RESUMO
The study of individuals with autosomal dominant Alzheimer's disease affords one of the best opportunities to characterize the biological and cognitive changes of Alzheimer's disease that occur over the course of the preclinical and symptomatic stages. Unifying the knowledge gained from the past three decades of research in the world's largest single-mutation autosomal dominant Alzheimer's disease kindred - a family in Antioquia, Colombia with the E280A mutation in the Presenilin1 gene - will provide new directions for Alzheimer's research and a framework for generalizing the findings from this cohort to the more common sporadic form of Alzheimer's disease. As this specific mutation is virtually 100% penetrant for the development of the disease by midlife, we use a previously defined median age of onset for mild cognitive impairment for this cohort to examine the trajectory of the biological and cognitive markers of the disease as a function of the carriers' estimated years to clinical onset. Studies from this cohort suggest that structural and functional brain abnormalities - such as cortical thinning and hyperactivation in memory networks - as well as differences in biofluid and in vivo measurements of Alzheimer's-related pathological proteins distinguish Presenilin1 E280A mutation carriers from non-carriers as early as childhood, or approximately three decades before the median age of onset of clinical symptoms. We conclude our review with discussion on future directions for Alzheimer's disease research, with specific emphasis on ways to design studies that compare the generalizability of research in autosomal dominant Alzheimer's disease to the larger sporadic Alzheimer's disease population.
Assuntos
Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagem , Fragmentos de Peptídeos/metabolismo , Presenilina-1/genética , Adolescente , Adulto , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Compostos de Anilina , Doenças Assintomáticas , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/metabolismo , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Criança , Colômbia , Imagem de Tensor de Difusão , Progressão da Doença , Eletroencefalografia , Etilenoglicóis , Feminino , Neuroimagem Funcional , Humanos , Imageamento por Ressonância Magnética , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Tomografia Computadorizada de Emissão de Fóton Único , Adulto JovemRESUMO
Lysine-containing polymers have seen broad application due to their amines' inherent ability to bind to a range of biologically relevant molecules. The synthesis of multiple generations of polyester dendrimers bearing lysine groups on their periphery is described in this report. Their hydrolytic stabilities with respect to pH and time, their toxicity to a range of cell lines, and their possible application as nano-detoxification agents of organophosphate compounds are all investigated. These zeroth-, first-, and second-generation water-soluble dendrimers have been designed to bear exactly 4, 8, and 16 lysine groups, respectively, on their dendritic periphery. Such monodisperse bioactive polymers show potential for a range of applications including drug delivery, gene delivery, heavy metal binding, and the sequestration of organic toxins. These monodisperse bioactive dendrimers were synthesized using an aliphatic ester dendritic core (prepared from pentaerythritol) and protected amino acid moieties. This library of lysine-conjugated dendrimers showed the ability to efficiently capture the pesticide dichlorvos, confirming the potential of dendrimer-based antidotes to maintain acetylcholinesterase activity in response to poisoning events.
Assuntos
Dendrímeros/química , Diclorvós/química , Lisina/química , Animais , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Concentração de Íons de Hidrogênio , Camundongos , Tamanho da Partícula , Polímeros/química , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por MatrizRESUMO
OBJECTIVES: To evaluate the evidence base used in policy and healthcare decision making by the Regional Health Authorities in Trinidad. DESIGN AND METHODS: The study focused on the five Regional Health Authorities (RHAs) in Trinidad where senior administrative employees at each Regional Health Authority were purposively sampled and interviewed using a structured questionnaire. Responses were initially reviewed individually to determine types of evidence used within each RHA. All responses were secondly compared between the various RHAs. RESULTS: All RHAs participated; each had an observatory type unit which was responsible for data collection, collation and production of reports on an annual basis. Reports focused on the number of patients accessing services (e.g. specialist clinics and surgical procedures), patient demographics and patient access to health services. All RHAs had annual service agreements with the Ministry of Health which acted as a guide with targets and as a check on accountability of money spent. Decision making in each RHA was tiered by financial cap; most decisions were made by the Chief Executive Officer and/or Board of Directors within their caps; decisions requiring monetary investment over the RHA limit had to be approved by the Ministry of Health. CONCLUSION: This study revealed that RHAs had systems in place whereby they engaged in evidence-based practice utilising the Authoritys observatory data plus other information sources, ran trial periods and economic analyses for healthcare related decision making.
Assuntos
Tomada de Decisões Gerenciais , Setor de Assistência à Saúde , Trinidad e TobagoRESUMO
Cytochrome P450 (CYP) enzyme inhibitory properties of six chromenylated amide compounds (CAs) from Amyris plumieri are described. Inhibition of CYP microsomes (CYP1A1, CYP1A2, CYP1B1, CYP2D6, CYP3A4 and CYP2C19) was monitored using a fluorescent assay. Potent inhibition was found against CYP1A1 with IC(50) and K(i) for CA1 (acetamide), being the lowest at 1.547 ± 1.0 µM and 0.37 µM respectively, displaying non-competitive kinetics. The selectivity for CYP1A1 was increased in CA3 (butanamide), which also exhibited cytotoxicity against breast cancer cells, MCF7 with an IC(50) of 47.46 ± 1.62 µM. Structure-activity relationship studies provide insight at a molecular level for CAs with implications in chemoprevention and chemotherapy.
Assuntos
Amidas/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Citocromo P-450 CYP1A1/antagonistas & inibidores , Fitoterapia , Extratos Vegetais/uso terapêutico , Rutaceae/química , Acetamidas/isolamento & purificação , Acetamidas/farmacologia , Acetamidas/uso terapêutico , Amidas/isolamento & purificação , Amidas/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Benzopiranos/isolamento & purificação , Benzopiranos/farmacologia , Benzopiranos/uso terapêutico , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Relação Estrutura-AtividadeRESUMO
Extracts of the stems of Jatropha divaricata have yielded the two new diterpenes ent-3 beta,14 alpha-hydroxypimara-7,9(11),15-triene-12-one (3) and the rearranged pimarane ent-15(13-->8)abeo-8 beta(ethyl)pimarane (4), which appears to be a new skeletal type. The rare cleistanthane diterpenes spruceanol (1) and cleistanthol (2) were also obtained.
Assuntos
Diterpenos/química , Euphorbiaceae/química , Plantas Medicinais/química , Diterpenos/isolamento & purificação , Jamaica , Espectroscopia de Ressonância Magnética , MetilaçãoRESUMO
Extracts of the fruit of Clusia havetiodes var. stenocarpa have yielded three new prenylated benzophenone derivatives, 28,29-epoxyplukenetione A (1), 33-hydroperoxyisoplukenetione C (2), and 15,16-dihydro-16-hydroperoxyplukenetione F (3), as well as four which have been previously described, plukenetiones C, F, and G and sampsonione G.
Assuntos
Benzofenonas/química , Plantas Medicinais/química , Benzofenonas/isolamento & purificação , Frutas/química , Espectroscopia de Ressonância Magnética , Extratos Vegetais/química , Prenilação de Proteína , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
The new ergostane steroid ergosta-5,24(24')-diene-3beta,4beta,22R-triol (1), a pregnane, (E)-volkendusin, characterised as the diacetate (3), cycloartanes 4-6 and protolimonoids 7-9 were obtained from the leaves and twigs of Trichilia reticulata.
Assuntos
Ergosterol/isolamento & purificação , Furanos/isolamento & purificação , Meliaceae/química , Plantas Medicinais/química , Pregnanos/isolamento & purificação , Saponinas/isolamento & purificação , Triterpenos , Fenômenos Químicos , Físico-Química , Cromatografia , Ergosterol/análogos & derivados , Ergosterol/química , Furanos/química , Espectrometria de Massas , Conformação Molecular , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Folhas de Planta/química , Caules de Planta/química , Pregnanos/química , Saponinas/química , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta , EstereoisomerismoRESUMO
The structures of three new compounds isolated from Peperomia proctorii, named proctoriones A-C, have been established by spectroscopic and chemical methods as 2,3-dihydro-5, 8-dihydroxy-2-pentadecyl-4H-benzopyran-4-one (1) and enolic forms of 4-hydroxy-2-octadecanoylcyclohexane-1,3-dione (2) and 4-hydroxy-2-octadec-(11Z)-enoylcyclohexane-1,3-dione (3).
Assuntos
Cicloexanos/isolamento & purificação , Plantas/química , Cicloexanos/química , Estrutura Molecular , Análise EspectralRESUMO
Portal vein thrombosis has been associated with umbilical venous catheterization. We studied the incidence of portal vein thrombosis associated with umbilical venous catheterization with the catheter tip not in the portal venous system. Appropriate placement of an umbilical venous catheter in sick neonates is associated with a low risk of portal vein thrombosis (actual incidence, 1.3%).
Assuntos
Cateterismo/efeitos adversos , Veia Porta/diagnóstico por imagem , Trombose/diagnóstico por imagem , Trombose/etiologia , Veias Umbilicais/cirurgia , Fibrinolíticos/uso terapêutico , Seguimentos , Heparina/uso terapêutico , Humanos , Recém-Nascido , Estudos Prospectivos , UltrassonografiaRESUMO
A method for the determination of salbutamol in both tablets and syrups is described. It utilizes the reduction of the Folin-Ciocalteau reagent by the phenolic group, monitoring the absorbance of the resulting complex at 760 nm. Results obtained are linear over the range 0-6 mug ml(-1) salbutamol. Coloring material was removed by anionexchange chromatography prior to analysis and there was no interference from sucrose, neutral flavorings or the common preservative sodium benzoate. This method appears suitable as a general assay for salbutamol.
RESUMO
A term infant without infection by human immunodeficiency virus had pneumocystis pneumonia at 17 days of life. Initial counts of T lymphocytes carrying the CD4 antigen were approximately 50% of the lower limits of normal; later the counts of T lymphocytes carrying the CD3 and CD8 antigens decreased as well. By 7 weeks after resolution of the pneumonia, CD3+, CD4+ and CD8+ cell counts had returned to normal. These observations suggest that a primary transient deficiency of T cell production or maturation, especially involving CD4+ cells, may occur in otherwise normal newborn infants.
Assuntos
Pneumonia por Pneumocystis/imunologia , Linfócitos T , Antígenos CD4 , Humanos , Recém-Nascido , Contagem de Leucócitos , Masculino , Linfócitos T/imunologiaRESUMO
Airway samples from infants with respiratory distress syndrome were recovered by suction immediately after tracheal intubation for respiratory failure. The minimum surface tension of these airway samples was 27.3 +/- 3.0 dynes/cm. Surfactant with low surface tension (1.4 +/- 1.0 dynes/cm) was recovered from these samples by centrifugation; the supernatant fractions from the samples had high minimum surface tensions. The supernatant fractions contained soluble proteins that inhibited the surface tension-lowering properties of natural sheep surfactant. Similar supernatant fractions collected from infants intubated for reasons other than respiratory distress syndrome were much less inhibitory to sheep surfactant. The minimum surface tension of sequential daily airway samples from infants with respiratory distress syndrome fell progressively to 5.7 +/- 2.4 dynes/cm on the day of extubation. These results document the presence of proteins in the airways of infants with respiratory distress syndrome that inhibit the surface tension-lowering properties of surfactant.