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OBJECTIVE: Pseudoxanthoma elasticum (PXE) is a rare autosomal disorder with a variable phenotype that may be modulated by environmental factors. Plasma vitamin K (VK) levels may be involved in the ectopic calcification process observed in PXE. Since VK2 is predominantly produced by the gut microbiota, we hypothesized that changes in the gut microbiota of PXE patients might exacerbate the calcification process and disease symptoms. METHODS: Twenty PXE patients were included in the study and 60 gut microbiota profiles from the Biofortis laboratory database were used as controls. RESULTS: The Rhodospirillaceae family was more abundant in the PXE group while the Sphingomonadaceae family was more abundant in the control group. In a PXE severity subgroup analysis, microbiota dispersion was lower in "severe" than in "non-severe" patients, which was confirmed by permutation multivariate analysis of variance at the phylum, family and genus ranks. However, no significant association was found in a model incorporating relative abundance of bacterial families, severity score, and different blood and fecal VK species. CONCLUSION: These results suggest slight compositional changes in the gut microbiota of PXE patients. Further studies are needed to substantiate their impact on VK metabolism and the calcification process.
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BACKGROUND: The French cancer control strategy 2021-2030 aims to achieve 80 % human papillomavirus (HPV) vaccination coverage. Since 2021, HPV vaccination is also recommended for boys aged 11-14 years, with a catch-up vaccination recommended for unvaccinated adolescents aged ≤19 years. The PAPILLON study used claims data to monitor the evolution of HPV Vaccination Coverage Rate (VCR) in the French population. METHODS: The annual HPV VCR was described from 2017 to 2022. Partial vaccination was defined as the dispensing of at least one dose of HPV vaccination. Full scheme vaccination was defined according to the current French recommendations as two or three doses of HPV vaccine over an 18-month period. Annual HPV vaccine initiation rates were estimated on 11-14 and 15-19-year-olds adolescents. Cumulative VCR were estimated on adolescents aged between 11 and 19 years at the time of first vaccination. RESULTS: Overall, 1,773,900 females and 592,167 males initiated HPV vaccination between 2017 and 2022. Initiations occurred between 11 and 14 years for 67.3 % of females and 62.4 % of males with a median time between the first two doses of 195 days and 190 days, respectively. In girls, the cumulative vaccination rate for the partial scheme vaccination at 15 y.o. increased from 28.1 % in 2017 to 50.9 % in 2022. Similarly, the cumulative vaccination rate for the full scheme vaccination at 16 y.o. increased from 15.5 % in 2017 to 33.8 % in 2022. In 2022, the initiation rates for males were 12.6 % at age 14 and 1.9 % at age 19. CONCLUSIONS: HPV vaccination coverage increased between 2017 and 2022 among girls targeted by the recommendation but remains insufficient. The results of this study show a tentative but promising start to vaccination in boys. This study will monitor the effects of actions taken to improve vaccination, including the extension of vaccination competencies to community pharmacists since end of 2022.
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OBJECTIVE/BACKGROUND: Social media use could have deleterious effects on mental health through short sleep duration and poor sleep quality among adolescents. This study aimed to investigate the mediating role of both sleep duration and sleep quality in the association between social media use and mental health among adolescents. PATIENTS/METHODS: We used cross-sectional data collected from adolescents in the EXIST pilot project conducted during COVID-19 pandemic. Adolescents self-reported wellbeing (WEMWBS), anxiety and depression (HADS) as mental health outcomes. We used ad-hoc questionnaires to assess social media use during weekdays and weekend days, and sleep duration and quality. Mediation analyses were carried out following Baron and Kenny's method, using adjusted linear regression models. RESULTS: A total of 340 adolescents (13.5 ± 0.6 years, 45.3 % girls) were included. Greater social media use, poorer sleep quality, and shorter sleep duration were associated with poorer mental health. Greater social media use was associated with poorer sleep quality only during the weekend days. The total effect of social media use during weekend days on anxiety (ß = 2.54; 95%CI [-1.59; 6.68]) was significantly conveyed through sleep quality (ß = 1.22; 95%CI [0.17; 2.62]; mediated proportion = 48.0 %) and duration (mediated proportion = 46.8 %). Mediated proportions ranged from 12.5 % to 20.6 % for wellbeing and depression. Mediating effects were not evident during weekdays. CONCLUSIONS: Sleep duration and quality mediated the association between social media use and mental health among adolescents during weekend days but not weekdays. Our findings highlight the importance of promoting healthy social media habits, especially during periods of increased reliance on digital platforms, such as COVID-19 pandemic.
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COVID-19 , Distúrbios do Início e da Manutenção do Sono , Transtornos do Sono-Vigília , Mídias Sociais , Feminino , Humanos , Adolescente , Masculino , Saúde Mental , Estudos Transversais , Projetos Piloto , Pandemias , COVID-19/epidemiologia , Sono , Inquéritos e QuestionáriosAssuntos
Anticonvulsivantes/farmacologia , Linfócitos T CD4-Positivos/metabolismo , Herpesvirus Humano 7/fisiologia , Oligossacarídeos/metabolismo , Ativação Viral/efeitos dos fármacos , Adulto , Idoso , Anticonvulsivantes/efeitos adversos , Contagem de Linfócito CD4 , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Toxidermias/etiologia , Feminino , Humanos , Leucócitos Mononucleares , Antígenos CD15/análogos & derivados , Antígenos CD15/metabolismo , Masculino , Pessoa de Meia-Idade , Antígeno Sialil Lewis X/análogos & derivados , Linfócitos T Reguladores , Ácido Valproico/farmacologiaRESUMO
Daptomycin exhibits clinical activity in the treatment of infections with Gram-positive organisms, including infections due to methicillin-resistant Staphylococcus aureus. However, little is known about its penetration into bone and synovial fluid. The aim of our study was to assess the penetration of daptomycin into bone and synovial fluid after a single intravenous administration. This study was conducted in 16 patients who underwent knee or hip replacement and received a single intravenous dose of 8 mg of daptomycin per kg of body weight prior to surgery. Plasma daptomycin concentrations were measured 1 h after the end of daptomycin infusion and when bone fragments were removed. Daptomycin concentrations were also measured on bone fragments and synovial fluid collected at the same time during surgery. All samples were analyzed with a diode array-high-performance liquid chromatography (HPLC) method. After a single-dose intravenous infusion, bone daptomycin concentrations were above the MIC of daptomycin for Staphylococcus aureus in all subjects, and the median bone penetration percentage was 9.0% (interquartile range [IQR], 4.4 to 11.4). These results support the use of daptomycin in the treatment of Staphylococcus aureus bone and joint infections.
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Antibacterianos/farmacocinética , Artroplastia de Substituição , Osso e Ossos/metabolismo , Daptomicina/farmacocinética , Líquido Sinovial/metabolismo , Idoso , Idoso de 80 Anos ou mais , Antibioticoprofilaxia , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-IdadeRESUMO
The microbiological quality of experimental animals can critically influence animal welfare and the validity and reproducibility of research data. It is therefore important for breeding and experimental facilities to establish a laboratory animal health monitoring (HM) programme as an integrated part of any quality assurance system. FELASA has published recommendations for the HM of rodent and rabbit colonies in breeding and experimental units (Nicklas et al. Laboratory Animals, 2002), with the intention of harmonizing HM programmes. As stated in the preamble, these recommendations need to be adapted periodically to meet current developments in laboratory animal medicine. Accordingly, previous recommendations have been revised and shall be replaced by the present recommendations. These recommendations are aimed at all breeders and users of laboratory mice, rats, Syrian hamsters, guinea pigs and rabbits as well as diagnostic laboratories. They describe essential aspects of HM, such as the choice of agents, selection of animals and tissues for testing, frequency of sampling, commonly used test methods, interpretation of results and HM reporting. Compared with previous recommendations, more emphasis is put on the role of a person with sufficient understanding of the principles of HM, opportunistic agents, the use of sentinel animals (particularly under conditions of cage-level containment) and the interpretation and reporting of HM results. Relevant agents, testing frequencies and literature references are updated. Supplementary information on specific agents and the number of animals to be monitored and an example of a HM programme description is provided in the appendices.
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BACKGROUND/PURPOSE: Contact between skin surface and external environment induces a microclimate at the skin surface. That microclimate affects skin interaction with xenobiotics substances. We have developed a new device to explore the influence of environmental parameters, on percutaneous absorption. The aim of this study was to study the influence of external humidity and temperature on percutaneous absorption of caffeine. METHODS: Six exposure conditions were tested: four by combining two temperatures (27°C and 42°C) with two relative humidities (28% and 70%), performed by our device and two others by using Franz diffusion cell (unoccluded conditions, with skin surface in contact with ambient laboratory environment (27°C/33%) and in occluded conditions with skin surface covering by impermeable membrane). RESULTS: Kinetic curve profile of percutaneous absorption of caffeine revealed different shapes characteristics depending on environmental exposure conditions. These profiles were related to evaporative process, of deposited preparation on skin surface combined with water uptake resulting from water flux through skin. CONCLUSION: Our results highlight a preponderant role of microclimate above the skin on percutaneous absorption of caffeine. The device used in this study will be a useful tool to investigate ex vivo, the influence of microclimate on percutaneous absorption.
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Ar Condicionado/instrumentação , Cafeína/administração & dosagem , Cafeína/farmacocinética , Ecossistema , Absorção Cutânea/fisiologia , Pele/metabolismo , Administração Cutânea , Adulto , Ambiente Controlado , Desenho de Equipamento , Análise de Falha de Equipamento , Feminino , Humanos , Umidade , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Temperatura , Perda Insensível de Água/fisiologiaRESUMO
The aim of this work was to look for a simple method to obtain synchronized ovulation in guinea pigs under farming conditions while respecting animal welfare. The luteolytic activity of three different prostaglandins F2alpha (PGF2α) analogs (D-cloprostenol, D,L-cloprostenol and luprostiol) and a daily treatment with oral progestagen (altrenogest) was tested successively at different stages of the estrous cycle on the same group of females during a period of 8 mo. The estrous cycle length was not modified by the administration of PGF2α analogs, whatever the stage of the estrous cycle when the treatment was initiated. Our results led us to reject the use of PGF2α analog to induce practical synchronization of the estrus in this species. In females (n = 29), given 15 days with altrenogest (0.1 mL po once a day), ovulation occurred 4.43 ± 0.13 days after the end of the treatment. Altrenogest treatment was followed by mating. No negative impacts of the treatment on the pregnancy rates, delivery rates and litter sizes were observed. This standard method of guinea-pig estrus synchronization is less stressful for the animals compared to techniques using progesterone tubing.
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Ciclo Estral/fisiologia , Sincronização do Estro/métodos , Cobaias/fisiologia , Animais , Cruzamento/métodos , Cloprostenol/administração & dosagem , Cloprostenol/farmacologia , Cloprostenol/uso terapêutico , Relação Dose-Resposta a Droga , Esquema de Medicação , Ciclo Estral/efeitos dos fármacos , Sincronização do Estro/efeitos dos fármacos , Feminino , Luteolíticos/farmacologia , Luteolíticos/uso terapêutico , Ovulação/efeitos dos fármacos , Ovulação/fisiologia , Gravidez , Prostaglandinas F Sintéticas/administração & dosagem , Prostaglandinas F Sintéticas/farmacologia , Prostaglandinas F Sintéticas/uso terapêutico , Fatores de Tempo , Acetato de Trembolona/administração & dosagem , Acetato de Trembolona/análogos & derivados , Acetato de Trembolona/farmacologia , Acetato de Trembolona/uso terapêuticoRESUMO
Therapeutic approaches of cancers have been recently improved by the development of targeted therapies. Amongst these new drugs, some anti-angiogenic molecules have been approved by either the EMEA or the Food and Drug Administration. Sorafenib, one of these inhibitors of angiogenesis, has been established as the standard of care for advanced hepatocellular and renal carcinoma. This paper reviews the safety profile of sorafenib and presents guidelines for the prevention and the treatment of the main side effects associated with this molecule.
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Antineoplásicos/uso terapêutico , Benzenossulfonatos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Piridinas/uso terapêutico , Antineoplásicos/efeitos adversos , Benzenossulfonatos/efeitos adversos , Carcinoma de Células Renais/patologia , Ensaios Clínicos como Assunto , Diarreia/induzido quimicamente , Diarreia/prevenção & controle , Fadiga/induzido quimicamente , Fadiga/prevenção & controle , Dermatoses do Pé/induzido quimicamente , Dermatoses do Pé/prevenção & controle , Dermatoses da Mão/induzido quimicamente , Dermatoses da Mão/prevenção & controle , Humanos , Hipertensão/induzido quimicamente , Hipertensão/prevenção & controle , Neoplasias Renais/patologia , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/efeitos adversos , Sorafenibe , Resultado do TratamentoRESUMO
The role of the SDF-1alpha chemokine-CXCR4 receptor system on tumor cell transendothelial migration was studied by culturing metastatic breast tumor cell lines, MDA-MB-231 and MDA-MB-435, either alone or on a HUVEC monolayer pre-established on a "Transwell" filter. After a 24-hour culture in the presence or absence of SDF-1alpha, tumor cell transmigration rates were compared. We showed that: CXCR4 is present on both cell lines; MDA-MB-231 but not MDA-MB-435 cell migration is stimulated by increasing concentrations of SDF-1alpha; neutralizing anti-CXCR4 antibody inhibits the SDF-1alpha chemoattractant effect; CXCR4 expression, measured by cytofluorometry, was enhanced after treatment with SDF-1alpha on MDA-MB-231 cells but remained unchanged on MDA-MB-435 cells; Scatchard analysis evidences 8.10(5) and 2.10(5) high affinity sites (KD range: 20 to 30 nM) on, respectively, MDA-MB-231 and MDA-MB-435 cells. These significant differences could explain the distinctive transendothelial migration responses of these two cell lines in the presence of SDF-1alpha.
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Adenocarcinoma/patologia , Neoplasias da Mama/patologia , Movimento Celular/fisiologia , Quimiocinas CXC/farmacologia , Endotélio Vascular/citologia , Receptores CXCR4/fisiologia , Adenocarcinoma/metabolismo , Neoplasias da Mama/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Quimiocina CXCL12 , Quimiocinas CXC/metabolismo , Técnicas de Cocultura , Relação Dose-Resposta a Droga , Endotélio Vascular/metabolismo , Citometria de Fluxo , Humanos , Cinética , Receptores CXCR4/biossíntese , Receptores CXCR4/metabolismoRESUMO
The evolutions in treatments and clinical practices in organ transplantations led to modifications in the therapeutic drug monitoring (TDM) of immunosuppressive drugs. A focus is made regarding the C2 sampling of cyclosporin, as well as the TDM of mycophenolate mofetil and sirolimus. A review of literature about the evolution of drug monitoring, technical methods and sampling strategies is described. Arguments in favour of TDM are thus a decrease in the frequency of both graft rejection and adverse drug reactions, however, new strategies or new targets are needed in new associations or indications.
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Ciclosporina/farmacocinética , Monitoramento de Medicamentos/métodos , Imunossupressores/farmacocinética , Ácido Micofenólico/farmacocinética , Sirolimo/farmacocinética , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Monitoramento de Medicamentos/normas , Técnica de Imunoensaio Enzimático de Multiplicação , Rejeição de Enxerto , Transplante de Coração , Humanos , Transplante de Rim , Transplante de Fígado , Ácido Micofenólico/análogos & derivados , Seleção de Pacientes , Reprodutibilidade dos Testes , Fatores de Tempo , Imunologia de TransplantesRESUMO
The adhesion of breast adenocarcinoma cells (MDA-MB-231) to human umbilical vein endothelial cells (HUVEC) was studied in whole blood and under varying flow conditions. This study was done on HUVEC either kept under static conditions or pre-conditioned in flow for 2 hours at a shear stress of 5 or 13 dyn/cm(2). Coverslips coated by HUVEC were placed in a parallel plate perfusion chamber and perfused at a shear rate of 300 or 1500 sec(-1) with heparin-anticoagulated blood containing 111In labelled MDA-MB-231 cells. We report here the optimal conditions for studying the adhesion of MDA-MB-231 to endothelial cells under shear constraints corresponding to those observed into small and medium sized arteries.
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Adenocarcinoma/patologia , Neoplasias da Mama/patologia , Endotélio Vascular/patologia , Células Neoplásicas Circulantes/patologia , Adesão Celular , Feminino , Humanos , Estresse Mecânico , Células Tumorais Cultivadas , Veias Umbilicais/patologiaRESUMO
The aim of this study was to determine the metabolism and the tolerance of a new amino acid (AA) solution administered under conditions mimicking cyclical parenteral nutrition (PN) in humans. Eight healthy volunteers received peripheral PN for 10 h providing 10.5 mg N x kg(-1) x h(-1) and 2.0 kcal x kg(-1) x h(-1) (glucose-to-lipids ratio: 70/30%). For adaptation, a non-protein energy intake was increased progressively for 90 min; thereafter, AA infusion was started and maintained at a constant rate for 10 h. Plasma and urine concentrations of all the AAs were measured before, during and after the PN. For each given AA, the relation between plasma variations at the steady-state and infusion rate, plasma clearance (Cl), renal clearance (Clr), re-absorption rate (Reab) and, retention rate (Reten) were determined. The nitrogen balance (DeltaN) was calculated during the PN period. The results are presented as means+/-sem. All plasma AA concentrations decreased during the starting period of non-protein energy intake. The plasma AA concentrations reached a steady-state within 3 h upon AA infusion, except for glycine and lysine (6 h). At the steady state, the plasma concentrations of the infused AAs were closely correlated to their infusion rate (y= -18.3+1.5x, r(2)=0.92). The plasma glutamine concentration was maintained during the PN, which indicates that the solution might stimulate the de novo synthesis of this AA. When the PN was stopped, plasma levels of the AAs decreased, most of them returning to their basal levels, or significantly below for lysine (P<0.05), alanine (P<0.05), proline (P<0.01) and glutamine (P<0.05). No volunteer showed any adverse effect during the infusion period. DeltaN was: 0.8+/-0.5 gN/10 h. Metabolic characteristics for essential AAs were: Cl<0.5 l min(-1), Clr <1.5 ml x min(-1) Reab >or= 99%, Reten >or=99% and for non-essential AAs: Cl <0.6 l x min(-1) except aspartate (2.8+/-0.3 l x min(-1)), Clr < 3 ml x min(-1) except glycine (6.8+/-0.7), aspartate (8.2+/-3.5) and histidine (8.8+/-1.3); Reab >or= 98% except glycine (95+/-1), aspartate (94+/-2) and histidine (94+/-1), Reten >or=97% except histidine (94+/-1), glycine (95+/-3). These results indicate that in healthy subjects, the amounts of AAs provided by the new solution were well balanced for an intravenous administration, and so were well utilized without excessive urinary excretion. The present study provides useful metabolic parameters for a further evaluation in disease.
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Aminoácidos/farmacocinética , Nutrição Parenteral Total/métodos , Adulto , Aminoácidos/administração & dosagem , Aminoácidos/efeitos adversos , Humanos , Masculino , Taxa de Depuração Metabólica , Nitrogênio/metabolismo , Nutrição Parenteral Total/efeitos adversos , SoluçõesRESUMO
OBJECTIVE: To study the correlation of urinary cotinine levels in mothers and newborns with the number of cigarettes smoked at the end of pregnancy. Population and methods. We recorded the smoking habits of 123 mothers attending a university maternity clinic and measured urinary cotitine levels in mothers and their newborns. All mothers were Europeans and gave birth to a normal full-term (37 weeks gestation) infant. Cotinine levels were measured with high-performance liquid chromatography from urine samples taken during the 6-hour period prior to or after delivery for the mothers and 24-h after birth for the newborns. RESULTS: The average cotinine level for non-smoking mothers, for those who smoked one to nine cigarettes a day and heavy smokers (ten or more cigarettes per day) were 0.21, 2.17 and 4.28 mol/l respectively (p<0.001). The average levels in their newborns were 0.04, 0.39 and 1.36 mol/l respectively (p<0.001). Thirteen percent of the mothers who claimed they did not smoke had cotinine levels higher than the significance cut-off (0.3 mol/l). There was a significant correlation 1) between the number of cigarettes the mothers stated they smoked at the end of pregnancy and their urinary cotinine concentrations (cotinine level=0.213 + 0.349 cigarettes, r=0.78, p<0.001); 2) between the number of cigarettes smoked and newborn's urinary cotinine concentration (cotinine level=0.002 + 0.104 cigarettes/day, r=0.81, p<0.001); and 3) between the mother's and the newborn's urinary cotinine concentrations (newborn cotinine=0.027 + 0.219 maternal cotinine, r=0.77, p<0.001). CONCLUSION: The number of cigarettes smoked at the end of pregnancy accounts for roughly 50% of the variance in the mother's urinary cotinine level and that in her newborn at birth. The urinary cotinine concentration in newborns is 3 to 5 times lower than that of their mothers. A woman smoking 3 cigarettes per day has a urinary cotinine concentration of 1 mol/l. The urinary cotinine level in newborns is 1 mol/l for mothers smoking 10 cigarettes per day.
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Cromatografia Líquida de Alta Pressão , Cotinina/urina , Troca Materno-Fetal , Fumar/urina , Feminino , Idade Gestacional , Humanos , Recém-Nascido , GravidezRESUMO
Affinity maturation of the B cell response to antigen (Ag) takes place in the germinal centers (GCs) of secondary follicles. Two sequential molecular mechanisms underpin this process. First, the B cell repertoire is diversified through hypermutation of the immunoglobulin (Ig) variable region genes. Second, mutant B cell clones with improved affinity for Ag are positively selected by Ag and CD40 ligand (L). This selection step is contingent upon "priming" of GC B cells for apoptosis. The molecular means by which B cell apoptosis is initiated and controlled in the GC remains unclear. Here, we show that GC B cell apoptosis is preceded by the rapid activation of caspase-8 at the level of CD95 death-inducing signaling complex (DISC). We found that GC B cells ex vivo display a preformed inactive DISC containing Fas-associated death domain-containing protein (FADD), procaspase-8, and the long isoform of cellular FADD-like IL-1beta-converting enzyme-inhibitory protein (c-FLIP(L)) but not the CD95L. In culture, c-FLIP(L) is rapidly lost from the CD95 DISC unless GC B cells are exposed to the survival signal provided by CD40L. Our results suggest that (a) the death receptor signaling pathway is involved in the affinity maturation of antibodies, and (b) c-FLIP(L) plays an active role in positive selection of B cells in the GC.
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Proteínas Adaptadoras de Transdução de Sinal , Apoptose , Linfócitos B/imunologia , Caspases/metabolismo , Centro Germinativo/imunologia , Peptídeos e Proteínas de Sinalização Intracelular , Linfócitos B/citologia , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD , Proteínas de Transporte , Caspase 8 , Caspase 9 , Inibidores de Caspase , Ativação Enzimática , Proteína de Domínio de Morte Associada a Fas , Centro Germinativo/citologia , Humanos , Modelos Imunológicos , Transdução de Sinais , Receptor fasRESUMO
OBJECTIVES: To study the effect of a parenteral nutrition solution enriched with potential precursors of glutamine, i.e., arginine and glutamate, on plasma glutamine concentrations and protein metabolism. DESIGN: Prospective, randomized, single-blind, comparative study. SETTING: Two intensive care units in two different hospitals. PATIENTS: Fifteen surgical patients. INTERVENTIONS: Patients were randomized to receive total parenteral nutrition for 5 days with the enriched glutamine precursor solution (GlnP+ group) or a conventional solution (control group), both total parenteral nutrition providing 0.25 gN/kg per day and 35 kcal/kg per day (glucose/lipids, 70%:30%). MEASUREMENTS AND MAIN RESULTS: Plasma amino acid concentrations before (T0) and after 3 hrs (T3) of perfusion, nitrogen balance (daily and cumulated), and urinary excretion of 3-methylhistidine were measured daily from day 1 to day 5. The two groups were identical for age, weight, severity score, and nitrogen and energy intakes. After a 3-hr perfusion, plasma concentrations of arginine, ornithine, and glutamine increased, and the differences (T3 - T0) were significantly higher in the GlnP+ group: arginine, 107.6+/-7.0 vs. 51.9+/-3.3 (mean over 5 days; p < .001); ornithine, 78.9+/-7.1 vs. 43.6+/-3.1 (p < .001); and glutamine, 32.4+/-8.6 vs. 6.7+/-5.0 micromol/L (p < .05), respectively. A positive correlation was found between arginine and glutamine plasma increases only in the GlnP+ group: r = .45; p < .01 (Spearman's rank-correlation test). Daily and cumulated nitrogen balances were not significantly different between the two groups but were positive (difference from 0) only in the GlnP+ group. The urinary 3-methylhistidine/creatinine ratio decreased significantly from day 1 to day 5 only in the GlnP+ group: 24.5+/-2.7 vs. 18.8+/-2.7 micromol/mmol (p < .05). CONCLUSIONS: Total parenteral nutrition enriched with arginine and glutamate promotes a better nitrogen balance, limits protein myofibrillar catabolism, and generates glutamine, with arginine (not glutamate) probably being the main contributor to the glutamine-generating effect of the solution through the formation of ornithine.
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Arginina/administração & dosagem , Cuidados Críticos , Ácido Glutâmico/administração & dosagem , Proteínas Musculares/metabolismo , Nutrição Parenteral Total , Complicações Pós-Operatórias/terapia , Adolescente , Adulto , Idoso , Arginina/metabolismo , Feminino , Ácido Glutâmico/metabolismo , Humanos , Masculino , Metilistidinas/metabolismo , Pessoa de Meia-Idade , Nitrogênio/metabolismo , Complicações Pós-Operatórias/fisiopatologia , Estudos Prospectivos , Método Simples-CegoRESUMO
The Fas/Fas ligand (L) system plays an important role in the maintenance of peripheral B cell tolerance and the prevention of misguided T cell help. CD40-derived signals are required to induce Fas expression on virgin B cells and to promote their susceptibility to Fas-mediated apoptosis. In the current study, we have analyzed the early biochemical events occurring upon Fas ligation in CD40L-activated primary human tonsillar B cells with respect to Fas-associated death domain protein (FADD), caspase-8/FADD-like IL-1beta-converting enzyme (FLICE), and c-FLICE inhibitory protein (FLIP). We report here that Fas-induced apoptosis in B cells does not require integrity of the mitochondrial Apaf-1 pathway and that caspase-8 is activated by association with the death-inducing signaling complex (DISC), i.e., upstream of the mitochondria. We show that both FADD and the zymogen form of caspase-8 are constitutively expressed at high levels in virgin B cells, whereas c-FLIP expression is marginal. In contrast, c-FLIP, but neither FADD nor procaspase-8, is strongly up-regulated upon ligation of CD40 or the B cell receptor on virgin B cells. Finally, we have found that c-FLIP is also recruited and cleaved at the level of the DISC in CD40L-activated virgin B cells. We propose that c-FLIP expression delays the onset of apoptosis in Fas-sensitive B cells. The transient protection afforded by c-FLIP could offer an ultimate safeguard mechanism against inappropriate cell death or allow recruitment of phagocytes to ensure efficient removal of apoptotic cells.
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Apoptose/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Proteínas de Transporte/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular , Receptor fas/metabolismo , Linfócitos B/citologia , Linfócitos B/enzimologia , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD , Antígenos CD40/metabolismo , Ligante de CD40 , Proteínas de Transporte/biossíntese , Proteínas de Transporte/metabolismo , Caspase 8 , Caspase 9 , Caspases/metabolismo , Células Cultivadas , Ativação Enzimática/imunologia , Proteína Ligante Fas , Humanos , Hidrólise , Ligantes , Ativação Linfocitária/imunologia , Glicoproteínas de Membrana/imunologia , Glicoproteínas de Membrana/metabolismo , Potenciais da Membrana/imunologia , Mitocôndrias/imunologia , Mitocôndrias/metabolismo , Transdução de Sinais/imunologia , Receptor fas/imunologia , Receptor fas/fisiologiaRESUMO
Using the validated probe drug debrisoquine and the 8 h urinary metabolic ratio debrisoquine/4 hydroxy-debrisoquine, we have determined the phenotype of the debrisoquine CYP2D6 dependent polymorphic metabolism in 464 Arabs, 227 Berbers and 215 Numides to elicit similarities or dissimilarities of poor metabolizer (PM) prevalence. We found 2.36 per cent of PM in Arabs, 3.08 per cent in Berbers and 2.33 per cent in Numides. These figures are similar to those observed in Middle East populations, and cannot be considered as different from those observed in Caucasians.
Assuntos
Citocromo P-450 CYP2D6/genética , Polimorfismo Genético/genética , Adolescente , Adulto , Árabes , Debrisoquina , Etnicidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , TunísiaRESUMO
The performance of the Olympus AU 600, a newly available open multiparametric analyzer, available for routine biochemical analysis of biological samples, was evaluated. The analytical and technical performance of the apparatus and the quality of the Olympus reagents were both examined in a single site study. Electrolyte concentrations were determined with patented ion-selective electrodes; substrate concentrations and enzyme activities were determined by spectrophotometric measurement after coloured reaction or UV detection-based-reactions. The protocol of the evaluation and the acceptability criteria were those recommended by the French Society for Clinical Biology. For the parameters studied, the upper limits of linearity were equal to or higher than those claimed by the manufacturer. The CV values for within-run and between-run precision were lower than the target values with few exceptions. The comparison study gave satisfactory results for most of the parameters. Only expected interferences occurred. In summary, the results obtained for the 25 parameters studied and the characteristics of the apparatus were satisfactory. The analyzer is rapid (800 to 1200 tests per hour) and easy to use. In addition, the analyzer complies with good analytical practice and its flexibility enables users to plan work according to local laboratory constraints.
Assuntos
Autoanálise/instrumentação , Análise Química do Sangue/instrumentação , Testes de Química Clínica/instrumentação , Análise Química do Sangue/métodos , Calibragem , Testes de Química Clínica/métodos , Eletrólitos/sangue , Eletrólitos/urina , Enzimas/sangue , Enzimas/urina , Humanos , Valores de ReferênciaRESUMO
Codeine and its main metabolites appear to have advantages for assessing drug metabolic phenotypes. The authors have further developed a high-performance liquid chromatography (HPLC) method for the quantification of codeine and six of its metabolites in urine. Quantification was performed by electrochemical detection for morphine, normorphine, morphine-6-glucuronide, and the internal standard 4-O-methyldopamine; and by ultraviolet detection for codeine, norcodeine, and morphine-3-glucuronide. The method had a detection limit of 2 nmol/L(-1) for morphine and normorphine, 4 nmol/L(-1) for morphine-6-glucuronide, 3 nmol/L for the internal standard, 20 nmol/L(-1) for morphine-3-glucuronide, and 60 nmol/L(-1) for codeine and norcodeine. The coefficients of variations were <9% for intraday and <10% for interday analyses. The recovery of codeine and its metabolites ranged from 55% (for morphine-3-glucuronide) to 90% (for codeine, norcodeine, morphine, and morphine-6-glucuronide). Eleven healthy volunteers were phenotyped for CYP2D6 using codeine as well as debrisoquine and dextromethorphan. Ten subjects were extensive metabolizers (EM) and one a poor metabolizer (PM) of codeine, debrisoquine, and dextromethorphan. Significant correlations between the metabolic ratios (MRs) of the different probe drugs were obtained (r2 > 0.95, p < 0.001). This HPLC method is simple, sensitive, accurate, and reproducible for assessing the CYP2D6 phenotype.