RESUMO
The ability of the N-methyl-d-aspartate receptor antagonist ketamine to alleviate symptoms in patients suffering from treatment-resistant depression (TRD) is well documented. In this paper, we directly compare in vivo biologic responses in rodents elicited by a recently discovered metabotropic glutamate (mGlu) 2/3 receptor antagonist 2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY3020371) with those produced by ketamine. Both LY3020371 and ketamine increased the number of spontaneously active dopamine cells in the ventral tegmental area of anesthetized rats, increased O2 in the anterior cingulate cortex, promoted wakefulness, enhanced the efflux of biogenic amines in the prefrontal cortex, and produced antidepressant-related behavioral effects in rodent models. The ability of LY3020371 to produce antidepressant-like effects in the forced-swim assay in rats was associated with cerebrospinal fluid (CSF) drug levels that matched concentrations required for functional antagonist activity in native rat brain tissue preparations. Metabolomic pathway analyses from analytes recovered from rat CSF and hippocampus demonstrated that both LY3020371 and ketamine activated common pathways involving GRIA2 and ADORA1. A diester analog of LY3020371 [bis(((isopropoxycarbonyl)oxy)-methyl) (1S,2R,3S,4S,5R,6R)-2-amino-3-(((3,4-difluorophenyl)thio)methyl)-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylate (LY3027788)] was an effective oral prodrug; when given orally, it recapitulated effects of intravenous doses of LY3020371 in the forced-swim and wake-promotion assays, and augmented the antidepressant-like effects of fluoxetine or citalopram without altering plasma or brain levels of these compounds. The broad overlap of biologic responses produced by LY3020371 and ketamine supports the hypothesis that mGlu2/3 receptor blockade might be a novel therapeutic approach for the treatment of TRD patients. LY3020371 and LY3027788 represent molecules that are ready for clinical tests of this hypothesis.
Assuntos
Antidepressivos/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Ketamina/uso terapêutico , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Depressão/metabolismo , Depressão/psicologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ketamina/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de Glutamato Metabotrópico/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Resultado do TratamentoRESUMO
Scopolamine produces rapid and significant symptom improvement in patients with depression, and most notably in patients who do not respond to current antidepressant treatments. Scopolamine is a nonselective muscarinic acetylcholine receptor antagonist, and it is not known which one or more of the five receptor subtypes in the muscarinic family are mediating these therapeutic effects. We used the mouse forced-swim test, an antidepressant detecting assay, in wild-type and transgenic mice in which each muscarinic receptor subtype had been genetically deleted to define the relevant receptor subtypes. Only the M1 and M2 knockout (KO) mice had a blunted response to scopolamine in the forced-swim assay. In contrast, the effects of the tricyclic antidepressant imipramine were not significantly altered by gene deletion of any of the five muscarinic receptors. The muscarinic antagonists biperiden, pirenzepine, and VU0255035 (N-[3-oxo-3-[4-(4-pyridinyl)-1-piper azinyl]propyl]-2,1,3-benzothiadiazole-4-sulfonamide) with selectivity for M1 over M2 receptors also demonstrated activity in the forced-swim test, which was attenuated in M1 but not M2 receptor KO mice. An antagonist with selectivity of M2 over M1 receptors (SCH226206 [(2-amino-3-methyl-phenyl)-[4-[4-[[4-(3 chlorophenyl)sulfonylphenyl]methyl]-1-piperidyl]-1-piperidyl]methanone]) was also active in the forced-swim assay, and the effects were deleted in M2 (-/-) mice. Brain exposure and locomotor activity in the KO mice demonstrated that these behavioral effects of scopolamine are pharmacodynamic in nature. These data establish muscarinic M1 and M2 receptors as sufficient to generate behavioral effects consistent with an antidepressant phenotype and therefore as potential targets in the antidepressant effects of scopolamine.
Assuntos
Antidepressivos/farmacologia , Receptor Muscarínico M1/metabolismo , Receptor Muscarínico M2/metabolismo , Escopolamina/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout/metabolismo , Atividade Motora/efeitos dos fármacos , Antagonistas Muscarínicos/farmacologia , Ratos , Ratos Sprague-Dawley , Natação/fisiologiaRESUMO
Diet influences host metabolism and intestinal microbiota; however, detailed understanding of this tripartite interaction is limited. To determine whether the nonfermentable fiber hydroxypropyl methylcellulose (HPMC) could alter the intestinal microbiota and whether such changes correlated with metabolic improvements, C57B/L6 mice were normalized to a high-fat diet (HFD), then either maintained on HFD (control), or switched to HFD supplemented with 10% HPMC, or a low-fat diet (LFD). Compared to control treatment, both LFD and HPMC reduced weight gain (11.8 and 5.7 g, respectively), plasma cholesterol (23.1 and 19.6%), and liver triglycerides (73.1 and 44.6%), and, as revealed by 454-pyrosequencing of the microbial 16S rRNA gene, decreased microbial α-diversity and differentially altered intestinal microbiota. Both LFD and HPMC increased intestinal Erysipelotrichaceae (7.3- and 12.4-fold) and decreased Lachnospiraceae (2.0- and 2.7-fold), while only HPMC increased Peptostreptococcaceae (3.4-fold) and decreased Ruminococcaceae (2.7-fold). Specific microorganisms were directly linked with weight change and metabolic parameters in HPMC and HFD mice, but not in LFD mice, indicating that the intestinal microbiota may play differing roles during the two dietary modulations. This work indicates that HPMC is a potential prebiotic fiber that influences intestinal microbiota and improves host metabolism.
Assuntos
Fibras na Dieta/administração & dosagem , Intestinos/microbiologia , Metagenoma , Metilcelulose/análogos & derivados , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Biodiversidade , Peso Corporal , Dieta com Restrição de Gorduras , Dieta Hiperlipídica , Derivados da Hipromelose , Metaboloma , Metagenoma/genética , Metilcelulose/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Filogenia , Prebióticos , RNA Bacteriano/genética , RNA Bacteriano/isolamento & purificação , RNA Ribossômico 16S/genética , RNA Ribossômico 16S/isolamento & purificaçãoRESUMO
Two primary chitinases have been identified in humans--acid mammalian chitinase (AMCase) and chitotriosidase (CHIT1). Mammalian chitinases have been observed to affect the host's immune response. The aim of this study was to test for association between genetic variation in the chitinases and phenotypes related to chronic obstructive pulmonary disease (COPD). Polymorphisms in the chitinase genes were selected based on previous associations with respiratory diseases. Polymorphisms that were associated with lung function level or rate of decline in the Lung Health Study (LHS) cohort were analyzed for association with COPD affection status in four other COPD case-control populations. Chitinase activity and protein levels were also related to genotypes. In the caucasian LHS population, the baseline forced expiratory volume in one second (FEV(1)) was significantly different between the AA and GG genotypic groups of the AMCase rs3818822 polymorphism. Subjects with the GG genotype had higher AMCase protein and chitinase activity compared with AA homozygotes. For CHIT1 rs2494303, a significant association was observed between rate of decline in FEV(1) and the different genotypes. In the African American LHS population, CHIT1 rs2494303 and AMCase G339T genotypes were associated with rate of decline in FEV(1). Although a significant effect of chitinase gene alleles was found on lung function level and decline in the LHS, we were unable to replicate the associations with COPD affection status in the other COPD study groups.
Assuntos
Quitinases/genética , Volume Expiratório Forçado , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Idoso , Líquido da Lavagem Broncoalveolar/química , Estudos de Casos e Controles , Quitinases/metabolismo , Feminino , Variação Genética , Genótipo , Humanos , Pulmão/metabolismo , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Doença Pulmonar Obstrutiva Crônica/enzimologia , Fenômenos Fisiológicos Respiratórios , FumarRESUMO
Cholecystokinin (CCK) and the different molecular forms of CCK are well established as biomarkers for satiety but accurate analysis has been limited by the multiple naturally occurring forms and extensive similarities to gastrin. Changes in levels of one form, CCK-8, a naturally occurring eight amino acid peptide of CCK, have been correlated with satiety responses. Endogenous CCK-8 has not been well characterized in Syrian Golden hamsters, an important model in the study of fat uptake and digestion. We have cloned and sequenced hamster CCK and identified and characterized endogenous CCK-8 from hamster plasma. Hamster CCK-8 is composed of eight amino acid residues which are highly conserved among other species. Following accurate identification and characterization of hamster CCK-8, we have developed a highly specific and sensitive immunoprecipitation based LC-MS/MS assay for its quantification. The present assay enables determination of active CCK-8 over a concentration range from 0.05 to 2.5 ng/mL in hamster plasma samples. This range covers both the basal and postprandial levels of CCK-8. Method performance validation samples were examined at three concentrations replicated over the course of 4 days. The assay accuracy (percent relative error, % RE) average was 11.3% with a precision (percent coefficient of variation, % CV) of 15.5% over all samples in this 4 day period. Additionally, the method was used to determine increases of endogenous plasma CCK-8 in hamsters challenged with a high-fat meal.
Assuntos
Colecistocinina/sangue , Cromatografia Líquida/métodos , Imunoprecipitação/métodos , Fragmentos de Peptídeos/sangue , Espectrometria de Massas em Tandem/métodos , Tirosina/análogos & derivados , Sequência de Aminoácidos , Animais , Sequência de Bases , Cricetinae , Gorduras na Dieta , Mesocricetus , Dados de Sequência Molecular , Alinhamento de Sequência , Tirosina/químicaRESUMO
Clinical evidence indicates that positive allosteric modulators (PAMs) of GABAA receptors have analgesic benefit in addition to efficacy in anxiety disorders. However, the utility of GABAA receptor PAMs as analgesics is compromised by the central nervous system side effects of non-selective potentiators. A selective potentiator of GABAA receptors associated with α2/3 subunits, KRM-II-81(5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole), has demonstrated anxiolytic, anticonvulsant, and antinociceptive effects in rodents with reduced motoric side effects. The present study evaluated the potential of KRM-II-81 as a novel analgesic. Oral administration of KRM-II-81 attenuated formalin-induced flinching; in contrast, diazepam was not active. KRM-II-81 attenuated nociceptive-associated behaviors engendered by chronic spinal nerve ligation (L5/L6). Diazepam decreased locomotion of rats at the dose tested in the formalin assay (10â¯mg/kg) whereas KRM-II-81 produced small decreases that were not dose-dependent (10-100â¯mg/kg). Plasma and brain levels of KRM-II-81 were used to demonstrate selectivity for α2/3- over α1-associated GABAA receptors and to define the degree of engagement of these receptors. Plasma and brain concentrations of KRM-II-81 were positively-associated with analgesic efficacy. GABA currents from isolated rat dorsal-root ganglion cultures were potentiated by KRM-II-81 with an ED50 of 32â¯nM. Measures of respiratory depression were reduced by alprazolam whereas KRM-II-81 was either inactive or produced effects with lower potency and efficacy. These findings add to the growing body of data supporting the idea that α2/3-selective GABAA receptor PAMs will have efficacy and tolerability as pain medications including those for neuropathic pain. Given their predicted anxiolytic effects, α2/3-selective GABAA receptor PAMs offer an additional inroad into the management of pain.
Assuntos
Analgésicos/farmacologia , Sinergismo Farmacológico , Formaldeído/farmacologia , Oxazóis/farmacologia , Medição da Dor , Receptores de GABA-A/metabolismo , Nervos Espinhais/cirurgia , Adjuvantes Anestésicos/farmacologia , Administração Oral , Alprazolam/administração & dosagem , Alprazolam/farmacologia , Analgésicos/administração & dosagem , Analgésicos/metabolismo , Analgésicos/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Diazepam/farmacologia , Relação Dose-Resposta a Droga , Moduladores GABAérgicos/administração & dosagem , Moduladores GABAérgicos/farmacologia , Ligadura , Masculino , Neuralgia/tratamento farmacológico , Oxazóis/administração & dosagem , Oxazóis/metabolismo , Oxazóis/uso terapêutico , Ratos , Ratos Sprague-DawleyRESUMO
Endothelin-1 (EDN1) has been reported to be implicated in the pathophysiology of asthma. Literature results on the genetic association of EDN1 in asthma are inconsistent. Eleven single nucleotide polymorphisms in EDN1 were genotyped in 342 and 100 families from UK and Norway, respectively. Asthma, bronchial hyperreactivity (BHR) and atopic asthma phenotypes were analyzed for the family-based association. Five single nucleotide polymorphisms (SNPs) were associated with asthma (0.0017Assuntos
Asma/genética
, Endotelina-1/genética
, Genética Populacional
, Polimorfismo de Nucleotídeo Único/genética
, Adolescente
, Adulto
, Alelos
, Estudos de Casos e Controles
, Criança
, Interpretação Estatística de Dados
, Família
, Feminino
, Frequência do Gene
, Marcadores Genéticos
, Haplótipos
, Humanos
, Desequilíbrio de Ligação
, Masculino
, Noruega
, Estatística como Assunto
, Reino Unido
RESUMO
BACKGROUND: Asthma is a clinically heterogeneous disease caused by a complex interaction between genetic susceptibility and diverse environmental factors. In common with other complex diseases the lack of a standardized scheme to evaluate the phenotypic variability poses challenges in identifying the contribution of genes and environments to disease expression. OBJECTIVE: To determine the minimum number of sets of features required to characterize subjects with asthma which will be useful in identifying important genetic and environmental contributors. Methods Probands aged 7-35 years with physician diagnosed asthma and symptomatic siblings were identified in 1022 nuclear families from 11 centres in six countries forming the Genetics of Asthma International Network. Factor analysis was used to identify distinct phenotypes from questionnaire, clinical, and laboratory data, including baseline pulmonary function, allergen skin prick test (SPT). RESULTS: Five distinct factors were identified:(1) baseline pulmonary function measures [forced expiratory volume in 1 s (FEV(1)) and forced vital capacity (FVC)], (2) specific allergen sensitization by SPT, (3) self-reported allergies, (4) symptoms characteristic of rhinitis and (5) symptoms characteristic of asthma. Replication in symptomatic siblings was consistent with shared genetic and/or environmental effects, and was robust across age groups, gender, and centres. Cronbach's alpha ranged from 0.719 to 0.983 suggesting acceptable internal scale consistencies. Derived scales were correlated with serum IgE, methacholine PC(20), age and asthma severity (interrupted sleep). IgE correlated with all three atopy-related factors, the strongest with the SPT factor whereas severity only correlated with baseline lung function, and with symptoms characteristic of rhinitis and of asthma. CONCLUSION: In children and adolescents with established asthma, five distinct sets of correlated patient characteristics appear to represent important aspects of the disease. Factor scores as quantitative traits may be better phenotypes in epidemiological and genetic analyses than those categories derived from the presence or absence of combinations of +ve SPTs and/or elevated IgE.
Assuntos
Asma/complicações , Asma/fisiopatologia , Volume Expiratório Forçado , Hipersensibilidade/complicações , Capacidade Vital , Adolescente , Adulto , Alérgenos/imunologia , Asma/diagnóstico , Asma/imunologia , Broncoconstritores , Criança , Análise Fatorial , Feminino , Humanos , Imunoglobulina E/sangue , Masculino , Cloreto de Metacolina , Fenótipo , Testes de Função Respiratória , Rinite/fisiopatologia , Índice de Gravidade de Doença , Testes CutâneosRESUMO
Anacardic (6-alkylsalicylic) acids and common lipids are efficiently synthesized by immature seeds of Ginkgo biloba. The seeds were incubated with 14C-labeled acetic, malonic and palmitoleic acids, glucose, and other potential precursors. Levels of 14C in common lipids and in anacardic acids, and the distribution of 14C in anacardic acids were determined. The results show that the salicylic moiety is synthesized by a polyketide pathway via malonic acid. The chain moiety for anacardic acid synthesis is in a different state of activation and/or site than chains that are used for synthesis of the common lipids. Labeled shikimic acid did not contribute 14C to anacardic acids, nor to other lipids, and palmitoleic acid was incorporated only into common lipids.
Assuntos
Plantas Medicinais/metabolismo , Salicilatos/biossíntese , Sementes/metabolismo , Acetatos/metabolismo , Caproatos/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Glucose/metabolismo , Malonatos/metabolismoRESUMO
In fibroblasts, the protein kinase C (PKC) activator phorbol 12-myristate (PMA) either inhibits or stimulates phospholipase C-mediated hydrolysis of phosphatidylethanolamine in the absence or presence of ethanol, respectively. Here, we demonstrate that the specific PKC inhibitor bisindolylmaleimide GF 109203X prevents only the inhibitory, but not the stimulatory, PMA effect.
Assuntos
Etanol/farmacologia , Indóis/farmacologia , Maleimidas/farmacologia , Fosfatidiletanolaminas/metabolismo , Proteína Quinase C/antagonistas & inibidores , Acetato de Tetradecanoilforbol/farmacologia , Fosfolipases Tipo C/metabolismo , Células 3T3 , Animais , Etanolaminas/metabolismo , Camundongos , Acetato de Tetradecanoilforbol/antagonistas & inibidoresRESUMO
The protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) stimulates both the synthesis and phospholipase D (PLD)-mediated hydrolysis of phosphatidylcholine (PtdCho). Here, attached and suspended NIH 3T3 fibroblasts as well as variants of the MCF-7 human breast carcinoma cell line expressing PKC-alpha and a PtdCho-specific PLD activity at widely different levels were used to determine the possible role of PKC-alpha, PtdCho hydrolysis, and choline uptake in the mediation of PMA effect on PtdCho synthesis. In wild-type MCF-7 cells, which express both PKC-alpha and PLD activities at very low levels, PMA had little effects on the uptake or incorporation [14C]choline into PtdCho. In multidrug resistant MCF-7/MDR1 cells, which highly express PKC-alpha but lack the PtdCho-specific PLD activity, 100-nM PMA had relatively small stimulatory effects on the uptake of [14C]choline (approximately 1.5-fold) and [14C]PtdCho synthesis (1.5- to 2-fold). In NIH 3T3 fibroblasts and MCF-7/PKC-alpha cells, both expressing PKC-alpha and PLD activities at high levels, 10-100-nM PMA enhanced [14C]choline uptake only slightly (1.7- to 2.2-fold), while it had much greater (approximately 4-9-fold) stimulatory effects on PtdCho synthesis. PMA significantly enhanced the formation of phosphatidic acid (PtdOH) in MCF-7/PKC-alpha cells (2.8-fold increase), but not in MCF-7/MDR1 cells (1.4-fold increase), while in both cell lines it had only small (1.3-1.5-fold) stimulatory effects on 1,2-diacylglycerol (1, 2-DAG) formation. In suspended NIH 3T3 cells, 200-300-mM ethanol blocked the stimulatory effect of PMA on PtdOH formation without affecting PtdCho synthesis indicating that neither PtdOH nor 1,2-DAG derived from it is a mediator of PMA effect on PtdCho synthesis. In attached NIH 3T3 cells, dimethylbenz[a]anthracene enhanced phosphocholine formation and, thus, choline uptake without increasing PtdCho synthesis or modifying the effect of PMA. While the results indicate that the stimulatory effect of PMA on PtdCho synthesis requires the expression of both PKC-alpha and a PtdCho-specific PLD, they do not support a role for 1,2-DAG, PtdOH or choline in the mediation of PMA effect.
Assuntos
Isoenzimas/metabolismo , Fosfatidilcolinas/biossíntese , Proteína Quinase C/metabolismo , Acetato de Tetradecanoilforbol/farmacologia , Fosfolipases Tipo C/metabolismo , Células 3T3 , 9,10-Dimetil-1,2-benzantraceno/farmacologia , Animais , Neoplasias da Mama , Colina/metabolismo , Colina Quinase/metabolismo , Diglicerídeos/farmacologia , Ativação Enzimática , Feminino , Humanos , Camundongos , Proteína Quinase C-alfa , Células Tumorais CultivadasRESUMO
Lipid classes from four species of mosses, Mnium cuspidatum, and Mnium medium from Minnesota, and Hylocomium splendens and Pleurozium schreberi from Alaska, were analyzed. The total lipids of all species contained 30-40% arachidonic and eicosapentaenoic acids. However, the lipids from the Alaskan mosses contained about 75% neutral lipids (triacylglycerols, steryl esters and wax esters) whereas the lipids of the other species contained only 20% or less of these neutral lipids. Consistently, monogalactosyldiacylglycerols and phosphatidylethanol-amines were enriched in arachidonic acid and the galactolipids in eicosapentaenoic acid. The distribution of these acids in the phospholipids shows some preference for position 2. Together, the highly unsaturated C20 acids represented 80% of acyl groups in steryl esters. In triacylglycerols they were at average levels, while they were much less in sulfolipids and phosphatidylglycerols. Wax esters contained very little of the highly unsaturated acids but appreciable amounts of phytol and phytenic acid were found as wax constituents.
Assuntos
Ácidos Araquidônicos/análise , Ácidos Graxos Insaturados/análise , Lipídeos , Plantas/análise , Glicerídeos/análise , Lipídeos/análise , Fosfatidilcolinas/análise , Fosfatidiletanolaminas/análise , Fosfatidilinositóis/análise , Especificidade da Espécie , Triglicerídeos/análise , Ceras/análiseRESUMO
The present study was undertaken to address the question whether lipid differentiation occurs in junctional domains which could imply a functional requirement for specific lipids in junctional structures. Junction enriched membranes were isolated from bovine lens fiber cells using Tris and urea treatment, and the presence of junctional structures was ascertained by electron microscopy. Enrichment in major intrinsic protein (MIP, MP26) was monitored by SDS polyacrylamide gel electrophoresis. Junctional lipids were extracted by a modified Folch procedure, to quantitatively recover cholesterol, and lipid classes were analyzed. While 99.5% of total lens protein was solubilized in the course of junction isolation, 43.9% of cell phospholipids (PL) and 64.1% of cell cholesterol (Chol) were conserved. Cholesterol was by far the predominant lipid in the junction enriched lens fiber cell membranes (833 nmol/mg protein) and was more abundant than all phospholipids combined (682 nmol/mg protein). In isolating the junctional membranes, cholesterol levels increased 144-fold, and average phospholipid levels increased 99-fold, which resulted in an increase in Chol/PL ratio from 0.84 to 1.22. Different phospholipids showed substantially different degrees of enrichment with highest enrichments seen for the phosphatidylethanolamine fraction (152-fold) and sphingomyelin (101-fold). Thus, the phospholipids of the junction enriched membranes consisted mainly of ethanolamine glycerophospholipids (37.3%) and sphingomyelin (28.6%), with lesser amounts of choline glycerophospholipids (23.5%) and phosphatidylserine (9.2%) present. Our data suggest that the MP26 junction enriched membranes of bovine lens fiber cells contain differentiated lipid domains, and that cholesterol, ethanolamine glycerophospholipids and sphingomyelin are the prevalent boundary lipids of the major intrinsic protein in these domains.
Assuntos
Membrana Celular/metabolismo , Junções Comunicantes/metabolismo , Cristalino/metabolismo , Glicoproteínas de Membrana , Lipídeos de Membrana/metabolismo , Animais , Aquaporinas , Bovinos , Fracionamento Celular/métodos , Colesterol/metabolismo , Proteínas do Olho/análise , Junções Comunicantes/ultraestrutura , Cristalino/citologia , Microscopia Eletrônica , Fosfatidiletanolaminas/metabolismo , Fosfolipídeos/metabolismo , Esfingomielinas/metabolismoRESUMO
Two cases of massive lower gastrointestinal hemorrhage in immunosuppressed patients were due to complicated infestation with Strongyloides stercoralis. The very high mortality of disseminated strongyloidiasis may in part be attributed to delays in diagnosis and treatment resulting from the complex life cycle of this nematode. Successful therapy in the cases presented consisted of reduction of corticosteroid dosage, use of thiabendazole in excess of that recommended for uncomplicated infestation, parenterally administered nutrition, multiple transfusion of blood products, and vigorous supportive management. Emphasis is given to proper categorization of patients and measures designed to prevent, detect, and treat hyperinfection in patients in whom immunosuppression is anticipated.
Assuntos
Terapia de Imunossupressão/efeitos adversos , Enteropatias Parasitárias/etiologia , Estrongiloidíase/etiologia , Adulto , Colo/patologia , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/etiologia , Humanos , Enteropatias Parasitárias/diagnóstico , Enteropatias Parasitárias/patologia , Masculino , Pessoa de Meia-Idade , Estrongiloidíase/diagnóstico , Estrongiloidíase/patologiaRESUMO
Porcine follicular fluid (pFF) contains a nonsteroidal factor(s) that modifies pituitary secretion of both FSH and LH under certain physiological and experimental conditions. The aim of this study was to further define the activity of pFF on basal and pulsatile gonadotropin secretion after bilateral oophorectomy in monkeys. Sexually mature female rhesus monkeys underwent bilateral oophorectomy during the early follicular phase of the menstrual cycle. For 10 consecutive days, beginning on the day of surgery, monkeys were given twice daily sc injections of 2.5 ml normal saline (group I, control; n = 3), 2.5 ml steroid-free pFF (group II; n = 3), or 5.0 ml steroid-free pFF (group III; n = 3). Blood was drawn daily for 32 days, beginning the day before castration. One day before and on days 6 and 20 after castration, monkeys were placed in a restraining chair, and blood samples were drawn every 15 min for 6 h via an indwelling venous catheter. All samples were radioimmunoassayed for FSH and LH. In group I, a significant increase in serum FSH and LH occurred on days 3 and 6 postcastration, respectively. A significant increase in serum FSH did not occur until day 13 postcastration in groups II and III. Serum LH was significantly increased on days 10 and 9 postcastration in groups II and III, respectively. The LH pulse frequency ranged from 60-105 min and did not change after castration in control or pFF-treated animals. The LH pulse increment was significantly increased on day 6 postcastration in group I, but not until day 20 postcastration in groups II and III. Only minor oscillations in FSH were found until day 20 postcastration, at which time there was no significant difference in FSH pulse frequency or increment among groups. These findings demonstrate that a nonsteroidal factor(s) in pFF suppresses basal FSH and LH concentrations and LH pulse increment in monkeys after surgical castration. Further, because LH, but not FSH, concentrations began to increase during pFF treatments, these data suggest a temporal disparity in the effects of pFF on FSH and LH secretory profiles.
Assuntos
Castração , Hormônio Foliculoestimulante/metabolismo , Hormônio Luteinizante/metabolismo , Folículo Ovariano/fisiologia , Animais , Feminino , Hormônio Foliculoestimulante/sangue , Hormônio Luteinizante/sangue , Macaca mulatta , Suínos , Fatores de TempoRESUMO
Physical illness may first declare itself as a disturbance in thinking, mood, or behavior. Recognition of physical disorders is enhanced by informed use of the relevant procedures of physical examination. Objections to physical examination are based on the assumptions that it is overly timeconsuming, is psychotherapeutically contraindicated, or requires unusual skill, but observation and minimally intrusive procedures can provide much information that may exclude emergent organic conditions. Different patients, illnesses, and settings require different levels of examination; the author describes the appropriate procedure for psychotic patients, substance abusers, patients taking psychotropic medications, and other patients.
Assuntos
Transtornos Neurocognitivos/diagnóstico , Humanos , Exame Neurológico , Exame Físico , Psicotrópicos/efeitos adversos , Transtornos Relacionados ao Uso de Substâncias/diagnósticoRESUMO
The computerized tomographic scans of five catatonic patients and five matched controls were blindly assessed. The catatonic patients showed preponderant atrophy of the brainstem and cerebellar vermis. Catatonia may be associated with lesions in these areas.
Assuntos
Tronco Encefálico/diagnóstico por imagem , Catatonia/diagnóstico , Cerebelo/diagnóstico por imagem , Idoso , Atrofia , Tronco Encefálico/patologia , Catatonia/patologia , Cerebelo/patologia , Feminino , Humanos , Hidrocefalia/diagnóstico , Hidrocefalia/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios XRESUMO
Twenty-four patients with acute functional psychoses were treated with intramuscular haloperidol in a three-hour period. There was almost complete remission of cardinal symptoms (thought disorder, hallucinations, and delusional activity) in this period for 11 patients. Acute dystonia, easily reversed, was the only significant side effect. The authors therefore suggest that outpatient management may be feasible and preferable in the treatment of some acute psychotic episodes.
Assuntos
Haloperidol/administração & dosagem , Transtornos Psicóticos/tratamento farmacológico , Doença Aguda , Relação Dose-Resposta a Droga , Haloperidol/efeitos adversos , Haloperidol/uso terapêutico , Humanos , Fatores de TempoRESUMO
We have shown that in an estrogen receptor-negative multidrug-resistant subline of MCF-7 human breast carcinoma cells longer-term (24 h), but not shorter-term (30 min), treatments with clinically relevant (2-5 microM) concentrations of tamoxifen (TAM) inhibited phorbol ester-stimulated phospholipase D (PLD) activity by 50-80%. TAM caused these inhibitory effects without inducing membrane translocation or down-regulation of protein kinase C-alpha, the major mediator of phorbol ester effects on PLD activation. The results raise the possibility that prolonged inhibition of the protein kinase C-alpha-regulated PLD system may contribute to the cytotoxic effects of tamoxifen in estrogen receptor-negative breast cancer cells.
Assuntos
Antagonistas de Estrogênios/farmacologia , Fosfolipase D/metabolismo , Proteína Quinase C/metabolismo , Transdução de Sinais/fisiologia , Tamoxifeno/farmacologia , Acetato de Tetradecanoilforbol/farmacologia , Células 3T3 , Animais , Neoplasias da Mama/patologia , Feminino , Humanos , Camundongos , Fatores de Tempo , Células Tumorais CultivadasRESUMO
Many human tumors contain high concentrations of ethanolamine phosphate (EtnP). An important question is whether increased formation of EtnP is merely the consequence of cell transformation, or is it associated with the process of carcinogenesis. Here we show that in C3H/10T1/2 embryonic fibroblasts, an established cellular model for the study of carcinogenesis, the environmental carcinogens, 7,12-dimethylbenz[a]anthracene (DMBA) and benzo[a]pyrene (B[a]P) (0.1-1 microgram/ml concentration; 24 h treatment), stimulate phosphorylation of ethanolamine derived from increased hydrolysis of phosphatidylethanolamine. The results suggest that increased formation of EtnP is associated with the early stages of carcinogenesis. This observation may have prognostic value.