1970 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-17752539

RESUMO

Marine assemblages of foraminifera, ostracods, mollusks, and echinoids were recovered from deposits stratigraphically beneath the classic vertebrate assemblages from the tar pits at Rancho La Brea. The marine fossils indicate deposition in quiet, shallow water and suggest that accumulation of the type Rancholabrean material began during Wisconsin time.

19.
Science ; 255(5048): 1113-5, 1992 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-1312257

RESUMO

Novel sol-gel synthetic techniques were used to immobilize copper-zinc superoxide dismutase (CuZnSOD), cytochrome c, and myoglobin (Mb) by encapsulation in stable, optically transparent, porous silica glass matrices under mild conditions such that the biomolecules retained their characteristic reactivities and spectroscopic properties. The resulting glasses allowed transport of small molecules into and out of the glasses at reasonable rates but nevertheless retained the protein molecules within their pores. Chemical reactions of the immobilized proteins could be monitored by means of changes in their visible absorption spectra. Silica glasses containing the immobilized proteins were observed to have similar reactivities and spectroscopic properties to those found for the proteins in solution. For example, encapsulated CuZnSOD was demetallated and remetallated, encapsulated ferricytochrome c was reduced and then reoxidized, and encapsulated met Mb was reduced to deoxy Mb and then reacted either with dioxygen to make oxy Mb or with carbon monoxide to make carbonyl Mb.


Assuntos
Vidro , Proteínas/química , Animais , Bovinos , Grupo dos Citocromos c/química , Géis , Cavalos , Mioglobina/química , Soluções , Análise Espectral , Superóxido Dismutase/química
20.
Science ; 262(5137): 1274-7, 1993 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-8235659

RESUMO

The proto-oncogene bcl-2 inhibits apoptotic and necrotic neural cell death. Expression of Bcl-2 in the GT1-7 neural cell line prevented death as a result of glutathione depletion. Intracellular reactive oxygen species and lipid peroxides rose rapidly in control cells depleted of glutathione, whereas cells expressing Bcl-2 displayed a blunted increase and complete survival. Modulation of the increase in reactive oxygen species influenced the degree of cell death. Yeast mutants null for superoxide dismutase were partially rescued by expression of Bcl-2. Thus, Bcl-2 prevents cell death by decreasing the net cellular generation of reactive oxygen species.


Assuntos
Morte Celular , Neurônios/citologia , Proteínas Proto-Oncogênicas/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Animais , Antioxidantes/farmacologia , Butionina Sulfoximina , Linhagem Celular , Glutationa/metabolismo , Radical Hidroxila/metabolismo , Ferro/metabolismo , Peroxidação de Lipídeos , Metionina Sulfoximina/análogos & derivados , Metionina Sulfoximina/farmacologia , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2 , Saccharomyces cerevisiae/crescimento & desenvolvimento , Saccharomyces cerevisiae/metabolismo , Superóxido Dismutase/metabolismo
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