ATP Synthase c-Subunit Leak Causes Aberrant Cellular Metabolism in Fragile X Syndrome.

Loss of the gene (Fmr1) encoding Fragile X mental retardation protein (FMRP) causes increased mRNA translation and aberrant synaptic development. We find neurons of the Fmr1-/y mouse have a mitochondrial inner membrane leak contributing to a "leak metabolism." In human Fragile X syndrome (FXS) fibroblasts and in Fmr1-/y mouse neurons, closure of the ATP synthase leak channel by mild depletion of its c-subunit or pharmacological inhibition normalizes stimulus-induced and constitutive mRNA translation rate, decreases lactate and key glycolytic and tricarboxylic acid (TCA) cycle enzyme levels, and triggers synapse maturation. FMRP regulates leak closure in wild-type (WT), but not FX synapses, by stimulus-dependent ATP synthase ß subunit translation; this increases the ratio of ATP synthase enzyme to its c-subunit, enhancing ATP production efficiency and synaptic growth. In contrast, in FXS, inability to close developmental c-subunit leak prevents stimulus-dependent synaptic maturation. Therefore, ATP synthase c-subunit leak closure encourages development and attenuates autistic behaviors.

Racial differences in red blood cell transfusion in hospitalized patients with anemia.

BACKGROUND: Guidelines recommend transfusion of red blood cells (RBC's) when a hospitalized patient's hemoglobin (Hb) drops below a restrictive transfusion threshold, either at 7 or 8 g. Hospitals have implemented transfusion policies to encourage compliance with guidelines and reduce variation in transfusion practice. However, variation in transfusion practice remains. The purpose of this study was to examine whether there is variation in the receipt of transfusion by patient race. METHODS: Hospitalized general medicine patients with anemia (Hb < 10 g/dL) were eligible. Chi-squared tests were used to compare the percent of patients receiving a transfusion by race overall and within strata of their nadir Hb. Linear regression was used to test the association between a patient's race, their nadir Hb, receipt of an RBC transfusion, and the number of units transfused. RESULTS: Four thousand nine hundred and fifty-one patients consented, including 1363 (28%) who received a transfusion. 71% of patients were African American, 25% were White, and 4% were Other Race. Overall African Americans were less likely to be transfused compared to Whites (25% vs. 30%, p < .01), and within Hb strata below a Nadir Hb of 9 g/dL (Hb 8.0-8.9 g/dL 1% vs. 7%, p < .01; 7.0-7.9 g/dL 15% vs. 28%, p < .01; <7 g/dL 80% vs. 86%, p < .01). African Americans also received fewer units of RBC's (ß = -.17, p < .01) overall and at lower Hb levels (ß = .14, p < .01) compared to Whites. DISCUSSION: The Hb level at which patients are transfused at and the total number of RBC units received during hospitalization differ by patient race.

Molecular Effects of Silver Nanoparticles on Monogenean Parasites: Lessons from Caenorhabditis elegans.

The mechanisms of action of silver nanoparticles (AgNPs) in monogenean parasites of the genus Cichlidogyrus were investigated through a microarray hybridization approach using genomic information from the nematode Caenorhabditis elegans. The effects of two concentrations of AgNPs were explored, low (6 µg/L Ag) and high (36 µg/L Ag). Microarray analysis revealed that both concentrations of AgNPs activated similar biological processes, although by different mechanisms. Expression profiles included genes involved in detoxification, neurotoxicity, modulation of cell signaling, reproduction, embryonic development, and tegument organization as the main biological processes dysregulated by AgNPs. Two important processes (DNA damage and cell death) were mostly activated in parasites exposed to the lower concentration of AgNPs. To our knowledge, this is the first study providing information on the sub-cellular and molecular effects of exposure to AgNPs in metazoan parasites of fish.

Genetic and functional diversity of allorecognition receptors in the urochordate, Botryllus schlosseri.

Allorecognition in Botryllus schlosseri is controlled by a highly polymorphic locus (the fuhc), and functionally similar to missing-self recognition utilized by Natural Killer cells-compatibility is determined by sharing a self-allele, and integration of activating and inhibitory signals determines outcome. We had found these signals were generated by two fuhc-encoded receptors, called fester and uncle fester. Here we show that fester genes are members of an extended family consisting of >37 loci, and co-expressed with an even more diverse gene family-the fester co-receptors (FcoR). The FcoRs are membrane proteins related to fester, but include conserved tyrosine motifs, including ITIMs and hemITAMs. Both genes are encoded in highly polymorphic haplotypes on multiple chromosomes, revealing an unparalleled level of diversity of innate receptors. Our results also suggest that ITAM/ITIM signal integration is a deeply conserved mechanism that has allowed convergent evolution of innate and adaptive cell-based recognition systems.

[Proposal for initial management of uncomplicated ST elevation myocardial infarction in centers without percutaneous coronary intervention capacity in Peru]. / Propuesta de manejo inicial del infarto de miocardio con elevación del segmento ST no complicado en centros sin capacidad de intervención coronaria percutánea en el Perú.

ST-segment elevation myocardial infarction (STEMI) is a clinical entity whose adequate treatment will depend on its prompt recognition, accurate diagnosis, and management in reperfusion networks. The first contact with these patients is generally done in centers without reperfusion capacity, attended by non-cardiologist doctors, and in centers far from hospitals with greater resolution capacity, something that is well known in our country. This manuscript proposes a strategy for the diagnosis and treatment of STEMI in centers without percutaneous coronary intervention capacity of the public health system in Peru, emphasizing not losing sight of electrocardiographic patterns compatible with coronary artery occlusion, adequate fibrinolysis and management of its complications, the treatment of infarction in special populations and highlighting the importance of the pharmacoinvasive strategy as the main form of reperfusion treatment in our country.

Information transfer dynamics in fixed-pathways networks.

Most complex technological networks are defined in such a way that their global properties are manifested at a dynamical level. An example of this is when internal dynamical processes are constrained to predefined pathways, without the possibility of alternate routes. For instance, large corporation software networks, where several flow processes take place, are typically routed along specific paths. In this work, we propose a model to describe the global characteristics of this kind of processes, where the dynamics depends on the state of the nodes, represented by two possibilities: responsive or blocked. We present numerical simulations that show rich global behavior with unexpected emerging properties. In particular, we show that two different regimes appear as a function of the total network load. Each regime is characterized by developing either a unimodal or a bimodal distribution for the density of responsive nodes, directly related to global efficiency. We provide a detailed explanation for the main characteristics of our results as well as an analysis of the implications for real technological systems.

Plasma Membrane Fluidity: An Environment Thermal Detector in Plants.

The lipid matrix in cell membranes is a dynamic, bidimensional array of amphipathic molecules exhibiting mesomorphism, which contributes to the membrane fluidity changes in response to temperature fluctuation. As sessile organisms, plants must rapidly and accurately respond to environmental thermal variations. However, mechanisms underlying temperature perception in plants are poorly understood. We studied the thermal plasticity of membrane fluidity using three fluorescent probes across a temperature range of -5 to 41 °C in isolated microsomal fraction (MF), vacuolar membrane (VM), and plasma membrane (PM) vesicles from Arabidopsis plants. Results showed that PM were highly fluid and exhibited more phase transitions and hysteresis, while VM and MF lacked such attributes. These findings suggest that PM is an important cell hub with the capacity to rapidly undergo fluidity modifications in response to small changes of temperatures in ranges spanning those experienced in natural habitats. PM fluidity behaves as an ideal temperature detector: it is always present, covers the whole cell, responds quickly and with sensitivity to temperature variations, functions with a cell free-energy cost, and it is physically connected with potential thermal signal transducers to elicit a cell response. It is an optimal alternative for temperature detection selected for the plant kingdom.

Krüppel-Like Factor 10 participates in cervical cancer immunoediting through transcriptional regulation of Pregnancy-Specific Beta-1 Glycoproteins.

Cervical cancer (CC) is associated with alterations in immune system balance, which is primarily due to a shift from Th1 to Th2 and the unbalance of Th17/Treg cells. Using in silico DNA copy number analysis, we have demonstrated that ~20% of CC samples exhibit gain of 8q22.3 and 19q13.31; the regions of the genome that encodes the KLF10 and PSG genes, respectively. Gene expression studies demonstrated that there were no alterations in KLF10 mRNA expression, whilst the PSG2 and -5 genes were up-regulated by 1.76 and 3.97-fold respectively in CC compared to normal tissue controls. siRNA and ChIP experiments in SiHa cells have demonstrated that KLF10 participates in immune response through regulation of IL6, IL25 and PSG2 and PSG5 genes. Using cervical tissues from KLF10-/- mice, we have identified down-regulation of PSG17, -21 and -23 and IL11. These results suggest that KLF10 may regulate immune system response genes in cervical cancer among other functions. KLF10 and PSG copy number variations and alterations in mRNA expression levels could represent novel molecular markers in CC.

Economic Evaluation of Four Drug Administration Systems in Intensive Care Units in Colombia.

INTRODUCTION: Intensive care units (ICUs) are the most frequent setting for serious medical errors, which not only have serious health consequences but also an economic impact. In this article, using a theoretical model, we evaluate four medication administration systems: conventional preparation by nursing staff, MINIBAG Plus delivery system, compounding center preparation, and premix drugs. METHODS: We designed a decision tree model from a third-party payer perspective, and the time horizon of the acute event. Local costs, in Colombian pesos (US $1 = 1784 COP$), were obtained from tariff manuals, medication costs from Sismed information system, and clinical variables from the published literature, and uncertainty was dealt with by an expert panel. The drug used for the model was dopamine. RESULTS: Average costs for each dopamine dose delivered were $46,995 for premix, $47,625 for compounding center, $101,934 for MINIBAG Plus, and $108,870 for drug prepared in the ICU. The variability of these results is higher for compounding center than for premix, and even higher for MINIBAG Plus and nurse delivery. CONCLUSIONS: The use of premix drugs can be a cost-saving strategy, which decreases medical errors in drug administration in the ICU, particularly if it is part of an integral error reduction program.

Identification of putative ortholog gene blocks involved in gestant and lactating mammary gland development: a rodent cross-species microarray transcriptomics approach.

The mammary gland (MG) undergoes functional and metabolic changes during the transition from pregnancy to lactation, possibly by regulation of conserved genes. The objective was to elucidate orthologous genes, chromosome clusters and putative conserved transcriptional modules during MG development. We analyzed expression of 22,000 transcripts using murine microarrays and RNA samples of MG from virgin, pregnant, and lactating rats by cross-species hybridization. We identified 521 transcripts differentially expressed; upregulated in early (78%) and midpregnancy (89%) and early lactation (64%), but downregulated in mid-lactation (61%). Putative orthologous genes were identified. We mapped the altered genes to orthologous chromosomal locations in human and mouse. Eighteen sets of conserved genes associated with key cellular functions were revealed and conserved transcription factor binding site search entailed possible coregulation among all eight block sets of genes. This study demonstrates that the use of heterologous array hybridization for screening of orthologous gene expression from rat revealed sets of conserved genes arranged in chromosomal order implicated in signaling pathways and functional ontology. Results demonstrate the utilization power of comparative genomics and prove the feasibility of using rodent microarrays to identification of putative coexpressed orthologous genes involved in the control of human mammary gland development.

An adenosine derivative compound, IFC305, reverses fibrosis and alters gene expression in a pre-established CCl(4)-induced rat cirrhosis.

Cirrhosis is a complex process that involves a dynamic modification of liver cell phenotype associated to gene expression changes. This study investigates the reversing capacity of an adenosine derivative compound (IFC305) on a rat model of liver cirrhosis and gene expression changes associated with it. Rats were treated with IFC305 or saline for 5 or 10 weeks after cirrhosis induction (CCl(4) treatment for 10 weeks). Fibrosis score, collagenase activity and amount of hepatic stellate cells (HSC, activated and with a lipid-storing phenotype) were measured in livers. In addition, gene expression analysis was performed using 5K DNA microarrays and quantitative RT-PCR. Treatment of cirrhotic rats with IFC305 for 5 or 10 weeks compared to saline control, induced: (1) reduction of fibrosis (50-70%) and of collagen, of alpha-SMA and desmin proteins, as well as of activated HSCs in liver, (2) increased collagenase activity and cell number of lipid-storing HSC, (3) improved serum parameters of liver function, such as reduced activity of aminotransferases and bilirubin. Expression of 413 differential genes, deregulated in cirrhotic samples, tended to be normalized by IFC305 treatment. Some genes modulated at transcript level by IFC305 were Tgfb1, Fn1, Col1a1, C9, Apoa1, Ass1, Cps1, and Pparg. The present study shows that IFC305 reverses liver fibrosis through modulation of adipogenic and fibrosis-related genes and by ameliorating hepatic function. Thus, understanding of the anti-cirrhotic effect of IFC305 might have therapeutical potential in patients with cirrhosis.

Tratamiento trombolítico exitoso de tromboembolismo pulmonar masivo en una gestante / Successful thrombolytic treatment of massive pulmonary embolism in a pregnant

El tromboembolismo pulmonar (TEP) es la obstrucción mecánica del flujo sanguíneo venoso por un trombo procedente de una trombosis venosa profunda (TVP). Es una entidad que continúa siendo una causa mayor de mortalidad materna, con muchas muertes asociadas al fracaso para obtener el diagnóstico y tratamiento precoz. La enfermedad tromboembólica venosa y, especialmente el tromboembolismo pulmonar masivo durante el embarazo, representan un gran desafío para el clínico, dado que los cambios fisiológicos propios de esta condición pueden llevar a un subdiagnóstico, de ahí la importancia de sospechar la entidad clínica pese al escenario tan confuso que ofrecen las mujeres gestantes. Presentamos el caso de una paciente de 19 años con embarazo de 25 semanas, sin antecedentes previos de enfermedad tromboembólica venosa, quien desarrolló tromboembolismo pulmonar masivo de alto riesgo, y en quien se realizó trombólisis con alteplase presentando mejoría clínica, evolución favorable y parto posterior.

Seroprevalencia de hidatidosis en escolares de Huancasancos, Ayacucho 2004 / Hydatidosis seroprevalence in schol children from Huancasancos, Ayacucho 2004

Objetivo. Estimar la prevalencia de hidatidosis humana en la población escolar de 6 a 15 años de edad en la provincia altoandina de Huancasancos, Ayacucho. Materiales y métodos. Estudio transversal, realizado en mayo de 2004, mediante pruebas serológicas dedoble difusión (DD5), ELISA e nmunoblot. Resultados. Se evaluó 473 escolares, 50,3 por ciento eran mujeres, 76,1 por ciento no conocía la enfermedad, 74,8 por ciento cría ganado y 79,1 por ciento tiene perros. Se encontró dos casos positivos a DD5 y 17 por ELISA, se confirmó seis por inmunoblot, dando una prevalencia de hidatidosis de 1,27 (IC95 por ciento: 0,15-2,38), los casos procedieron de los distritos de Sacsamarca (3/129), Carapo (1/66), Sancos (2/186) y Lucanamarca (0/92). Cinco de los seis casos criaban ganado y tenían perros, cuatro eran varones y tenían entre 9 a 15 años. Conclusión. Se demuestra la presencia de hidatidosis en zonas rurales ganaderas de Ayacucho, es necesaria la implementaciónde programas de intervención para el control de la hidatidosis.

Objective. To estimate the prevalence of human hydatidosis in the school population from 6 to 15 years of age in the highland province of Huancasancos, Ayacucho. Material and methods. Cross-sectional study, conducted in May 2004 by serology test as double diffusion(DD5), ELISA and immunoblot. Results. 473 schools were assessed, 50.3 per cent were women, 76.1 per cent did not know the disease, 74.8 per cent livestock breeding, 79.1 per cent have dogs. Two cases were found positive by DD5 and 17 by ELISA, six were confirmed by immunoblot, giving a prevalence of hydatid disease was 1.27 (CI95 per cent: 0.15-2.38), the cases were from the districts of Sacsamarca (3/129), Carapa (1/66), Sanco (2/186) and Lucanamarca (0/92). Five of the six cases had raised cattle and dogs, four were male and were between 9 to 15 years. Conclusions. It shows the presence of hydatidosis in rural livestock areas in Ayacucho, is needed to implement programs for the control of hydatidosis.

Aborto en el Hospital Universitario Ramón González Valencia: Incidencia y consecuencias

Se presenta un estudio prospectivo de 174 pacientes que consultaron en un período de dos meses al Hospital Universitario Ramón González Valencia y a quienes se les diagnóstico aborto y que constituye el 6,9 por ciento de la consulta gineco-obstétrica de urgencia. La edad promedio fue de 25.6 años, con un promedio de 2,27 gestaciones previas y una escolaridad promedio de 6,27 años cursados. El 85 por ciento fueron abortos espontáneos, 10,1 por ciento de los cuales se produjeron luego de retirar DIU (8,6 por ciento del total), 9,1 por ciento fueron admitidos por las pacientes como provocados, y el 5,7 pro ciento fueron accidentales. La gran moayoría se clasificó como aborto incompleto al momento del ingreso. Los dos síntomas más frecuentes como causa de consulta fueron la hemorragia vaginal (93,1 por ciento) y el dolor abdominal (85.6 por ciento), generalmente sociados. La principal complicación fue la infección (21,8 por ciento), sin mortalidad secundaria de esta. Se considera necesario ampliar la cobertura de la educación sexual a la escuela primaria, así como se hace evidente descartar la relación causal entre aborto y extracción de DIU luego del diagnosticar embarazo