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BACKGROUND: Acute flaccid myelitis (AFM) syndrome consists of loss of lower motor neurons following a viral infection, with preserved sensory function. It usually affects the upper limbs asymmetrically, with proximal more than distal muscle involvement. METHODS: Five cases were surgically treated with nerve transfers: spinal accessory to suprascapular nerve transfer (4 patients), branch of radial nerve to axillary nerve transfer (Somsak's procedure) (2 patients), and transfer of a fascicle of the ulnar nerve to the motor branch to the biceps (Oberlin's procedure) (1 patient). RESULTS: Motor improvement was seen in three cases. Widespread motor involvement was associated with poor outcome. CONCLUSION: This small series of cases reinforces that nerve transfers are a reliable option for treatment of selected children with AFM.
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Enfermedades Virales del Sistema Nervioso Central , Mielitis , Transferencia de Nervios , Enfermedades Neuromusculares , Niño , Humanos , Mielitis/cirugía , Nervio CubitalRESUMEN
OBJECTIVES: Medication reconciliation is widely promoted by international health authorities. Its expansion requires human resources, which are limited and unequally distributed among health care facilities. Recent international studies support the involvement of pharmacy technician in the medication reconciliation process but his role remains unstructured in France. We aimed to assess pharmacy technicians' opinions and willingness to be involved in the medication reconciliation process expansion and to identify the levers and barriers of the project. METHODS: A field study was conducted among health facilities of our territory hospital group. Semi-structured interviews were carried out with different pharmacy technicians. Data were analyzed using a qualitative thematic analysis approach. RESULTS: Overall, 12 pharmacy technicians from 5 hospitals were interviewed and almost all assumed their rightful place in the medication reconciliation process (n=11), with a view to revaluating tasks. For all pharmacy technicians, the main barriers to participate in medication reconciliation were the lack of time and training. The spread of a "patient culture", the supervision by pharmacists, the desire to be part of the care team in the ward and additional training requests were major levers of change. CONCLUSIONS: Pharmacy technicians' role in expanding medication reconciliation process is legitimate and must be standardized in France. The deployment of the project requires to be formalized within a territory and should consider and develop local organisations.
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Conciliación de Medicamentos/métodos , Servicio de Farmacia en Hospital/organización & administración , Técnicos de Farmacia , Actitud del Personal de Salud , Francia , Humanos , Organización y Administración , Farmacéuticos , Técnicos de Farmacia/educaciónRESUMEN
The diagnosis and follow-up of candidemia still rely on blood cultures (BCs). In vitro studies show that antifungals can significantly modify the result of blood culture not containing adsorbing agents. We aimed to evaluate, under clinical conditions, the impact on BC yeast detection of systemic antifungal therapy (SAT). Patients (n = 125) experiencing candidemia at Grenoble University Hospital (France) were included in a 4-year retrospective study. The Plus Aerobic/F (Aerobic) and Plus Anaerobic/F (Anaerobic) bottles, which both contain adsorbing resins and the non-resin selective Mycosis IC/F (Mycosis) bottles, were compared using multivariate hierarchical models adjusted for clinical characteristics. The positivity rate (PR) is decreased in patients with SAT (p < 0.01), abdominal surgery (p = 0.01), and hemodialysis (p = 0.02). In all bottles, SAT reduces PR by a factor of 0.16 (95 % CI: [0.08; 0.32]) and increases the time to positivity (TTP) by a factor of 1.76 ([1.30; 2.40]; p < 0.01). In the presence of SAT, TTP is higher in non-resin bottles (Mycosis) than in resin bottles (RR = 1.76, [1.30; 2.40]); however, the TTP in nonresin and resin bottles remains comparable. Although discordant results are observed with and without SAT (37 and 58 % respectively), we showed that the presence of SAT decreases significantly the agreement rate by a factor of 0.29 (CI: [0.12; 0.68]). The combination of Anaerobic and Mycosis bottles allowed a 100 % positivity rate for C. glabrata. SAT significantly affects BC results. Because they provide additional and complementary results, this study supports the concomitant use of resin and selective bottles, especially in patients receiving SAT.
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Antifúngicos/uso terapéutico , Candida , Candidemia , Candidiasis/tratamiento farmacológico , Candidiasis/microbiología , Anciano , Candida/aislamiento & purificación , Candidiasis/diagnóstico , Femenino , Humanos , Masculino , Técnicas Microbiológicas , Persona de Mediana Edad , Oportunidad Relativa , Estudios RetrospectivosRESUMEN
INTRODUCTION: Within the cystic fibrosis patients' home care, EMERAA network ("Together against Cystic fibrosis in Rhone-Alpes and Auvergne") organizes parenteral antibiotics cures at home prepared in elastomeric infusion devices by hospital pharmacies. However, patients and nurses found that the durations of infusion with these devices were often longer than the nominal duration of infusion indicated by their manufacturer. This study aimed to identify the potential different causes in relation to these discordances. MATERIAL AND METHODS: Three hundred and ninety devices of two different manufacturers are tested in different experimental conditions: three antibiotics each at two different doses, duration of cold storage (three days or seven days) or immediate tests without cold storage, preparation and storage of the solution in the device (protocol Device) or transfer in the device just before measurement (protocol Pocket). RESULTS: All tests highlighted a longer flow duration for devices prepared according to the protocol Device versus the protocol Pocket (P=0.004). Flow duration is increased in the case of high doses of antibiotics with high viscosity such as piperacilline/tazobactam. DISCUSSION: The results of this in vitro study showed the impact of: (1) the time between the filling of the device and the flow of the solution; (2) cold storage of elastomeric infusion devices; (3) concentration of antibiotics and therefore the viscosity of the solution to infuse. CONCLUSION: It is therefore essential that health care teams are aware of factors, which may lead to longer infusion durations with these infusion devices. When the additional time for infusion remain acceptable, it should be necessary to inform the patient and to relativize these lengthening compared to many benefits that these devices provide for home care.
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Antibacterianos/análisis , Frío , Almacenaje de Medicamentos , Elastómeros/administración & dosificación , Análisis de Inyección de Flujo , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Fibrosis Quística/tratamiento farmacológico , Estabilidad de Medicamentos , Almacenaje de Medicamentos/métodos , Bombas de Infusión , Soluciones FarmacéuticasRESUMEN
Ataxia-telangiectasia (A-T) is a recessive multi-system disorder caused by mutations in the ATM gene at 11q22-q23 (ref. 3). The risk of cancer, especially lymphoid neoplasias, is substantially elevated in A-T patients and has long been associated with chromosomal instability. By analysing tumour DNA from patients with sporadic T-cell prolymphocytic leukaemia (T-PLL), a rare clonal malignancy with similarities to a mature T-cell leukaemia seen in A-T, we demonstrate a high frequency of ATM mutations in T-PLL. In marked contrast to the ATM mutation pattern in A-T, the most frequent nucleotide changes in this leukaemia were missense mutations. These clustered in the region corresponding to the kinase domain, which is highly conserved in ATM-related proteins in mouse, yeast and Drosophila. The resulting amino-acid substitutions are predicted to interfere with ATP binding or substrate recognition. Two of seventeen mutated T-PLL samples had a previously reported A-T allele. In contrast, no mutations were detected in the p53 gene, suggesting that this tumour suppressor is not frequently altered in this leukaemia. Occasional missense mutations in ATM were also found in tumour DNA from patients with B-cell non-Hodgkin's lymphomas (B-NHL) and a B-NHL cell line. The evidence of a significant proportion of loss-of-function mutations and a complete absence of the normal copy of ATM in the majority of mutated tumours establishes somatic inactivation of this gene in the pathogenesis of sporadic T-PLL and suggests that ATM acts as a tumour suppressor. As constitutional DNA was not available, a putative hereditary predisposition to T-PLL will require further investigation.
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Ataxia Telangiectasia/genética , Leucemia de Células T/genética , Mutación , Proteínas Serina-Treonina Quinasas , Proteínas/genética , Secuencia de Aminoácidos , Animales , Proteínas de la Ataxia Telangiectasia Mutada , Secuencia de Bases , Proteínas de Ciclo Celular , Cartilla de ADN , Proteínas de Unión al ADN , Mutación del Sistema de Lectura , Genes p53 , Granulocitos , Humanos , Leucina Zippers , Leucemia de Células T/epidemiología , Ratones , Datos de Secuencia Molecular , Mutación Puntual , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple , Biosíntesis de Proteínas , Proteínas/química , Factores de Riesgo , Alineación de Secuencia , Eliminación de Secuencia , Homología de Secuencia de Aminoácido , Proteínas Supresoras de TumorRESUMEN
OBJECTIVES AND DESIGN: To establish whether in diabetic patients with peripheral artery obstructive disease (PAOD) vasa vasorum (vv) neoangiogenesis is altered with increased arterial damage. MATERIALS: Thirty-three patients with PAOD and critical lower limb ischaemia, 22 with type II diabetes. METHODS: Immunohistochemistry for endothelial cell markers (CD34 and von Willebrand Factor); real-time reverse transcription polymerase chain reaction (RT-PCR) to quantify arterial wall expression of vascular endothelial growth factor (VEGF); enzyme-linked immunosorbent assay (ELISA) to assess blood VEGF; flow cytometry to detect circulating endothelial cells (CECs). RESULTS: Patients with PAOD and diabetes have a higher frequency (60% vs. 45%) of advanced atherosclerotic lesions and a significant reduction (p = 0.0003) in CD34(+) capillaries in the arterial media. Adventitial neoangiogenesis was increased equally (CD34(+) and vWF(+)) in all patients. Likewise, all patients have increased CEC and VEGF concentration in the blood as well as in-situ VEGF transcript expression. CONCLUSIONS: Patients with PAOD have remarkable arterial damage despite increased in-situ and circulating expression of the pro-angiogenic VEGF; a dysfunctional vv angiogenesis was seen in diabetics which also showed a higher frequency of parietal damage; it is suggested that in diabetic arterial wall, injury is worsened by vv inability to finalise an effective VEGF-driven arterial wall neoangiogenesis.
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Arteriopatías Oclusivas/fisiopatología , Angiopatías Diabéticas/fisiopatología , Isquemia/fisiopatología , Extremidad Inferior/irrigación sanguínea , Extremidad Inferior/fisiopatología , Neovascularización Fisiológica , Vasa Vasorum/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD34/análisis , Arteriopatías Oclusivas/metabolismo , Arteriopatías Oclusivas/patología , Estudios de Casos y Controles , Enfermedad Crítica , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Diabetes Mellitus Tipo 2/fisiopatología , Angiopatías Diabéticas/metabolismo , Angiopatías Diabéticas/patología , Células Endoteliales/patología , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Humanos , Inmunohistoquímica , Isquemia/metabolismo , Isquemia/patología , Italia , Masculino , Persona de Mediana Edad , ARN Mensajero/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Vasa Vasorum/química , Vasa Vasorum/patología , Factor A de Crecimiento Endotelial Vascular/sangre , Factor A de Crecimiento Endotelial Vascular/genética , Factor de von Willebrand/análisisRESUMEN
In chronic-phase chronic myeloid leukaemia (CP-CML), residual BCR-ABL1+ leukaemia stem cells are responsible for disease persistence despite TKI. Based on in vitro data, CHOICES (CHlorOquine and Imatinib Combination to Eliminate Stem cells) was an international, randomised phase II trial designed to study the safety and efficacy of imatinib (IM) and hydroxychloroquine (HCQ) compared with IM alone in CP-CML patients in major cytogenetic remission with residual disease detectable by qPCR. Sixty-two patients were randomly assigned to either arm. Treatment 'successes' was the primary end point, defined as ≥0.5 log reduction in 12-month qPCR level from trial entry. Selected secondary study end points were 24-month treatment 'successes', molecular response and progression at 12 and 24 months, comparison of IM levels, and achievement of blood HCQ levels >2000 ng/ml. At 12 months, there was no difference in 'success' rate (p = 0.58); MMR was achieved in 80% (IM) vs 92% (IM/HCQ) (p = 0.21). At 24 months, the 'success' rate was 20.8% higher with IM/HCQ (p = 0.059). No patients progressed. Seventeen serious adverse events, including four serious adverse reactions, were reported; diarrhoea occurred more frequently with combination. IM/HCQ is tolerable in CP-CML, with modest improvement in qPCR levels at 12 and 24 months, suggesting autophagy inhibition maybe of clinical value in CP-CML.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Análisis Citogenético/métodos , Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Anciano , Femenino , Estudios de Seguimiento , Humanos , Hidroxicloroquina/administración & dosificación , Mesilato de Imatinib/administración & dosificación , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
The GTP-binding protein ADP-ribosylation factor 6 (Arf6) regulates endosomal membrane trafficking and the actin cytoskeleton in the cell periphery. GTPase-activating proteins (GAPs) are critical regulators of Arf function, controlling the return of Arf to the inactive GDP-bound state. Here, we report the identification and characterization of two Arf6 GAPs, ACAP1 and ACAP2. Together with two previously described Arf GAPs, ASAP1 and PAP, they can be grouped into a protein family defined by several common structural motifs including coiled coil, pleckstrin homology, Arf GAP, and three complete ankyrin-repeat domains. All contain phosphoinositide-dependent GAP activity. ACAP1 and ACAP2 are widely expressed and occur together in the various cultured cell lines we examined. Similar to ASAP1, ACAP1 and ACAP2 were recruited to and, when overexpressed, inhibited the formation of platelet-derived growth factor (PDGF)-induced dorsal membrane ruffles in NIH 3T3 fibroblasts. However, in contrast with ASAP1, ACAP1 and ACAP2 functioned as Arf6 GAPs. In vitro, ACAP1 and ACAP2 preferred Arf6 as a substrate, rather than Arf1 and Arf5, more so than did ASAP1. In HeLa cells, overexpression of either ACAP blocked the formation of Arf6-dependent protrusions. In addition, ACAP1 and ACAP2 were recruited to peripheral, tubular membranes, where activation of Arf6 occurs to allow membrane recycling back to the plasma membrane. ASAP1 did not inhibit Arf6-dependent protrusions and was not recruited by Arf6 to tubular membranes. The additional effects of ASAP1 on PDGF-induced ruffling in fibroblasts suggest that multiple Arf GAPs function coordinately in the cell periphery.
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Factores de Ribosilacion-ADP/metabolismo , Citoplasma/enzimología , Proteínas Activadoras de GTPasa/metabolismo , Células 3T3 , Factor 6 de Ribosilación del ADP , Factores de Ribosilacion-ADP/genética , Actinas/metabolismo , Compuestos de Aluminio/farmacología , Secuencia de Aminoácidos , Sustitución de Aminoácidos/genética , Animales , Arginina/genética , Arginina/metabolismo , Proteínas Portadoras/química , Proteínas Portadoras/metabolismo , Membrana Celular/efectos de los fármacos , Membrana Celular/enzimología , Membrana Celular/metabolismo , Extensiones de la Superficie Celular/efectos de los fármacos , Secuencia Conservada/genética , Citoplasma/efectos de los fármacos , Citoplasma/metabolismo , Citoesqueleto/efectos de los fármacos , Citoesqueleto/metabolismo , Fluoruros/farmacología , Proteínas Activadoras de GTPasa/química , Proteínas Activadoras de GTPasa/genética , Guanosina Difosfato/metabolismo , Células HeLa , Humanos , Ratones , Datos de Secuencia Molecular , Familia de Multigenes/genética , Ácidos Fosfatidicos/metabolismo , Fosfatidilinositol 4,5-Difosfato/metabolismo , Factor de Crecimiento Derivado de Plaquetas/farmacología , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Especificidad por SustratoRESUMEN
Drug supply chain safety has become a priority for public health which implies a collective process. This process associates all health professionals including the pharmacist who plays a major role. The objective of this present paper is to describe the several approaches proven effective in the reduction of drug-related problem in hospital, illustrated by the Grenoble University Hospital experience. The pharmacist gets involved first in the general strategy of hospital drug supply chain, second by his direct implication in clinical activities. The general strategy of drug supply chain combines risk management, coordination of the Pharmacy and Therapeutics Committee, selection and purchase of drugs and organisation of drug supply chain. Computer management of drug supply chain is a major evolution. Nominative drug delivering has to be a prior objective and its implementation modalities have to be defined: centralized or decentralized in wards, manual or automated. Also, new technologies allow the automation of overall drug distribution from central pharmacy and the implementation of automated drug dispensing systems into wards. The development of centralised drug preparation allows a safe compounding of high risk drugs, like cytotoxic drugs. The pharmacist should develop his clinical activities with patients and other health care professionals in order to optimise clinical decisions (medication review, drug order analysis) and patients follow-up (therapeutic monitoring, patient education, discharge consultation).
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Errores de Medicación/prevención & control , Sistemas de Medicación en Hospital/organización & administración , Servicio de Farmacia en Hospital/organización & administración , Automatización , Servicios Centralizados de Hospital/organización & administración , Control de Costos , Composición de Medicamentos/métodos , Composición de Medicamentos/normas , Monitoreo de Drogas , Almacenaje de Medicamentos/métodos , Prescripción Electrónica , Francia , Hospitales Universitarios/estadística & datos numéricos , Humanos , Errores de Medicación/legislación & jurisprudencia , Sistemas de Medicación en Hospital/economía , Sistemas de Medicación en Hospital/estadística & datos numéricos , Política Organizacional , Educación del Paciente como Asunto , Farmacéuticos , Servicio de Farmacia en Hospital/estadística & datos numéricos , Gestión de Riesgos/organización & administración , RolRESUMEN
The fabrication of biodegradable 3-D scaffolds enriched with multipotent stem cells seems to be a promising strategy for the repair of irreversibly injured tissues. The fine mechanisms of the interaction of rat mesenchymal stem cells (rMSCs) with a hyaluronan-based scaffold, i.e. HYAFF(R)11, were investigated to evaluate the potential clinical application of this kind of engineered construct. rMSCs were seeded (2 x 10(6) cells cm(-2)) on the scaffold, cultured up to 21 days and analysed using appropriate techniques. Light (LM), scanning (SEM) and transmission (TEM) electron microscopy of untreated scaffold samples showed that scaffolds have a highly porous structure and are composed of 15-microm-thick microfibres having a rough surface. As detected by trypan blue stain, cell adhesion was high at day 1. rMSCs were viable up to 14 days as shown by CFDA assay and proliferated steadily on the scaffold as revealed by MTT assay. LM showed rMSCs in the innermost portions of the scaffold at day 3. SEM revealed a subconfluent cell monolayer covering 40 +/- 10% of the scaffold surface at day 21. TEM of early culture showed rMSCs wrapping individual fibres with regularly spaced focal contacts, whereas confocal microscopy showed polarized expression of CD44 hyaluronan receptor; TEM of 14-day cultures evidenced fibronexus formation. Immunohistochemistry of 21-day cultures showed that fibronectin was the main matrix protein secreted in the extracellular space; decorin and versican were seen in the cell cytoplasm only and type IV collagen was minimally expressed. The expression of CD90, a marker of mesenchymal stemness, was found unaffected at the end of cell culture. Our results show that HYAFF(R)11 scaffolds support the adhesion, migration and proliferation of rMSCs, as well as the synthesis and delivery of extracellular matrix components under static culture conditions without any chemical induction. The high retention rate and viability of the seeded cells as well as their fine modality of interaction with the substrate suggest that such scaffolds could be potentially useful when wide tissue defects are to be repaired as in the case of cartilage repair, wound healing and large vessel replacement.
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Ácido Hialurónico , Células Madre Mesenquimatosas/fisiología , Andamios del Tejido , Cicatrización de Heridas , Animales , Materiales Biocompatibles , Adhesión Celular , Movimiento Celular , Proliferación Celular , Técnica del Anticuerpo Fluorescente , Receptores de Hialuranos/análisis , Inmunohistoquímica , Células Madre Mesenquimatosas/ultraestructura , Microscopía Confocal , Ratas , Ingeniería de Tejidos/métodosRESUMEN
Most modern treatment protocols for acute lymphoblastic leukaemia (ALL) include the analysis of minimal residual disease (MRD). To ensure comparable MRD results between different MRD-polymerase chain reaction (PCR) laboratories, standardization and quality control are essential. The European Study Group on MRD detection in ALL (ESG-MRD-ALL), consisting of 30 MRD-PCR laboratories worldwide, has developed guidelines for the interpretation of real-time quantitative PCR-based MRD data. The application of these guidelines ensures identical interpretation of MRD data between different laboratories of the same MRD-based clinical protocol. Furthermore, the ESG-MRD-ALL guidelines will facilitate the comparison of MRD data obtained in different treatment protocols, including those with new drugs.
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Reordenamiento Génico , Neoplasia Residual/genética , Reacción en Cadena de la Polimerasa/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Receptores de Antígenos de Linfocitos T/genética , ADN de Neoplasias/genética , Genes de Inmunoglobulinas , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/microbiologíaRESUMEN
Polymerase chain reaction (PCR) assessment of clonal T-cell receptor (TCR) and immunoglobulin (Ig) gene rearrangements is an important diagnostic tool in mature T-cell neoplasms. However, lack of standardized primers and PCR protocols has hampered comparability of data in previous clonality studies. To obtain reference values for Ig/TCR rearrangement patterns, 19 European laboratories investigated 188 T-cell malignancies belonging to five World Health Organization-defined entities. The TCR/Ig spectrum of each sample was analyzed in duplicate in two different laboratories using the standardized BIOMED-2 PCR multiplex tubes accompanied by international pathology panel review. TCR clonality was detected in 99% (143/145) of all definite cases of T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, peripheral T-cell lymphoma (unspecified) and angioimmunoblastic T-cell lymphoma (AILT), whereas nine of 43 anaplastic large cell lymphomas did not show clonal TCR rearrangements. Combined use of TCRB and TCRG genes revealed two or more clonal signals in 95% of all TCR clonal cases. Ig clonality was mostly restricted to AILT. Our study indicates that the BIOMED-2 multiplex PCR tubes provide a powerful strategy for clonality assessment in T-cell malignancies assisting the firm diagnosis of T-cell neoplasms. The detected TCR gene rearrangements can also be used as PCR targets for monitoring of minimal residual disease.
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Genes de Inmunoglobulinas , Leucemia de Células T/genética , Linfoma de Células T/genética , Reacción en Cadena de la Polimerasa/métodos , Receptores de Antígenos de Linfocitos T/genética , Amplificación de Genes , Reordenamiento Génico , Genotipo , Humanos , Inmunohistoquímica , Leucemia Prolinfocítica/genética , Leucemia Prolinfocítica/inmunología , Leucemia Prolinfocítica/patología , Leucemia de Células T/inmunología , Leucemia de Células T/patología , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/inmunología , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células T/inmunología , Linfoma de Células T/patología , Linfocitos T/inmunologíaRESUMEN
The LIM-only family of proteins comprises four members; two of these (LMO1 and LMO2) are involved in human T-cell leukemia via chromosomal translocations, and LMO2 is a master regulator of hematopoiesis. We have carried out gene targeting of the other members of the LIM-only family, viz., genes Lmo1, Lmo3 and Lmo4, to investigate their role in mouse development. None of these genes has an obligatory role in lymphopoiesis. In addition, while null mutations of Lmo1 or Lmo3 have no discernible phenotype, null mutation of Lmo4 alone causes perinatal lethality due to a severe neural tube defect which occurs in the form of anencephaly or exencephaly. Since the Lmo1 and Lmo3 gene sequences are highly related and have partly overlapping expression domains, we assessed the effect of compound Lmo1/Lmo3 null mutations. Although no anatomical defects were apparent in compound null pups, these animals also die within 24 h of birth, suggesting that a compensation between the related Lmo1 and 3 proteins can occur during embryogenesis to negate the individual loss of these genes. Our results complete the gene targeting of the LIM-only family in mice and suggest that all four members of this family are important in regulators of distinct developmental pathways.
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Sistema Nervioso Central/embriología , Proteínas de Unión al ADN/genética , Desarrollo Embrionario y Fetal , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Morfogénesis , Mutación , Proteínas Oncogénicas/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Secuencia de Aminoácidos , Animales , Animales Recién Nacidos , Sistema Nervioso Central/patología , Sistema Nervioso Central/fisiología , Proteínas de Unión al ADN/metabolismo , Femenino , Marcación de Gen , Genotipo , Humanos , Proteínas con Dominio LIM , Masculino , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Proteínas Oncogénicas/metabolismo , Alineación de SecuenciaRESUMEN
OBJECTIVES: The aim of this study was to evaluate the adequacy and the conformity of prescriptions of new systemic antifungal drugs to guidelines and scientific data. PATIENTS AND METHODS: Each prescription of liposomal amphotericin B (lip Amb), voriconazole, and caspofungin made between May 2003 and May 2004 in a teaching hospital were reviewed by an infectious diseases specialist. He used criteria based on marketing authorization, national recommendations, and scientific data. RESULTS: One hundred and fifteen files were studied during the 12-month period and 203 prescriptions analyzed. Most patients were immunodepressed. The indication of the treatment was appropriate for 127 prescriptions (62.6%). Dose and drug interactions were compliant with prescription rules for 158 prescriptions (77.8%). Among the causes of misuse, 16.3% concerned combinations of antifungals. Prescriptions of liposomal amphotericin B, voriconazole and caspofungin complied with guidelines respectively in 69.7, 60.6 and 36.8% of the cases. Among the 127 appropriate prescriptions, the use of cheaper molecules with an equivalent clinical effectiveness would have allowed saving 13.6% of the total cost of these prescriptions. CONCLUSIONS: This study will lead us to implement policies for new antifungal prescription.
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Antifúngicos/uso terapéutico , Adhesión a Directriz/normas , Prescripciones de Medicamentos/normas , Prescripciones de Medicamentos/estadística & datos numéricos , Femenino , Francia , Hospitales de Enseñanza , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
BACKGROUND: The aim of this study was to investigate whether fatty and clear cell areas in large regenerative nodules (LRN), dysplastic nodules (DN), and hepatocellular carcinoma (HCC) show higher degree of genomic mutation compared to non-fatty/clear cell area in the same nodule or non-lesional tissue. METHODS: We examined 22 nodular lesions (9 HCC, 5 DN and 8 LRN) from seven cirrhotic livers removed at transplantation. Frozen sections were used for manual microdissection of areas with fatty/clear cell change. DNA from microdissected tissue was amplified using arbitrarily primed polymerase chain reaction (AP-PCR), and PCR products were run on polyacrilamide gel generating a "fingerprint" band pattern. Autoradiographs were analysed using Adobe Photoshop version 6.0. Fingerprints from lesional tissue were compared to reference tissue and the total number of bands in excess or defect was calculated and divided by the total number of bands identified, obtaining the genomic damage fraction (GDF). RESULTS: Increasing GDF average values were seen from cirrhotic liver (0.13+/-0.04), to LRN (0.16+/-0.1), DN (0.28+/-0.08) and HCC (0.30+/-0.07). A statistically significant difference in GDF values was documented between cirrhotic liver and DN (p=0.008) and HCC (p=0.005) and between HCC and LRN (p=0.02). No significant difference was documented between DN and HCC, and between LRN and cirrhotic liver. Eleven nodules containing fat/clear cell areas were compared to the other 11 nodules without fat/clear cell areas. The GDF was not different between the two groups: 0.29+/-0.11 versus 0.25+/-0.12; p=0.5. The average value of genomic damage fraction between fat/clear cell areas (0.29+/-0.11) and no fat/clear cell areas (0.25+/-0.1) within the same nodules were not significantly different (p=0.11). CONCLUSION: Fatty and clear cell change in nodular lesions in cirrhotic liver may be an epigenetic phenotypic modification caused by microenvironmental factors such as ischaemia rather than indicating areas of increased malignant potential per se.
RESUMEN
OBJECTIVE: We estimated the adequacy of antibiotic therapy to guidelines for nosocomial and community-acquired urinary tract infections in hospital. DESIGN: For 4 weeks, all adult patients hospitalized with positive bacteriuria were included in our retrospective study. Data was collected from urine culture results and from patient medical files. Adequacy to guidelines was analyzed by two infectious disease specialists, focusing on the indication, antibiotic choice, dosage, route of administration, and duration of treatment. RESULTS: Overall 202 patients were enrolled in the study (63.9% women). The decision of initiating or not antibiotic therapy was appropriate in 66.8% of cases. Antibiotherapy indication and antibiotic choice were adequate in 94 cases in empiric prescription (50.8%) and in 123 cases (60.9%) after receiving culture antibiogram results. Route of administration was adequate in 94.4% and dosage in 70.8% of prescriptions. This poor compliance with guidelines was mainly due to unnecessary prescriptions in asymptomatic bacteriuria, unnecessary biotherapies and spectrum errors. CONCLUSIONS: It seems important to remind prescribers of recommendations for urinary tract infections.
Asunto(s)
Antibacterianos/uso terapéutico , Infecciones Urinarias/tratamiento farmacológico , Adulto , Anciano , Antibacterianos/normas , Femenino , Francia , Humanos , Pacientes Internos , Masculino , Guías de Práctica Clínica como Asunto , Resultado del TratamientoRESUMEN
Lymphoma-derived immunoglobulin idiotype (Id) is a well-characterized, tumor-specific antigen on B-cell malignancies. Immunotherapy using lymphoma immunoglobulin can lead to clinical responses mostly associated with anti-Id antibody. We cloned the Id from B-cell lymphomas, sequenced them, and used bioinformatics to select autologous MHC class I binding peptides from somatically mutated regions of the lymphoma Id. Peptides from patients who were HLA-A1, HLA-A2, HLA-A3, or HLA-A11 positive were analyzed in the T2 stabilization assay and a competitive peptide-binding assay. By both methods, approximately half of the peptides analyzed, regardless of HLA type, bound with intermediate or high affinity. Peptide binding affinity was similar to viral peptide sequences known to provide targets for cytotoxic T cells. Further investigation of lymphocyte responses to stimulation by autologous Id peptides versus Id peptides from other patients revealed that three of five patients in complete remission or with low volume, stable disease responded to self-peptides by IFN-gamma secretion greater than that seen with non-self peptides, whereas none of five patients with progressive disease responded to their own lymphoma Id. We have shown that mutated regions of lymphoma Id contain MHC class I binding peptides that are potential targets for cytotoxic T cells. Immunotherapy using the tumor-specific mutated regions from lymphoma Id avoids the need to break innate tolerance toward the germ-line protein sequences present on normal and malignant B cells.
Asunto(s)
Antígenos HLA-A/inmunología , Idiotipos de Inmunoglobulinas/genética , Linfoma de Células B/genética , Linfoma de Células B/inmunología , Mutación , Oligopéptidos/inmunología , Linfocitos T Citotóxicos/inmunología , Secuencia de Aminoácidos , Unión Competitiva , Línea Celular , Epítopos de Linfocito T/genética , Epítopos de Linfocito T/inmunología , Antígenos HLA-A/metabolismo , Humanos , Idiotipos de Inmunoglobulinas/inmunología , Interferón gamma/biosíntesis , Interferón gamma/metabolismo , Activación de Linfocitos/inmunología , Oligopéptidos/genética , Oligopéptidos/metabolismo , Biblioteca de Péptidos , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Two distinct regions of minimal deletion (RMD) have been identified at 6q25-q27 in non-Hodgkin's lymphoma (RMD-1), and at 6q21-q23 in acute lymphoblastic leukemia (ALL; RMD-2) by loss of heterozygosity and fluorescence in situ hybridization studies. In this study, 30 overlapping yeast artificial chromosomes (YACs), 1 expressed sequence tag, and 11 novel YAC ends were identified using bidirectional YAC walks between markers D6S447 (proximal) and D6S246 (distal) in RMD-2. The genes AF6q21, human homologue of the Drosophila tailless (HTLX), CD24 antigen, the Kruppel-like zinc finger BLIMP1, and cyclin C (CCNC), previously mapped to 6q21, were accurately positioned in a telomere-to-centromere orientation. Approximately 3.5 Mb were found to separate the BLIMP1 (adjacent to D6S447) and AF6q21 genes (telomeric to D6S246). Deletions of 6q were investigated in 21 cases of ALL using the newly characterized YAC clones in dual-color fluorescence in situ hybridization studies. A region centromeric to D6S447 (containing marker D6S283) and a region telomeric to marker CHLC.GGAT16CO2 (and containing marker D6S268) were identified as distinct and nonoverlapping regions of deletion in ALL.
Asunto(s)
Deleción Cromosómica , Mapeo Cromosómico , Cromosomas Humanos Par 6 , Linfoma no Hodgkin/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Centrómero , Cromosomas Artificiales de Levadura , Etiquetas de Secuencia Expresada , Biblioteca de Genes , Marcadores Genéticos , Humanos , Hibridación Fluorescente in Situ , Modelos Genéticos , Lugares Marcados de SecuenciaRESUMEN
The ATM gene deficient in ataxia-telangiectasia, a recessive multisystem disease associated with a high risk of lymphomas and leukemias, was found previously to be inactivated in a rare sporadic malignancy, T-cell prolymphocytic leukemia (T-PLL), which is often associated with cytogenetic aberrations of chromosome 14. The ATM gene was shown to sustain frequent loss-of-function mutations in T-PLL tumor cells, consistent with functioning as a tumor suppressor gene in this leukemia. To investigate the possibility of nonmutational or nonrecombinational mechanisms of T-PLL development, we have used bisulfite genomic sequencing to analyze DNA methylation in the putative bidirectional promoter region of the closely linked ATM and NPAT/E14 genes within the CpG island at 11q22-q23. We show that this region is completely demethylated in lymphocytes expressing ATM; however, no extensive hypermethylation was found in 9 T-PLL tumor DNA samples without evidence of ATM/p53 mutations. Because acute T-cell lymphoblastic leukemias (T-ALL) were also observed in ataxia-telangiectasia patients and T-ALL tumor cells contain chromosome 14 abnormalities, 19 presentation samples of T-ALL patients were analyzed for ATM mutations. Although T-ALL patients exhibited rare nucleotide substitutions not previously found in ATM, all were identified in the germ-line, indicating constitutional polymorphisms, potentially confined to ethnic subpopulations. The absence of somatic nucleotide changes in ATM in T-ALL as compared with T-PLL suggests a distinct pattern of genetic events in the development of the two leukemias.