RESUMEN
The main objective of this paper is to address the following question: are the containment measures imposed by most of the world governments effective and sufficient to stop the epidemic of COVID-19 beyond the lock-down period? In this paper, we propose a mathematical model which allows us to investigate and analyse this problem. We show by means of the reproductive number, ${\cal R}_0$ that the containment measures appear to have slowed the growth of the outbreak. Nevertheless, these measures remain only effective as long as a very large fraction of population, p, greater than the critical value $1-1/{\cal R}_0$ remains confined. Using French current data, we give some simulation experiments with five scenarios including: (i) the validation of model with p estimated to 93%, (ii) the study of the effectiveness of containment measures, (iii) the study of the effectiveness of the large-scale testing, (iv) the study of the social distancing and wearing masks measures and (v) the study taking into account the combination of the large-scale test of detection of infected individuals and the social distancing with linear progressive easing of restrictions. The latter scenario was shown to be effective at overcoming the outbreak if the transmission rate decreases to 75% and the number of tests of detection is multiplied by three. We also noticed that if the measures studied in our five scenarios are taken separately then the second wave might occur at least as far as the parameter values remain unchanged.
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Control de Enfermedades Transmisibles/métodos , Infecciones por Coronavirus/prevención & control , Pandemias/prevención & control , Neumonía Viral/prevención & control , Betacoronavirus , COVID-19 , Simulación por Computador , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/transmisión , Francia/epidemiología , Humanos , Modelos Teóricos , Neumonía Viral/epidemiología , Neumonía Viral/transmisión , Reproducibilidad de los Resultados , SARS-CoV-2RESUMEN
Salmonellosis is a foodborne disease of humans and animals caused by infection with Salmonella. The aim of this paper is to improve a deterministic model (DM) and an individual-based model (IBM) with reference to Salmonella propagation in flocks of laying hens taking into account variations in hens housed in the same cage and to compare both models. The spatio-temporal evolution, the basic reproduction number, R 0, and the speed of wave propagation were computed for both models. While in most cases the DM allows summary of all the features of the model in the formula for computation of R 0, slight differences between individuals or groups may be observed with the IBM that could not be expected from the DM, especially when initial environmental contamination is very low and some cages may get rid of bacteria. Both models suggest that the cage size plays a role on the risk and speed of propagation of the bacteria, which should be considered when designing new breeding systems.
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Pollos/microbiología , Vivienda para Animales , Enfermedades de las Aves de Corral/epidemiología , Salmonelosis Animal/epidemiología , Animales , Femenino , Modelos Estadísticos , Enfermedades de las Aves de Corral/microbiología , Enfermedades de las Aves de Corral/transmisión , Prevalencia , Salmonelosis Animal/transmisiónRESUMEN
BACKGROUND: Hair follicles house a permanent pool of epithelial stem cells. Intense pulsed light (IPL) sources have been successfully used for hair removal, but long-term hair reduction may require several treatments. Many questions remain regarding the impact of IPL treatment on the structure of the hair follicle, more specifically on hair follicular stem cells and dermal papilla cells, a group of specialized cells that orchestrate hair growth. OBJECTIVES: To characterize the destruction of human hair follicles and surrounding tissues following IPL treatment, with more attention paid to the bulge and the bulb regions. METHODS: Human scalp specimens of Fitzpatrick skin phototype II were exposed ex vivo to IPL pulses and were then processed for histological analysis, immunodetection of stem cell-associated keratin 19, and revelation of the endogenous alkaline phosphatase activity expressed in dermal papilla cells. RESULTS: Histological analysis confirmed that pigmented structures, such as the melanin-rich matrix cells of the bulb in anagen follicles and the hair shaft, are principally targeted by IPL treatment, while white hairs and epidermis remained unaffected. Damage caused by heat sometimes extended over the dermal papilla cells, while stem cells were mostly spared. CONCLUSIONS: IPL epilation principally targets pigmented structures. Our results suggest that, under the tested conditions, collateral damage does not deplete stem cells. Damage at the dermal papilla was observed only with high-energy treatment modalities. Extrapolated to frequently treated hairs, these observations explain why some hairs grow back after a single IPL treatment.
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Folículo Piloso/efectos de la radiación , Luz , Fototerapia/métodos , Células Madre/efectos de la radiación , Anciano , Células Epiteliales/efectos de la radiación , Remoción del Cabello/métodos , Humanos , Persona de Mediana Edad , Cuero Cabelludo/efectos de la radiación , Pigmentación de la Piel/efectos de la radiaciónRESUMEN
The synthesis of ferritin, the iron-storing molecule, is regulated at the translational level by iron through interaction between a cytoplasmic protein, iron regulatory protein (IRP), and a conserved nucleotide motif present in the 5' non-coding region of all ferritin mRNAs--the iron responsive element (IRE). This region forms a stem-loop structure and when the supply of iron to the cells is limited, the IRP is bound to IRE and represses ferritin synthesis. Ferritin is composed of a 24-subunit protein shell surrounding an iron core. The two types of subunit, H and L, are encoded by two genes located on chromosomes 11q13 and 19q13.1, respectively. Both genes are ubiquitously expressed but transcriptional regulation mediates tissue-specific changes in the H/L mRNA ratio and isoferritin profiles. We now report the identification of a single point mutation in the IRE of the L-ferritin mRNA in members from a family affected with dominantly inherited hyperferritinaemia and cataract. This mutation consists of an A to G change in the highly conserved CAGUGU motif that constitutes the IRE loop and mediates the high-affinity interaction with the IRP. We show that this mutation abolishes the binding of IRP in vitro and leads to a high constitutive, poorly regulated L-ferritin synthesis in cultured lymphoblastoid cells established from affected patients. This is, to our knowledge, the first mutation affecting the IRP-IRE interaction and the iron-mediated regulation of ferritin synthesis. We suggest that excess production of ferritin in tissues is responsible for the hyperferritinaemia and that intracellular accumulation of ferritin leads to cataract.
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Catarata/genética , Ferritinas/sangre , Ferritinas/genética , Hierro/sangre , Mutación Puntual , ARN Mensajero/genética , Secuencia de Bases , Catarata/metabolismo , Células Cultivadas , Femenino , Ferritinas/análisis , Ferritinas/biosíntesis , Ferritinas/metabolismo , Genes Dominantes , Humanos , Proteínas Reguladoras del Hierro , Hígado/química , Linfocitos , Masculino , Datos de Secuencia Molecular , Proteínas de Unión al ARN/metabolismoRESUMEN
Salmonella propagation by apparently healthy chickens could be decreased by the selection and use of chicken lines that are more resistant to carrier state. Using a reduced set of markers, this study investigates, for the first time to the authors' knowledge, the feasibility of a genomic selection approach for resistance to carrier state in hen lines. In this study, commercial laying hen lines were divergently selected for resistance to Salmonella carrier state at 2 different ages: young chicks and adults at the peak of lay. A total of 600 birds were typed with 831 informative SNP markers and artificially infected with Salmonella Enteritidis. Phenotypes were collected 28 d (389 young animals) or 38 d (208 adults) after infection. Two types of variance component analyses, including SNP data or not, were performed and compared. The set of SNP used was efficient in capturing a large part of the genetic variation. Average accuracies from mixed model equations did not change between analyses, showing that using SNP data does not increase information in this data set. These results confirm that genomic selection for Salmonella carrier state resistance in laying hens is promising. Nevertheless, a denser SNP coverage of the genome on a greater number of animals is still needed to assess its feasibility and efficiency.
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Portador Sano/veterinaria , Pollos/genética , Enfermedades de las Aves de Corral/genética , Enfermedades de las Aves de Corral/microbiología , Salmonelosis Animal/prevención & control , Salmonella enteritidis/crecimiento & desarrollo , Animales , Portador Sano/microbiología , Femenino , Genotipo , Modelos Lineales , Polimorfismo de Nucleótido Simple , Selección GenéticaRESUMEN
OBJECTIVES: Patients with major depression (MD) express frequent memory complaints leading to consultations in memory clinics. The 5-word test (5WT) is a verbal memory test with semantic cueing, which has shown its sensitivity and its specificity in identifying patients with Alzheimer's disease (AD). Our objective was to evaluate memory performances of aged patients with MD compared with controls and AD patients. METHODS: Characteristics of the 5WT were investigated in a sample of 37 patients with MD (66.8±7.5 years) compared with 36 normal controls (67.3±6.8 years) and 35 mild AD patients (67.5±6.1 years). RESULTS: Duration of depression was 15.3±11.5 years. Memory complaints of MD patients were ancient (4.6±5.5 years) and severe (McNair memory questionnaire=47.6±20.7). The Total score of MD patients did not differ from controls but was greater than those of AD patients. Learning and Memory scores of MD patients were significantly lower than those of controls and significantly greater than those of AD patients. Forgetting rate between Learning and Memory scores was more important in AD (72.4%) than in controls (2.8%) and MD (13.6%). No intrusions were recorded in controls, three MD patients each made one intrusion, whereas 80% of AD patients made between one to six intrusions (mainly during cued delayed recall). Receiver operating characteristic curves determined the most significant cut-off scores of the Total score. It appeared easy to discriminate AD patients from controls (cut-off=9, sensitivity=94.3%, specificity=100%) or MD patients (cut-off=8, sensitivity=88.5%, specificity=89.2%) whereas it was more difficult to discriminate MD patients from controls (cut-off=10, specificity=88.9%, sensitivity=37.8%). DISCUSSION: MD patients had significant difficulties with the 5WT as compared to controls, without being of the magnitude of those observed in AD patients. CONCLUSION: The 5WT allows a reliable evaluation of memory in MD patients. The presence of true memory deficits with the 5WT could not be ascribed to depression but to other pathological conditions. Consequently, further memory testing should be conducted.
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Enfermedad de Alzheimer/diagnóstico , Trastorno Depresivo Mayor/diagnóstico , Recuerdo Mental , Pruebas Neuropsicológicas/estadística & datos numéricos , Aprendizaje Verbal , Anciano , Enfermedad de Alzheimer/psicología , Enfermedad Crónica , Señales (Psicología) , Trastorno Depresivo Mayor/psicología , Femenino , Humanos , Masculino , Memoria a Corto Plazo , Persona de Mediana Edad , Psicometría/estadística & datos numéricos , Valores de Referencia , Reproducibilidad de los Resultados , Retención en Psicología , SemánticaRESUMEN
Exercise-related affective responses, particularly in-task, have been implicated as influencing behavioral maintenance. An extensive body of literature, primarily using aerobic modes in laboratory settings, has identified a relatively consistent inverse relationship between intensity and affect. This relationship is purported to be partially accounted for by the saliency of interoceptive sensations (i.e., respiratory and heart rates, muscular effort), such that increased saliency elicits decreased affect. In naturalistic settings, exercise is volitional, individuals have comparatively more autonomy over exercise components (i.e., volume, duration, exercise intensity), and less is known regarding contributing factors of affective responses. Recalled affect may be perceived as a less invasive, more logistically feasible construct to measure in such settings. Thus, the purpose of the current study is to explore the basis of recalled affective valence following an acute bout of volitional exercise. Upon leaving the designated exercise area of a university recreation center, respondents (Nâ¯=â¯236, 23y±10, 176cm±9.5, 76.9kg±16.2, 31.8% identified women, 68.2% identified men) were asked to complete a pen-and-paper survey regarding the bout they had just completed. Recalled affective valence was rated via 100â¯mm Visual Analog Scale, and respondents were asked to provide written explanation for the basis of recalled affective valence scores. Recalled affective valence scores were non-normally distributed (Mdn=81; IQR=30.5). Qualitative results indicate that interpretation of exertion and salient interoceptive sensations were mixed, resulting in both pleasant and unpleasant affective responses. Pre-exercise readiness factors (i.e., energy levels, substrate intake, and physical components) also contribute to recalled affective valence and could potentially explain variance in the interpretation of interoceptive sensations. Further research should expand on these findings through a more in-depth interview process and measuring factors of readiness before exercise.
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Afecto , Ejercicio Físico , Prueba de Esfuerzo , Fatiga , Femenino , Frecuencia Cardíaca , Humanos , MasculinoRESUMEN
Treacher Collins syndrome (TCS) is a congenital malformation of the craniofacial structures derived from the first and second pharyngeal arches. The craniofacial deformities are well described in the literature. However, little is known about whether there are associated extracraniofacial anomalies. A retrospective study was conducted using data from four craniofacial units. Medical charts were reviewed for the presence and type of extracraniofacial anomalies, as well as age at diagnosis. A possible correlation between the severity of the phenotype and the presence of extracraniofacial anomalies was assessed using the Hayashi classification. A total of 248 patients with TCS were identified; 240 were confirmed to have TCS, of whom 61 (25.4%) were diagnosed with one or more extracraniofacial anomalies. Ninety-five different extracraniofacial anomalies were found; vertebral (n=32) and cardiac (n=13) anomalies were most frequently seen, followed by reproductive system (n=11), central nervous system (n=7), and limb (n=7) anomalies. No correlations between tracts were found. Extracraniofacial anomalies were more prevalent in these patients with TCS compared to the general population (25.4% vs 0.001-2%, respectively). Furthermore, a positive trend was seen between the severity of the syndrome and the presence of extracraniofacial anomalies. A full clinical examination should be performed on any new TCS patient to detect any extracraniofacial anomalies on first encounter with the craniofacial team.
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Anomalías Craneofaciales , Disostosis Mandibulofacial , Humanos , Disostosis Mandibulofacial/diagnóstico por imagen , Fenotipo , Estudios Retrospectivos , Columna VertebralRESUMEN
Preclinical information on the biliary metabolites of a drug candidate is typically obtained through the collection of bile after surgical cannulation of the bile duct. In this study, we describe a novel approach using the Entero-Test, a simple device that facilitates the noninvasive sampling of duodenal bile. The Entero-Test was used to collect bile from six fasted dogs that had been dosed either orally with simvastatin (SV) or intravenously with simvastatin hydroxy acid (SVA), compounds that have been previously reported to undergo extensive metabolism and biliary secretion in the dog. The devices, consisting of a weighted gelatin capsule containing 90 cm of a highly absorbent nylon string, were swallowed by each dog with the proximal end of the string taped to the animal's face. Once the weighted string had reached the duodenum, gallbladder contraction was stimulated to release bile. Each bile-stained string was then retrieved via the mouth and, after solvent extraction, samples were analyzed for drug-related material by ultraperformance liquid chromatography-mass spectrometry and NMR spectroscopy. Numerous metabolites of SV and SVA were observed, and, in general, the major metabolites have been reported previously from studies with bile duct-cannulated animals dosed with [14C]SV or [14C]SVA. The results from this study demonstrate the utility of deploying the Entero-Test in absorption, distribution, metabolism, and elimination studies to provide information on the nature of biliary metabolites, which, on occasion, may be sufficient to negate the need for more invasive sampling techniques. The benefits and limitations of the technique are discussed.
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Bilis/metabolismo , Técnicas de Diagnóstico del Sistema Digestivo/instrumentación , Duodeno/metabolismo , Preparaciones Farmacéuticas/metabolismo , Animales , Bilis/química , Cromatografía Líquida de Alta Presión , Técnicas de Diagnóstico del Sistema Digestivo/efectos adversos , Perros , Duodeno/química , Glucurónidos/análisis , Glucurónidos/metabolismo , Hidroxilación , Espectroscopía de Resonancia Magnética , Estructura Molecular , Oxidación-Reducción , Preparaciones Farmacéuticas/análisis , Simvastatina/administración & dosificación , Simvastatina/análogos & derivados , Simvastatina/análisis , Simvastatina/metabolismo , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
An F(2) population (695 individuals) was established from broiler chickens divergently selected for either high (HG) or low (LG) growth, and used to localize QTL for developmental changes in body weight (BW), shank length (SL9) and shank diameter (SD9) at 9 weeks. QTL mapping revealed three genome-wide QTL on chromosomes (GGA) 2, 4 and 26 and three suggestive QTL on GGA 1, 3 and 5. Most of the BW QTL individually explained 2-5% of the phenotypic variance. The BW QTL on GGA2 explained about 7% of BW from 3 to 7 weeks of age, while that on GGA4 explained 15% of BW from 5 to 9 weeks. The BW QTL on GGA2 and GGA4 could be associated with early and late growth respectively. The GGA4 QTL also had the largest effect on SL9 and SD9 and explained 7% and 10% of their phenotypic variances respectively. However, when SL9 and SD9 were corrected with BW9, a shank length percent QTL was identified on GGA2. We identified novel QTL and also confirmed previously identified loci in other chicken populations. As the foundation population was established from commercial broiler strains, it is possible that QTL identified in this study could still be segregating in commercial strains.
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Peso Corporal , Pollos/genética , Variación Genética , Extremidad Inferior/anatomía & histología , Sitios de Carácter Cuantitativo , Selección Genética , Animales , Pollos/anatomía & histología , Pollos/crecimiento & desarrollo , Cromosomas , Femenino , Estudio de Asociación del Genoma Completo , MasculinoRESUMEN
Farm animal welfare is a major issue in Europe, which resulted in regulations and development of research dedicated to animal welfare, especially on standard poultry production, which is often considered as resulting in very poor welfare. The effect of selection is also often questioned. Indeed, capacities of adaptation have been very little considered during the first years of commercial selection and thus have been reduced. Nowadays, a much greater importance is given to welfare-related traits and genomic selection should alleviate the need for their measurements in the short-term. However, the choice of the fittest selection criteria is still to be made. Because behavioral traits are highly dependent on environment, general reactivity may be more efficient. For example, selection against undesirable behavior such as feather pecking has been proven to be efficient, but selection for reduced mortality rates in collective cages proved to be preferable. Most often, selection should not exacerbate extreme values, which are most often detrimental, as in the case of social motivation, which, when increased to too large of an extent, results in increased aggressivity. Moreover, a general propensity will not result in overall improvement; for example, reducing fearfulness has positive effects but does not modify response to social stress. Detrimental effects on other traits may also be observed: although genetic resistance to diseases should increase animal welfare, it may also result in increased frequency of silent carriers and in turn to human transmission. Indeed, an optimum must be found. Studying lines selected for or against these traits will be of great help to choose the best strategy of selection. Another and longer term concern should be on links with other production traits but also on sustainability, which will probably be of greater importance in the coming years.
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Bienestar del Animal/tendencias , Animales Domésticos/fisiología , Aves de Corral/fisiología , Enfermedades de los Animales/prevención & control , Bienestar del Animal/normas , Animales , Animales Domésticos/genética , Animales Domésticos/psicología , Ambiente , Europa (Continente) , Vivienda para Animales/normas , Conducta SocialRESUMEN
INTRODUCTION: The five-word test (5WT) is a serial verbal memory test with semantic cuing. It is proposed to rapidly evaluate memory of aging people and has previously shown its sensitivity and its specificity in identifying patients with AD. It measures the efficacy of free and cued recalls during a procedure of immediate and delayed recalls. METHODS: The 5WT was compared in a group of 202 normal subjects and a group of 302 mild AD patients (MMS of 20 or more) aged from 60 to 92 years, in three age classes (60 years, 70 years, 80 years). Nine scores were measured (Total Score, Total Weighted Score, Free Immediate Recall, Learning Score=total of Immediate Recalls, Free Delayed Recall, Memory Score=total of Delayed Recalls, Forgetting Rate, Percentage of Immediate Cuing, Percentage of Delayed Cuing) as well as the presence of intrusions. For each age class, Receiver Operating Characteristic curves determined the most significant cut-off scores. RESULTS: For each score of the 5WT, AD patients differed significantly from controls. The cut-off scores were not the same according to age. For the Total Score, the cut-off scores were 10 (60 years), 9 (70 years) and 8 (80 years), whereas the cut-off scores of the Total Weighted Score were 17 (60 years), 16 (70 years) and 14 (80 years). As suggested by Cowppli-Bony et al. (2005), the Total Weighted Score (which gives a higher coefficient to free recalls) was better than the Total Score for discriminating mild AD. The 5WT is useful to discriminate normal controls and mild AD patients. Normal aged subjects displayed good encoding, efficient stocking and consolidation (few forgetting, efficient cued recall), intrusions were rare. Mild AD patients were characterized by weak encoding of words and severe deficit for stocking and consolidation (important forgetting, impaired cued recall), they made numerous intrusions. This psychometric profile is characteristic of the amnestic hippocampal syndrome found in AD. CONCLUSION: The 5WT is a simple and reliable test for investigating memory in elderly people above 60 years old. According to age, different cut-offs are needed for the Total Score and the Total Weighted Score, the latter appearing more discriminating than the Total Score for the diagnosis of mild AD. It is also interesting to evaluate the presence of intrusions. Lastly, it is important to consider the forgetting rate (between Learning and Memory Scores) in order to confirm the presence of a hippocampal amnesia.
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Enfermedad de Alzheimer/diagnóstico , Trastornos de la Memoria/diagnóstico , Pruebas Neuropsicológicas , Índice de Severidad de la Enfermedad , Anciano , Anciano de 80 o más Años , Envejecimiento/psicología , Trastornos del Conocimiento/diagnóstico , Señales (Psicología) , Femenino , Hipocampo/fisiopatología , Humanos , Masculino , Trastornos de la Memoria/fisiopatología , Recuerdo Mental , Persona de Mediana Edad , Factores Socioeconómicos , Aprendizaje VerbalRESUMEN
INTRODUCTION: The Rapid BAttery of Denomination (BARD) is a short 10-item naming test derived from the 60-item Boston Naming Test. It is easily performed in less than 15 seconds by normal controls independently of age, gender and education (Croisile, 2005,2007,2008). Our aim was to evaluate the BARD in various conditions seen in a memory clinic. PATIENTS AND METHODS: The BARD was used in 382 normal subjects (165 men and 217 women, aged from 20 to 97 years) and 1004 patients attending a memory clinic. Three groups of 505 patients with Alzheimer's disease (AD) were compared: mild patients (n=402), moderate patients (n=84) and moderately severe patients (n=19). The BARD was also used in 499 patients with a Mini Mental Status (MMSE)>or=20: 173 patients with amnestic Mild Cognitive Impairment (aMCI), 56 patients with frontotemporal dementia (FTD), 41 patients with Lewy Body dementia (LBD), 36 patients with nonfluent primary progressive aphasia (NFPPA), 27 patients with semantic dementia (SD), 16 patients with posterior cortical atrophy (PCA), 150 patients with anxiety or depression (ADD). RESULTS: The performance of the patients was not affected by age, gender or education. aMCI had a score of 9.97+/-0.18, ADD a score of 9.97+/-0.2. A mild anomia was observed in three groups: mild AD (9.78+/-0.5), FTD (9.79+/-0.65) et LBD (9.98+/-0.16). A more pronounced anomia was present in moderate AD (9.10+/-1.06), moderately severe AD (8.05+/-1.27), PCA (8.12+/-3.28) and NFPPA (8.44+/-1.61). The anomia was severe in SD (5.85+/-2.46). The 10 items were perfectly named by 98 % of ADD, 96.53 % of aMCI, 82.09 % of mild AD, 87.5 % of FTD patients, 97.56 % of LBD patients, 68.75 % of PCA patients, but only 45.24 % moderate AD, 5.26 % of moderately severe AD, 27.78 % of NFPPA, and 3.7 % of SD. In the patients with MMS>or=20, Anova showed that the BARD scores of the ADD, aMCI, mild AD, FTD and LBD groups were significantly greater than the BARD scores of NFPPA, SD and PCA. PCA and NFPPA groups did not differ for BARD scores whereas they were significantly better than SD. A ROC curve comparing the 822 mild anomic patients (AD, FTD, LBD, aMCI, ADD) with the 79 more anomic patients (NFPPA, SD, PCA) showed that for a BARD score of 10, sensitivity was 72.2 %, specificity was 89.2 %, and 87.7 % of the patients were correctly classified. CONCLUSION: The BARD is a quick and useful tool for identifying naming disorders in a memory clinic. In patients with MMSE>or=20, making one error at the BARD is highly abnormal and significantly characteristic of cognitive disorders: the more frequent the errors are, the more probable is the presence of a visual agnosia (PCA), an aphasia (NFPPA), or a semantic disorder (SD).
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Anomia/diagnóstico , Demencia/psicología , Pruebas del Lenguaje , Nombres , Pruebas Neuropsicológicas , Índice de Severidad de la Enfermedad , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/psicología , Instituciones de Atención Ambulatoria , Anomia/psicología , Afasia/psicología , Trastornos del Conocimiento/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Curva ROCRESUMEN
Uroporphyrinogen decarboxylase deficiency in man is responsible for familial porphyria cutanea tarda and hepatoerythropoietic porphyria. A recent study of a family with hepatoerythropoietic porphyria showed that the enzyme defect resulted from rapid degradation of the protein in vivo. Cloning and sequencing of a complementary DNA for the mutated gene revealed that the mutation was due to the replacement of a glycine residue by a glutamic acid residue at position 281. This base change leads to a protein that is very rapidly degraded in the presence of cell lysate. Characterization of the mutation will allow comparison of this defect in a homozygous patient with defects in other patients with familial porphyria cutanea tarda.
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Carboxiliasas/genética , Porfirias/genética , Uroporfirinógeno Descarboxilasa/genética , Secuencia de Aminoácidos , Clonación Molecular , ADN/genética , Humanos , Hepatopatías/genética , Mutación , Enfermedades de la Piel/genética , Relación Estructura-Actividad , Uroporfirinógeno Descarboxilasa/deficiencia , Uroporfirinógeno Descarboxilasa/metabolismoRESUMEN
Partial deficiency of the last enzyme of the heme biosynthetic pathway (namely ferrochelatase, FECH) in humans is responsible for erythropoietic protoporphyria (EPP). This disorder is characterised by painful photosensitivity, due to excessive production of protoporphyrin IX (PPIX) by erythrocytes. Controversial hypotheses have been proposed to explain the hematologic and iron status of EPP patients. In the present work, we explored these parameters in 55 patients with dominant EPP recruited at the French Center of Porphyrias (Colombes, France) and confirmed by molecular analysis. Our data show that erythrocyte accumulation of PPIX in EPP patients influences hematologic and iron status. Patients studied had a mild anemia and thrombocytopenia, as shown by the downward shift of hematologic parameters, which positively correlated with the amount of erythrocyte PPIX. Interestingly, erythropoiesis did not seem to be limited by iron supply in patients, since serum iron and soluble transferring (Tf) receptor (sTfR) were normal. However, iron and Tf saturation negatively correlated with erythrocyte PPIX. Moreover, and as previously described in a mouse model of EPP, we noted a positive correlation between erythrocyte PPIX and Tf levels. Altogether, these results suggest a positive effect of PPIX on the synthesis on Tf, which could facilitate the mobilization of tissue iron stores to meet erythropoiesis requirement. Based on these observations and previous results in EPP mouse model, we propose that the PPIX-liver transferrin pathway plays a role in the orchestration of iron distribution between peripheral iron stores, the spleen and the bone marrow.
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Eritrocitos/metabolismo , Hierro/metabolismo , Protoporfiria Eritropoyética/sangre , Protoporfiria Eritropoyética/metabolismo , Protoporfirinas/metabolismo , Adolescente , Adulto , Niño , Eritropoyesis/fisiología , Femenino , Humanos , Lípidos/sangre , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Porfirinas/metabolismo , Protoporfiria Eritropoyética/genética , Adulto JovenRESUMEN
The ability of chickens to carry Salmonella without displaying disease symptoms is responsible for Salmonella propagation in poultry stocks and for subsequent human contamination through the consumption of contaminated eggs or meat. The selection of animals more resistant to carrier state might be a way to decrease the propagation of Salmonella in poultry stocks and its transmission to humans. Five QTL controlling variation for resistance to carrier state in a chicken F(2) progeny derived from the White Leghorn inbred lines N and 6(1) had been previously identified using a selective genotyping approach. Here, a second analysis on the whole progeny was performed, which led to the confirmation of two QTL on chromosomes 2 and 16. To assess the utility of these genomic regions for selection in commercial lines, we tested them together with other QTL identified in an [Nx6(1)] x N backcross progeny and with the candidate genes SLC11A1 and TLR4. We used a commercial line divergently selected for either low or high carrier-state resistance both in young chicks and in adult hens. In divergent chick lines, one QTL on chromosome 1 and one in the SLC11A1 region were significantly associated with carrier-state resistance variations; in divergent adult lines, one QTL located in the major histocompatibility complex on chromosome 16 and one in the SLC11A1 region were involved in these variations. Genetic studies conducted on experimental lines can therefore be of potential interest for marker-assisted selection in commercial lines.
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Portador Sano/veterinaria , Pollos , Inmunidad Innata/genética , Enfermedades de las Aves de Corral/genética , Sitios de Carácter Cuantitativo/genética , Salmonelosis Animal/genética , Animales , Cruzamiento/métodos , Portador Sano/microbiología , Genotipo , Enfermedades de las Aves de Corral/microbiología , Salmonelosis Animal/microbiología , Selección GenéticaRESUMEN
DMT1 deficiency causes microcytic hypochromic anemia due to decreased erythroid iron utilization. Anemia is present from birth. Transferrin saturation is high and serum ferritin is mildly elevated, despite liver iron overload. DMT1 deficiency must be considered in the differential diagnosis of microcytic hypochromic anemia observed in the newborn period.
Asunto(s)
Anemia Hipocrómica/genética , Proteínas de Transporte de Catión/genética , Genes Recesivos , Mutación , Anemia Hipocrómica/diagnóstico , Anemia Hipocrómica/tratamiento farmacológico , Proteínas de Transporte de Catión/deficiencia , Diagnóstico Diferencial , Eritrocitos/metabolismo , Eritropoyetina/uso terapéutico , Ferritinas/sangre , Genotipo , Humanos , Recién Nacido , Quelantes del Hierro/uso terapéutico , Fenotipo , Transferrina/metabolismoRESUMEN
Definitive information on the metabolism of a drug candidate in humans is achieved through dosing radiolabelled drug as part of a clinical study, and is typically conducted post-proof of concept in Phase III of the clinical development plan. Here we describe a novel approach, using preparative high performance liquid chromatography and cryoprobe-nuclear magnetic resonance spectroscopy, to determine the human systemic exposure to a drug and its metabolites using samples derived from Phase I clinical studies. Using the described methodology, novel human plasma metabolites, as low as 10 ng/ml can be detected and quantified. This provides an opportunity, early in the development process to understand the potential role of metabolites in the safety and efficacy of drugs in humans.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Espectroscopía de Resonancia Magnética/métodos , Preparaciones Farmacéuticas/sangre , Preparaciones Farmacéuticas/metabolismo , Ensayos Clínicos Fase I como Asunto , Monitoreo de Drogas/métodos , Humanos , Espectroscopía de Resonancia Magnética/instrumentaciónRESUMEN
Increasing resistance to acute Salmonellosis (that is, contamination level shortly after infection) is not sufficient to reduce the risk for consumers to be contaminated by Salmonella. Indeed, animals may remain contaminated at a low level for weeks or months. Increased resistance to the Salmonella carrier state, i.e., animals' ability to clear bacteria, is needed; it involves measuring bacterial contamination several weeks after inoculation with a low dose. To study such resistance traits, three convergent approaches were used. A quantitative trait loci (QTL) study was performed, taking advantage of inbred lines differing in resistance. Several QTLs controlling resistance at a younger age were identified and are currently being confirmed in a new cross before finer mapping, using advanced intercross lines. These inbred lines are also presently being compared using functional genomics. In parallel, a selection experiment for increased or decreased resistance at a younger and a later age was undertaken. Besides providing genetic models differing in their levels of resistance, it underlined the importance of the choice of selection criterion, whether marker assisted or not. Indeed, genes controlling resistance are strongly dependant on age; selecting for resistance at a younger age might result in increased susceptibility at an older age. Finally, the results of this experiment were used in a model of the intra-flock propagation of Salmonella. It showed that introducing a proportion of resistant animals within a flock of susceptible hens could dramatically change the evolution of contamination. Moreover, it demonstrated the magnitude of synergy between selection and vaccination, which should enhance the interest of increased resistance. The results show that selection for increased resistance to the Salmonella carrier state may be efficient, providing that the appropriate criteria of selection are used.
Asunto(s)
Portador Sano , Pollos/genética , Genómica , Salmonelosis Animal/genética , Animales , Sitios de Carácter Cuantitativo , Salmonelosis Animal/inmunologíaRESUMEN
In order to determine the molecular basis of uroporphyrinogen (URO) decarboxylase deficiency responsible for hepatoerythropoietic porphyria (HEP) and familial porphyria cutanea tarda, we used a human URO decarboxylase cDNA to analyze the organization and expression of the URO decarboxylase gene in lymphoblastoid cells from normal individuals and from two patients with HEP. We could detect neither deletions nor rearrangements in the URO decarboxylase gene. Synthesis, processing, and cell-free translation of the specific transcripts appeared to be normal. The half-life of the abnormal protein was 12 times shorter than that of the normal enzyme. The results indicate that the enzyme defect is due to a rapid degradation of the protein in vivo. This study is the first to provide information regarding the molecular mechanism responsible for the URO decarboxylase deficiency in HEP.