Diamond Blackfan anemia is mediated by hyperactive Nemo-like kinase.

Diamond Blackfan Anemia (DBA) is a congenital bone marrow failure syndrome associated with ribosomal gene mutations that lead to ribosomal insufficiency. DBA is characterized by anemia, congenital anomalies, and cancer predisposition. Treatment for DBA is associated with significant morbidity. Here, we report the identification of Nemo-like kinase (NLK) as a potential target for DBA therapy. To identify new DBA targets, we screen for small molecules that increase erythroid expansion in mouse models of DBA. This screen identified a compound that inhibits NLK. Chemical and genetic inhibition of NLK increases erythroid expansion in mouse and human progenitors, including bone marrow cells from DBA patients. In DBA models and patient samples, aberrant NLK activation is initiated at the Megakaryocyte/Erythroid Progenitor (MEP) stage of differentiation and is not observed in non-erythroid hematopoietic lineages or healthy erythroblasts. We propose that NLK mediates aberrant erythropoiesis in DBA and is a potential target for therapy.

Proton affinity of uracil. A computational study of protonation sites.

Relative stabilities of uracil tautomers and cations formed by gas-phase protonation were studied computationally with the B3LYP, MP2, QCISD, and QCISD(T) methods and with basis sets expanding from 6-31G(d,p) to 6-311+G(3df,2p). In accordance with a previous density functional theory study, the dioxo tautomer 1a was the most stable uracil isomer in the gas phase. Gibbs free energy calculations using effective QCISD(T)/6-311+G(3df,2p) energies suggested >99.9% of 1a at equilibrium at 523 K. The most stable ion isomer corresponded to N-1 protonated 2,4-dihydroxypyrimidine, which however is not formed by direct protonation of 1a. The topical proton affinities in 1a followed the order O-8 > O-7 > C-5 > N-3 > N-1. The thermodynamic proton affinity of 1a was calculated as 858 kJ mol(-1) at 298 K. A revision is suggested for the current estimate included in the ion thermochemistry database.

[Block of the lateral perforant branches of the subcostal and iliohypogastric nerves for proximal femur surgery]. / Bloc des branches perforantes latérales des nerfs sous-costal et iliohypogastrique pour la chirurgie proximale du fémur.

We describe an original method to block the lateral cutaneous rami of the subcostal and iliohypogastric nerves or'iliac crest point block'to complete plexular block of the lower limb for hip surgery. The local anaesthetic is injected in front of an osterofibrous orifice of the iliac crest. In nine cases out of ten, the lateral cutaneous rami of the iliohypogastric nerve pass through this orifice and in one case out of ten, it is the one arising from the subcostal nerve. This complementary block allows the surgical incision at the level of the great trochanter.

[The experience in emergency medical care in Lagos (Nigeria): cost-benefit analysis ... politics?]. / L'experience du SAMU de Lagos (Nigeria): rapport cout-efficacite ... politique?

In both the South and North, meeting the demand for health care services is a major issue in establishing political stability for sustainable development. Neither the need for emergency medicine nor the emergency need for medical care can escape this reality. At first glance, "bringing medical care outside hospitals ... to the bottom of the tree" by implementing an advanced rescue system would seem to overstep the usual goal of providing basic health services and capabilities in a developing country. However, the operational, tactical and strategic implications of a "French style SAMU" medical controlled system may contribute to the fair and equitable distribution of emergency health care resources during critical situations in a given environment. In this respect, such system cannot only become a measurable component in responding to increasingly intolerable health disasters, but also an institutional tool for health resources management in any insecure environment, where access to medical facilities usually involves a number of economic, structural, and ethical obstacles. In France, the effectiveness of such a system is still under evaluation with good results in terms of overall health performance for the year 2000. In 1997 the Nigerian authorities with the support of the French Embassy began a novel experience by setting up a state run SAMU services in Lagos. The purpose of this prospective approach was to answer the question "what emergency care system, for what environment?" with an ultimate goal: developing a sustainable service, not only in terms of medical and economic factors, but also ethical and political considerations.

Is timely and appropriate antifungal drug enough for survival of adult cases with candidaemia? Five-year experience / ¿Es el uso oportuno y adecuado de antimicóticos suficiente para la supervivencia de casos de adultos con candidemia? Cinco años de experiencia

OBJECTIVE: Candidaemia is the fourth most common cause of nosocomial bloodstream infections. The objective of this paper was to evaluate the risk factors associated with mortality in patients with candidaemia with respect to Candida species and their susceptibilities, retrospectively. METHODS: All consecutive patients who developed candidaemia at an 800-bed training and research hospital were enrolled in this retrospective, observational, single centre study during the period June 2006 to December 2011. RESULTS: A total of 97 candidaemia episodes were identified in 97 patients during the study period with an overall incidence of four episodes/10 000 admissions in adults. Crude 30-day mortality rates among patients with candidaemia were 56% (55 of 97 cases). Urinary catheterization, immunosuppressive therapy, acute physiology and chronic health evaluation (APACHE) II score (>16) and hypoal-buminaemia were found to be independent risk factors for fatal candidaemia. CONCLUSIONS: Adult cases with candidaemia who have risk factors associated with mortality are more likely to have poor prognosis despite appropriate and timely initiated antifungal drug treatment. Empiric antifungal drug should be tailored according to the severity of the patients ' conditions and local antifungal susceptibility.

OBJETIVO: La candidemia es la cuarta causa más común de infecciones nosocomiales del flujo sanguíneo. El objetivo del presente trabajo fue evaluar los factores de riesgo asociados con la mortalidad en pacientes con candidemia con respecto a las especies de Candida y sus susceptibilidades, de manera retrospectiva. MÉTODOS: Todos los pacientes consecutivos que desarrollaron candidemia en un hospital de capacitación e investigación de 800 camas, fueron inscritos en este estudio retrospectivo, observacional, monocéntrico, durante el período de junio de 2006 a diciembre de 2011. RESULTADOS: Se identificaron un total de 97 episodios de candidemia en 97 pacientes durante el período de estudio con una incidencia general de cuatro episodios/10 000 ingresos en adultos. Las tasas brutas de mortalidad de 30 días entre los pacientes con candidemia fueron 56% (55 de 97 casos). Se halló que la cateterización urinaria, la terapia inmunosupresiva, y la puntuación (> 16) de la escala de Evaluación de la fisiología aguda y salud crónica (APACHE II) así como la hipoalbuminemia, constituyen factores de riesgo para una candidemia fatal. CONCLUSIONES: Los casos adultos con candidemia que tienen factores de riesgo asociados con mortalidad son más propensos a tener un pronóstico pobre a pesar del tratamiento apropiado y oportuno con medicamentos antimicóticos. Los antimicóticos empírico se deben adaptar según la severidad de las condiciones de los pacientes y la susceptibilidad antifúngica local.

Tuberculous meningitis: a report of 60 adult cases / Meningitis tuberculosa: reporte de 60 casos adultos

OBJECTIVE: This was to evaluate the history, clinical and laboratory findings, outcome and prognosis of patients with tuberculous meningitis (TBM). METHOD: Between 1998 and 2009, 60 patients with TBM were evaluated, retrospectively. RESULT: Overall, 60 patients were selected, of which 33 (55%) were male. The patients' ages ranged from 14 to 62 years. In the majority of the patients, disease was in an advanced stage on admission (66% in stage III according to the British Research Council neurological criteria). The rate of complications was highest among patients in stages II and III with an overall mortality rate of 6.6% (n= 2 of stage II patients and n= 2 of stage III patients). CONCLUSIONS: Earlier admission of the patients with TBM could provide better outcomes with regard to sequelae and mortality. Fatal cases presented with rapid deterioration and were refractory to treatment.

OBJETIVO: El propósito de este trabajo fue evaluar la historia, los hallazgos clínicos y de laboratorio, la evolución, y la prognosis de pacientes con meningitis tuberculosa (MTB). MÉTODO: Entre 1998 y 2009, se evaluaron 60 pacientes con TBM, retrospectivamente. RESULTADOS: En general, se seleccionaron 60pacientes, de los cuales 33 (55%) fueron varones. La edad de los pacientes osciló de 14 a 62 años. En la mayoría de los pacientes, la enfermedad se encontraba en etapa avanzada al momento del ingreso (66% en la etapa III de acuerdo con los criterios neurológicos del Consejo Británico de Investigación). La tasa de complicaciones fue más alta entre los pacientes en las etapas IIy III con una tasa de mortalidad general de 6.6% (n = 2 en los pacientes de etapa IIy n = 2 en los pacientes de etapa III). CONCLUSIONES: El ingreso temprano de los pacientes con MTB podría proporcionar mejores resultados con respecto a las secuelas y la mortalidad. Los casos fatales se presentaron con deterioro rápido y fueron refractarios al tratamiento.