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BACKGROUND: MRT5005, a codon-optimized CFTR mRNA, delivered by aerosol in lipid nanoparticles, was designed as a genotype-agnostic treatment for CF lung disease. METHODS: This was a randomized, double-blind, placebo-controlled Phase 1/2 study performed in the US. Adults with 2 severe class I and/or II CFTR mutations and baseline ppFEV1 values between 50 and 90% were randomized 3:1 (MRT5005: placebo). Six dose levels of MRT5005 (4, 8, 12, 16, 20, and 24 mg) or placebo (0.9% Sodium Chloride) were administered by nebulization. The single ascending dose cohort was treated over a range from 8 to 24 mg; the multiple ascending dose cohort received five weekly doses (range 8-20 mg); and the daily dosing cohort received five daily doses (4 mg). RESULTS: A total of 42 subjects were assigned to MRT5005 [31] or placebo [11]. A total of 14 febrile reactions were observed in 10 MRT5005-treated participants, which were mild [3] or moderate [11] in severity; two subjects discontinued related to these events. Additionally, two MRT5005-treated patients experienced hypersensitivity reactions, which were managed conservatively. The most common treatment emergent adverse events were cough and headache. No consistent effects on FEV1 were noted. CONCLUSIONS: MRT5005 was generally safe and well tolerated through 28 days of follow-up after the last dose, though febrile and hypersensitivity reactions were noted. The majority of these reactions resolved within 1-2 days with supportive care allowing continued treatment with MRT5005 and careful monitoring. In this small first-in-human study, FEV1 remained stable after treatment, but no beneficial effects on FEV1 were observed.
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Fibrose Cística , Adulto , Humanos , Fibrose Cística/diagnóstico , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/uso terapêutico , RNA Mensageiro , Aerossóis e Gotículas Respiratórios , Mutação , Método Duplo-CegoRESUMO
OBJECTIVE: Develop a methodological guide on the implementation of a PDSS (pharmaceutical decision support system). METHOD: Observational study, retrospective conducted at Lille University Hospital from May 2017 to December 2020, corresponding to the period of implementation and then use of the software. The different phases of the project are described as well as the methodology at each stage. RESULTS: Four stages seem necessary for the establishment of the PDSS: reflection and preparation of the project, contracting, implementation, use and evaluation. Based on these results and our experience, in particular the difficulties encountered, a methodological diagram of the various steps necessary for the implementation of a PDSS is proposed. CONCLUSION: The establishment of a PDSS, especially in the field of clinical pharmacy, is a long multidisciplinary process. Several steps, from project preparation to production start-up are necessary. Planning the different stages is essential for the proper implementation of the SADP so that the installation is as efficient as possible.
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Farmácia , Humanos , Retroalimentação , Estudos Retrospectivos , Hospitais , Preparações FarmacêuticasRESUMO
BACKGROUND: Less-invasive surfactant administration (LISA) is a recent technique used extensively in Europe but rarely used in North America. The aim of this study was to describe our experience following LISA implementation using poractant in a Canadian neonatal intensive care (NICU). METHODS: A retrospective analysis was conducted from June 2017 to April 2021 of LISA procedures in preterm infants. Data were collected on patient characteristics, outcomes following LISA, laryngoscopy, and adverse events. The primary outcome was the rate of successful LISA procedures. SETTING: Level IIIa academic NICU. RESULTS: LISA was successful in 93 of 101 infants (92%). Median gestational age was 30.9 weeks (interquartile range [IQR]: 29.4-33.0). All infants received atropine and fentanyl premedication. Eight LISA procedures were unsuccessful: five because of thoracic rigidity and three because of inability to expose the vocal cords. In the 93 successful procedures, a second dose of surfactant was needed for 15 of 93 infants (16.1%), either by repeated LISA (7/15; 7.5%) or by endotracheal intubation (8/15; 8.6%). In 63.4% of successful procedures, one laryngoscopy attempt was made. The median duration of laryngoscopy attempts was 60 s (IQR: 52-110). Two types of catheters were used: the multi-access catheter (MAC) or the Angiocath in 67% and 33% of procedures, respectively. One infant had bradycardia and 30.6% had profound desaturation of <75%. CONCLUSION: LISA with poractant alfa was implemented in a Canadian NICU with a high degree of procedural success. Fentanyl may lead to more adverse events with a risk of interrupting LISA and may not be the ideal agent for this procedure. These results may encourage wider dissemination of LISA in North America.
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Surfactantes Pulmonares , Síndrome do Desconforto Respiratório do Recém-Nascido , Canadá , Fentanila , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Unidades de Terapia Intensiva Neonatal , Surfactantes Pulmonares/uso terapêutico , Síndrome do Desconforto Respiratório do Recém-Nascido/induzido quimicamente , Estudos Retrospectivos , Tensoativos/uso terapêuticoRESUMO
HIV cure research is increasingly focused on anatomical tissues as sites for residual HIV replication during combined antiretroviral therapy (cART). Tissue-based HIV could contribute to low-level immune activation and viral rebound over the course of infection and could also influence the development of diseases, such as atherosclerosis, neurological disorders and cancers. cART-treated subjects have a decreased and irregular presence of HIV among tissues, which has resulted in a paucity of actual evidence concerning how or if HIV persists, replicates and evolves in various anatomical sites during therapy. In this study, we pooled 1806 HIV envelope V3 loop sequences from twenty-six tissue types (seventy-one total tissues) of six pre-cART subjects, four subjects with an unknown cART history who died with profound AIDS, and five subjects who died while on cART with an undetectable plasma viral load. A computational approach was used to assess sequences for their ability to utilize specific cellular coreceptors (R5, R5 and X4, or X4). We found that autopsied tissues obtained from virally suppressed cART+ subjects harbored both integrated and expressed viruses with similar coreceptor usage profiles to subjects with no or ineffective cART therapy (i.e., significant plasma viral load at death). The study suggests that tissue microenvironments provide a sanctuary for the continued evolution of HIV despite cART.
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Fármacos Anti-HIV/uso terapêutico , Microambiente Celular/imunologia , Infecções por HIV/imunologia , Evasão da Resposta Imune , Neoplasias/imunologia , Receptores CCR5/genética , Receptores CXCR4/genética , Terapia Antirretroviral de Alta Atividade , Autopsia , Biologia Computacional , Feminino , Expressão Gênica , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/patologia , HIV-1/genética , HIV-1/crescimento & desenvolvimento , HIV-1/imunologia , Humanos , Masculino , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Receptores CCR5/imunologia , Receptores CXCR4/imunologia , Análise de Sequência de RNA , Carga Viral/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologiaRESUMO
OBJECTIVES: The main objective of this study was to compare the responses of pharmacy residents regarding critical steps for medication order review, in the presence or absence of clinical pharmacists on patient care units, to describe the sequence of these steps and to compare them to an optimal sequence. The secondary objectives were to test this sequence in a simulation and to assess the residents' level of agreement on medication order review. METHODS: Twenty-two validation steps were selected from guidelines. A simulation on order review was organized in three steps: selecting elements judged to be necessary or not for the order review critical path, then organizing this sequence in chronological order, implementation of this critical path on two simulated practical cases, resident perceptions about order review in their training. RESULTS: Forty-one residents participated in the activity. Responses were heterogeneous regarding the elements' sequence and the time required for the review of a simulated case (3-13minutes). A majority of residents considered that their training was insufficient (29/41), that pharmacists validated differently (27/41), and that it was impossible to review the 22 proposed items for each prescription (30/41). CONCLUSIONS: This article highlights heterogeneous medication order review practices among pharmacy residents, due to a lack of training in their curriculum according to them. It is essential to acquire medication order review standard both locally and nationally.
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Educação de Pós-Graduação em Farmácia/organização & administração , Internato não Médico , Conduta do Tratamento Medicamentoso/educação , Conduta do Tratamento Medicamentoso/organização & administração , Farmacêuticos , Serviço de Farmácia Hospitalar , Simulação por Computador , Humanos , Erros de Medicação/prevenção & controleRESUMO
This study highlights the usefulness of gastropods for water quality monitoring. Gastropods were caged upstream and downstream of an effluent discharge. Exposure was assessed by measurement of organic contaminants in water. Contamination of the Potamopyrgus antipodarum mudsnail was also measured using innovative techniques at the end of the 42 days of exposure. Biological effects were measured at the individual level (growth, reproduction) and subindividual level (energy reserves, vitellin-like proteins, steroid levels, expression of genes involved in estrogen signaling pathways), thus providing a better understanding of reprotoxic effects. The effluent was mainly contaminated by pharmaceutical compounds, as was the mudsnail. The highest concentrations were measured for oxazepam and were higher than 2 mg/kg downstream of the effluent discharge. Alkylphenols, bisphenol A, and vertebrate-like sex-steroid hormones were also bioaccumulated by the mudsnail downstream of the effluent. The combined use of water and snail contamination provided a complete exposure assessment. Exposure was further linked to biological effects. The mudsnail was shown to be a better adapted species for in situ exposures than Valvata piscinalis. Reproduction was sharply decreased after 6 weeks of exposure in the mudsnail. Feeding issues were excluded, confirming the toxic origin. These effects were related to estrogen signaling pathways using genomic analysis. Genes coding for proteins involved in nongenomic signaling pathways were inhibited, and those of genomic pathway repressors were induced. These results suggest that the chemical contamination due to the effluent discharge altered steroid control of reproduction and blocked the transition between oocyte and unshelled embryo, resulting in a drastic decrease of embryo production, while survival was not affected.
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Monitoramento Ambiental , Caramujos/fisiologia , Poluentes Químicos da Água/toxicidade , Poluição da Água/análise , Animais , Bioensaio , Biomarcadores/metabolismo , França , Regulação da Expressão Gênica/efeitos dos fármacos , Modelos Biológicos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Estrogênio/metabolismo , Reprodução/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Caramujos/efeitos dos fármacos , Caramujos/crescimento & desenvolvimento , Caramujos/metabolismo , Esteroides/metabolismo , Testes de Toxicidade , Vitelogeninas/metabolismo , Eliminação de Resíduos Líquidos , Água/químicaRESUMO
A tunnel-type semi-enclosed atmosphere is characterized by a higher particulate pollution than urban zones and highlights the particulate species having an impact on material degradation. Therefore, a transverse approach between air composition and its consequences upon longevity of materials is necessary, requiring a better knowledge of tunnel atmosphere and a better understanding of material degradation inside a tunnel for operating administration. The characterization of particulate matter collected inside a road tunnel in Rouen (France) allows us to set up the features of the particle characteristics of the real conditions of field exposure. Two sampling campaigns include analyses of organic and water-soluble ionic fractions. The current work shows that organic species, grouped into two sets derived primarily from engine exhaust and debris with wear particles resuspended by the traffic, are divided into two groups: a majority comprising n-alkanes, alkanoic acids, phthalates, ketones, and benzothiazole and a minority one composed of BTEX (benzene, toluene, ethylbenzene, and xylenes), polycyclic aromatic hydrocarbons (PAHs), fatty acid methyl esters (FAMEs), furans, phenols, and alkenes. As regards the water-soluble ionic fraction, the ionic species such as Cl(-), SO4(2-), CH3COO(-), HCOO(-), NO3(-), NH4+, and Na+ are involved in the degradation process. The inorganic particles (insoluble and slightly soluble), debris and wear particles, organic acids, and relative humidity play a key role and are important factors to consider in the degradation process.
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Ar/análise , Material Particulado/química , Corrosão , França , Emissões de Veículos/análiseRESUMO
OBJECTIVE: The estimation of the fetal weight is of major interest in many situations when the route of delivery has to be determined: breech presentations, diabetes and suspected macrosomia. The objective was to evaluate the accuracy of different methods for estimating fetal weight (EFW) during labour. A quality audit of the ultrasound images was also performed. PATIENTS AND METHODS: This was a prospective study performed in thirty patients at 37 weeks gestation or more, during the second stage of labour. The accuracy of clinical versus ultrasonographic (US) approach for EFW was tested (by two formulas according to Hadlock, with one that does not account head circumference [HC]). The ultrasound images' quality was also evaluated. RESULTS: The clinical assessment was significantly more accurate (-1 ± 8.5%) than the US approach using the formula with HC (-8 ± 9.8 %) (P<0.01). This difference was not found when choosing the formula without HC. Analysis of ultrasound images for abdomen and femur showed 74% and 89% of satisfactory measurements respectively, but only 43% for HC. CONCLUSION: These results did not demonstrate a superiority of the US over the clinical approach for EFW during labour. Taking into account the cephalic measurements appeared as a limitation of the accuracy of US formulas.
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Peso Fetal/fisiologia , Trabalho de Parto , Diagnóstico Pré-Natal/normas , Ultrassonografia Pré-Natal/normas , Adolescente , Adulto , Feminino , Idade Gestacional , Humanos , Gravidez , Adulto JovemRESUMO
In the pivotal phase II/III trial of idursulfase administered intravenously to treat mucopolysaccharidosis II, approximately half of the patients developed antibodies to idursulfase. This post-hoc analysis of data from the phase II/III trial and extension study examined the relationship between antibody status and outcomes. A total of 63 treatment-naïve patients received 0.5 mg/kg of intravenous idursulfase weekly for two years. Thirty-two patients (51%) were positive for anti-idursulfase IgG antibodies, 23 of whom (37%) became persistently positive. All patients who developed an antibody response did so by their scheduled Week 27 study visit. Positive antibody status appeared to have no statistically significant effect upon changes in six-minute walk test distance, percent predicted forced vital capacity, or liver and spleen volume. All patients showed significant decreases in urinary GAG levels, although the antibody positive group maintained somewhat higher urinary GAG levels than their antibody-negative counterparts at the end of study (138.7 vs. 94.7 µg/mg creatinine, p = 0.001). Antibody positivity was not associated with a higher event rate for serious adverse events. Among patients who had no prior infusion-related reactions, antibody positive patients were 2.3 times more likely to have a first infusion-related reaction than those who would remain negative (p = 0.017); the risk increased to 2.5 times more likely for those who were persistently positive (p = 0.009). These differences in risk disappeared among patients with a previous infusion-related reaction, likely because of preventive measures. A genotype analysis for the 36 patients with available data found that patients with nonsense or frameshift mutations may be more likely to develop antibodies, to experience infusion-related reactions, and to have a reduced uGAG response than those with missense mutations, suggesting the possibility that antibodies are not a driver of clinical outcomes but rather a marker for genotype.
Assuntos
Anticorpos/imunologia , Terapia de Reposição de Enzimas , Iduronato Sulfatase/imunologia , Iduronato Sulfatase/uso terapêutico , Mucopolissacaridose II/tratamento farmacológico , Mucopolissacaridose II/imunologia , Administração Intravenosa , Adolescente , Adulto , Criança , Pré-Escolar , Terapia de Reposição de Enzimas/efeitos adversos , Genótipo , Glicoproteínas/genética , Glicosaminoglicanos/urina , Humanos , Iduronato Sulfatase/administração & dosagem , Iduronato Sulfatase/efeitos adversos , Fígado/metabolismo , Fígado/patologia , Mucopolissacaridose II/genética , Tamanho do Órgão , Baço/metabolismo , Baço/patologia , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: To identify the defence mechanisms manifested by medical staff which could disturb the decision making, revealed by professionals of human science (PHS) in morbidity and mortality conferences (MMC). MATERIALS AND METHODS: Application of two methods of psychological intervention in MMC, conducted between March 1st, 2009 and November 30, 2010, in 20 randomized maternity among five perinatal networks: the method of inter-active problem solving targeted at the functioning of the teams and the method for developing professional practice centred on individual. The data collection was realized during analyse of case in MMC, with note-taking by two pair PHS. The oral expressions of RMM' participant were secondarily re-written, analyzed and classed by theme. RESULTS: Fifty-four MMC were performed. The mechanisms of defence have been identified by PHS intervention in MMC: denial of situation, pact of denegation, rift and overprotection. They were be identified by two PHS intervention methods, this consolidates these results. This intervention began staff medical to transformation at different level, in particular to improve the capacity of cooperation. CONCLUSION: The identification of the mechanisms of defence in MMC enables staff medical to improve communication and quality relationship between healthcare professionals. This could constitute an actual factor of practices improvement. However, complementary studies must be performed to confirm this hypothesis.
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Auditoria Clínica/métodos , Eticistas , Pessoal de Saúde/psicologia , Obstetrícia , Complicações na Gravidez/epidemiologia , Complicações na Gravidez/mortalidade , Psicologia Médica , Atitude do Pessoal de Saúde , Auditoria Clínica/organização & administração , Tomada de Decisões/ética , Mecanismos de Defesa , Feminino , Pessoal de Saúde/ética , Maternidades/estatística & dados numéricos , Humanos , Recém-Nascido , Masculino , Morbidade , Obstetrícia/ética , Mortalidade Perinatal , Gravidez , Prática Profissional , Psicologia Médica/organização & administração , Recursos HumanosRESUMO
With regard to automotive traffic, a tunnel-type semi enclosed atmosphere is characterized by a higher concentration of gaseous pollutants than on urban traffic roads and highlights the gaseous effluent species having an impact on material degradation. Therefore, a transverse approach between air quality and its consequences upon the longevity of materials is necessary, implying better knowledge of tunnel atmosphere and a better understanding of material degradation inside a tunnel for operating administration. Gaseous pollutant measurements carried out in a road tunnel in Rouen (Normandy) give the real world traffic concentrations of experimental exposure conditions. The sampling campaigns, achieved in summer and winter include SO2, NO2, BTEX and aldehyde analyses. Effluent profiles in the upward and downward tubes have been established. The current work shows that SO2, NO2, formaldehyde, acetaldehyde, propanal and butanal must be considered in the degradation process of materials in a stuffy environment. As regards NO2, its concentration depends on the modification of the automotive fleet. The total aldehyde concentrations indicate no particular trend between the two bores. Formaldehyde, acetaldehyde, propanal, butanal and acrolein species are the most abundant species emitted by vehicles and represent 90% to 95% of the total aldehyde emissions.
Assuntos
Aldeídos/análise , Dióxido de Nitrogênio/análise , Dióxido de Enxofre/análise , Emissões de Veículos/análise , Compostos Orgânicos Voláteis/análise , Ar/análise , Materiais de ConstruçãoRESUMO
We have previously shown that neonatal high oxygen (O2) exposure in rats leads to hypertension and vascular dysfunction in adulthood. Pulse-wave velocity (PWV), an indirect measure of vascular biophysical properties (arterial stiffness or distensibility), is a sensitive marker of cardiovascular health. Its measurement in rats is mostly based on invasive hemodynamics measurements, prohibiting longitudinal studies particularly relevant in models of developmental programming of cardiovascular dysfunctions. With this study, we sought (1) to verify the feasibility and validity of measuring of aortic PWV in Sprague-Dawley rats by ultrasound; (2) to use the technique to compare aortic PWV in adult rats exposed to O2 as newborns (80% day 3-10 of life) v. controls; and (3) to develop an algorithm to calculate PWV in a non-invasive manner. We calculated aortic PWV using standard echocardiography and electrocardiogram, and validated the measures with PWV obtained by intraaortic catheters. Aortic full length was measured at sacrifice. PWV was significantly increased in O2 exposed (505 ± 18 cm/s) v. control animals (421 ± 17 cm/s, P < 0.01). With regard to weight, femur length and distance from the manubrium to the anal margin (MA length), the latter showed the best correlation (R = 0.84, P < 0.0001) with full aorta length derived from (L) = 0.339 × (MA length) + 4.281. The current data using echo-Doppler method demonstrated increased aortic stiffness in adult rats exposed to hyperoxia as newborns and suggests that non-invasive longitudinal studies of aortic PWV can be performed using the proposed algorithm for estimation of the full aorta length.
RESUMO
We report a new macroscopic first-field-induced magnetic anisotropy for Co/α-Fe2O3(0001) layers, a prototypical ferromagnetic-antiferromagnetic interface for which the antiferromagnetic film has small in-plane magnetic anisotropy as compared to the interface coupling. We demonstrate that the effect is due to a first-field-induced irreversible magnetic domain motion in the antiferromagnetic layer, dragged by the ferromagnetic Co one. Whereas the initial domain matching is lost, the macroscopic manifestations of the exchange coupling remain stable. Therefore, the initial domain matching probably has only a marginal role in the explanation of the magnetic exchange coupling.
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BACKGROUND: Recent studies suggested substantial differences between primary tumors and metastases for EGFR expression in colorectal cancer (CRC). The aim of the study was to correlate the expression of a panel of molecular markers between primary CRC samples and metastases. METHODS: Expressions of EGFR, pEGFR, VEGF, pVEGF, PTEN, pAKT and p21 were analyzed in 28 primary tumors and 32 liver metastases by immunohistochemistry performed on formalin-fixed, paraffin-embedded sections from 46 CRC patients. The molecular profiles were evaluated by tissue micro-array. The correlation between tumor and metastasis biomarker expressions was tested. RESULTS: Among 60 CRC samples, 25% were EGFR positive, 38% were pEGFR positive, 38% were VEGF positive, 48% were pVEGF positive, 70% were pAKT positive and 51% were p21 positive. PTEN was deleted in 39% of cases and absence of p21 expression was found in 49% of cases. A significant correlation was observed between primary tumors and metastases for pAKT (p = 0.037) and pEGFR (p = 0.0002) status. In patients treated with cetuximab-based therapy (n = 18), p21 appeared as a significant predictive factor of response (p = 0.036). CONCLUSION: Biomarkers status may change between primary and metastatic sites in CRC, with potential implications for the identification of patients who are likely to respond to anti-EGFR treatment.
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Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/metabolismo , Proteínas de Neoplasias/metabolismo , Adulto , Idoso , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Antineoplásicos/uso terapêutico , Bevacizumab , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Cetuximab , Neoplasias Colorretais/tratamento farmacológico , Inibidor de Quinase Dependente de Ciclina p21 , Receptores ErbB/metabolismo , Feminino , Humanos , Irinotecano , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Masculino , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
We present a case of analytical interference on three parameters (lactate dehydrogenase, uric acid and alkalin phosphatase), caused by a monoclonal IgM, evidenced in a patient with Waldenström disease. Mechanism of interference was probably related to the formation of complexes between paraprotein and lithium heparin, which result in precipitation during clinical chemistry assays, inducing a bias in the results. Management recommendations in case of suspicion of interference in clinical chemistry analysis are detailed. Are discussed for the case report, clinical consequences, possible mechanisms and evolution of interference under treatment, according to the concentration of the monoclonal protein.
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Anticorpos Monoclonais/sangue , Imunoglobulina M/sangue , Macroglobulinemia de Waldenstrom/sangue , Idoso , Fosfatase Alcalina/sangue , Erros de Diagnóstico , Humanos , L-Lactato Desidrogenase/sangue , Masculino , Reprodutibilidade dos Testes , Ácido Úrico/sangue , Macroglobulinemia de Waldenstrom/enzimologia , Macroglobulinemia de Waldenstrom/imunologiaRESUMO
The role of histaminergic neurotransmission in the promotion of waking has been extensively studied in preclinical species. Appreciation for the role of histamine continues to expand with increasing understanding of the interaction of histamine within the broad network of neuromodulators that regulate sleep and wake. The effects of histamine on waking are transduced through the H(1) and the H(3) receptors in the central nervous system. Brain penetrant over-the-counter antihistamines comprised of antagonist actions at H(1) receptors as well as varying degrees of antimuscarinic properties are marketed as sleep aids, based on their well-known daytime drowsiness side effects. The data supporting their use as sedatives, however, are not consistent. H(3) receptors are presynaptic receptors that limit histamine release as well as that of monoamine neurotransmitters thought to participate in the maintenance of waking. In this review, we discuss the existing studies on various antihistamines and antagonists of the H(1) receptor in the regulation of sleep in preclinical studies, normal subjects and in subjects with sleep disorders. In addition, we review the current data available on the use of ligands at H(3) receptors for the modulation of sleep and wake.
Assuntos
Ritmo Circadiano/fisiologia , Histamínicos/uso terapêutico , Histamina/fisiologia , Transtornos do Sono do Ritmo Circadiano/tratamento farmacológico , Animais , Ritmo Circadiano/efeitos dos fármacos , Histamínicos/farmacologia , Humanos , Receptores Histamínicos H3/fisiologiaRESUMO
OBJECTIVE: Primiparity has been identified as the main risk factor of type 3 and 4 perineal injuries The purpose of our study, according to a population-based observational study, was to identify other clinical risk factors for lesions during vaginal delivery. PATIENTS AND METHODS: Two groups have been compared. Group A or study group (n=63) was defined as parturients with three or four-degree perineal tears. Group B or control group (n=67) included women who delivered vaginally without any perineal lesion during the same period. Characteristics of the population were compared: maternal age, race, maternal weight, BMI (Body Mass Index), parity, mode of anaesthesia, gestational age, post maturity, length of labor, fetal weight, mode of delivery (assisted or not). Specific characteristics were also compared, obesity, shoulder dystocia, type of presentation, episiotomy and dose of ocytocin. RESULTS: Primiparity was significantly associated with higher frequency of sphincter lacerations (71 vs 43%, p=0.001). The patients of group A were with significantly higher weight than the patients of control group (67 vs 63 kg, p=0.036). Futhermore the BMI was different in the two groups (25,6 vs 23,4, p=0.003). There was a significant difference according to the length of the second part of labor (68 vs 48 min, p=0.037) and the posterior variety (32 vs 4%, p<0.001). The occurrence of shoulder dystocia was only just significant (6 vs 0%, p=0.052). Assisted-extraction is highly associated with perineal injuries (44 vs 1%, p<0.001). Futhermore the instrument has been concerned by the difference: Tarnier's forceps-assisted extraction (14 vs 1%, p=0.003), Suzor's forceps-assisted extraction (16 vs 0%, p=0.0005), Thierry's spatula-assisted extraction (14 vs 0%, p=0,0005). The association forceps and episiotomy has been found with higher frequency of perineal injury (43 vs 1%, p<0,0001). There were no difference between the 2 groups according fetal characteristics, type of analgesia, maternal age, gestational age, post-maturity or dose of ocytocin. DISCUSSION AND CONCLUSION: Primiparity is not the only risk factor of perineal injuries. Other risk factors have been found: assisted-extraction, occiput posterior fetal head position, and association episiotomy and assisted-extraction. Black origin seems to be protective.
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Parto Obstétrico/efeitos adversos , Episiotomia/efeitos adversos , Forceps Obstétrico/efeitos adversos , Paridade , Períneo/lesões , Adulto , Canal Anal/lesões , Parto Obstétrico/métodos , Distocia , Etnicidade , Feminino , Humanos , Ocitocina/efeitos adversos , Gravidez , Fatores de RiscoRESUMO
1 1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidine (JNJ-5207852) is a novel, non-imidazole histamine H3 receptor antagonist, with high affinity at the rat (pKi=8.9) and human (pKi=9.24) H3 receptor. JNJ-5207852 is selective for the H3 receptor, with negligible binding to other receptors, transporters and ion channels at 1 microm. 2 JNJ-5207852 readily penetrates the brain tissue after subcutaneous (s.c.) administration, as determined by ex vivo autoradiography (ED50 of 0.13 mg kg(-1) in mice). In vitro autoradiography with 3H-JNJ-5207852 in mouse brain slices shows a binding pattern identical to that of 3H-R-alpha-methylhistamine, with high specific binding in the cortex, striatum and hypothalamus. No specific binding of 3H-JNJ-5207852 was observed in brains of H3 receptor knockout mice. 3 In mice and rats, JNJ-5207852 (1-10 mg kg(-1) s.c.) increases time spent awake and decreases REM sleep and slow-wave sleep, but fails to have an effect on wakefulness or sleep in H3 receptor knockout mice. No rebound hypersomnolence, as measured by slow-wave delta power, is observed. The wake-promoting effects of this H3 receptor antagonist are not associated with hypermotility. 4 A 4-week daily treatment of mice with JNJ-5207852 (10 mg kg(-1) i.p.) did not lead to a change in body weight, possibly due to the compound being a neutral antagonist at the H3 receptor. 5 JNJ-5207852 is extensively absorbed after oral administration and reaches high brain levels. 6 The data indicate that JNJ-5207852 is a novel, potent and selective H3 antagonist with good in vitro and in vivo efficacy, and confirm the wake-promoting effects of H3 receptor antagonists.
Assuntos
Antagonistas dos Receptores Histamínicos/farmacologia , Piperidinas/farmacologia , Receptores Histamínicos H3/efeitos dos fármacos , Vigília/efeitos dos fármacos , Administração Oral , Animais , Autorradiografia , Temperatura Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , AMP Cíclico/metabolismo , Eletrodos , Eletroencefalografia/efeitos dos fármacos , Eletromiografia/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos/administração & dosagem , Antagonistas dos Receptores Histamínicos/farmacocinética , Humanos , Injeções Intravenosas , Masculino , Camundongos , Camundongos Knockout , Camundongos Obesos , Atividade Motora/efeitos dos fármacos , Piperidinas/administração & dosagem , Piperidinas/farmacocinética , Polissonografia , Ratos , Ratos Sprague-Dawley , Receptores Histamínicos H3/genética , Sono/efeitos dos fármacos , TransdutoresRESUMO
OBJECTIVE: To investigate cognitive and behavioural effects of bilateral lead implants for high frequency stimulation (HFS) of the subthalamic nucleus in patients with Parkinson's disease; and to discriminate between HFS and the effects of surgical intervention on cognitive function by carrying out postoperative cognitive assessments with the stimulators turned on or off. METHODS: Motor, cognitive, behavioural, and functional assessments were undertaken in 20 patients with Parkinson's disease before implantation and then at three, six, and 12 months afterwards. Nine patients were also examined 18 months after surgery. Postoperative cognitive assessments were carried out with stimulators turned off at three and 18 months, and turned on at six and 12 months. RESULTS: Cognitive assessment showed a significant postoperative decline in performance on tasks of letter verbal fluency (across all postoperative assessments, but more pronounced at three months) and episodic verbal memory (only at three months, with stimulators off). At three, six, and 12 months after surgery, there was a significant improvement in the mini-mental state examination and in a task of executive function (modified Wisconsin card sorting test). On all postoperative assessments, there was an improvement in parkinsonian motor symptoms, quality of life, and activities of daily living while off antiparkinsonian drugs. A significant postoperative decrease in depressive and anxiety symptoms was observed across all assessments. Similar results were seen in the subgroup of nine patients with an 18 month follow up. Following implantation, three patients developed transient manic symptoms and one showed persistent psychic akinesia. CONCLUSIONS: Bilateral HFS of the subthalamic nucleus is a relatively safe procedure with respect to long term cognitive and behavioural morbidity, although individual variability in postoperative cognitive and behavioural outcome invites caution. Stimulation of the subthalamic nucleus does not per se appear to impair cognitive performance in patients with Parkinson's disease and may alleviate the postoperative decline in verbal fluency.
Assuntos
Transtornos Cognitivos/terapia , Terapia por Estimulação Elétrica , Testes Neuropsicológicos , Doença de Parkinson/terapia , Transtornos do Comportamento Social/terapia , Núcleo Subtalâmico/fisiopatologia , Idoso , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/fisiopatologia , Avaliação da Deficiência , Dominância Cerebral/fisiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Exame Neurológico , Avaliação de Processos e Resultados em Cuidados de Saúde , Doença de Parkinson/diagnóstico , Doença de Parkinson/fisiopatologia , Transtornos do Comportamento Social/diagnóstico , Transtornos do Comportamento Social/fisiopatologia , Comportamento Verbal/fisiologiaRESUMO
Safety Pharmacology is now specified by various European and international guidelines. The ICHS7A text, which has now been implemented, requires all new compounds to be tested before any administration in humans. The compound should be evaluated under GLPs for its potential effects on so-called vital functions (cardio-vascular, respiratory and central nervous system). Also, the potential risk for QT prolongation and Torsades de Pointes should be appropriately assessed using in vitro and in vivo models (CPMP/986/96 and draft ICHS7B) before the initiation of Phase I. Various other European or international guidelines relate to more specific evaluations: abuse liability, anti-osteoporotic compounds, etc. Safety Pharmacology should also, as other studies required for regulatory submission, be conform to the electronic records and signature constraints (CFR23 part 11 for the USA) and to the format of the Common Technical Document (ICHM4). To address all these requirements, the pharmaceutical industry should now be creating specially assigned Safety Pharmacology teams.