Brain injuries from fisting. Front impact model / Traumas cerebrales por golpe de puño. Modelo de impacto en la frente

Boxing and other combat sports are associated with repetitive head trauma related to damage to the central nervous system. This work aimed to model the effect of a punch to the forehead given by a heavyweight boxer. Methodology: the Finite Element Method (FEM) was used. The research was based on simulating the effects of a dynamic impact and thus predicting, locating, and quantifying changes in the brain due to the blow. This simulation was validated by comparing medical research on brain injuries caused by impacts to the head. Results: The mathematical predictions showed significant brain effects: figures that exceed 100% risk. The MEF appears to be a practical, universal, inexpensive, and quick calculation tool, with important applications to detect evidence of brain trauma. (AU)

El boxeo y otros deportes de combate están asociados a traumas repetitivos en la cabeza, que pueden relacionarse con daños en el sistema nervioso central. El objetivo de este trabajo fue modelar el efecto de un golpe de puño en la frente, dado por un boxeador de peso pesado. Metodología: se utilizó el Método de Elementos Finitos (MEF). La investigación se basó en simular los efectos de un impacto dinámico y de esta forma predecir, localizar y cuantificar cambios en el cerebro debido al golpe. Para validar esta simulación, se comparó con investigaciones médicas sobre lesiones cerebrales, causadas por impactos en la cabeza. Resultados: Las predicciones matemáticas demostraron grandes efectos cerebrales: cifras que superan el 100% de riesgo. El MEF aparece pudiera ser una herramienta de cálculo práctica, universal, económica y rápida, con importantes aplicaciones para detectar evidencia de traumas cerebrales. (AU)

Staphtox predictor - A dynamic mathematical model to predict formation of Staphylococcus enterotoxin during heating and fermentation of meat products.

Existing growth models for S. aureus predict growth in relation to temperature, aw/NaCl and pH, and the assessment of probable Staphylococcus enterotoxin (SE) formation is based solely on the number of S. aureus. However, during the production of meat products such as fermented sausages and semi-processed hams, growth of S. aureus is a critical control point in HACCP plans. There is a need to develop a model that evaluates the safety of the product regarding SE formation in relation to the product composition, changes in pH or temperature during the processing and the number of S. aureus in the final product. The objective of the present work is to develop a mathematical model that predicts both the increase in the number of S. aureus and whether SE formation is possible in different meat product processes. A total of 78 experiments were carried out in a meat model system. The experiments covered a range of different temperatures (10-40 °C), pH (4.6-6.0), water phase salt (WPS) (2.2-5.6%) and Sodium nitrite concentrations (0-150 ppm). The meat model system was inoculated with approximately 103 CFU/g of a multi-strain cocktail and incubated at the different temperatures. The cocktail consisted of three strains of S. aureus producing the Staphylococcus enterotoxins A to D (SEA to SED) and a methicillin-resistant strain producing SEG, SEI, SEM, SEN, SEO and SEU. Enumeration of S. aureus was performed several times during the incubation, SE was extracted from samples with >5 log CFU/g, and the SEA-E content was analysed by an ELISA method. Maximum growth rates and lag times calculated from microbiological data, together with temperature, pH, WPS and Sodium nitrite, were used to develop a SE and a growth model. The growth model was developed by training a neural network and the SE model based on logistic regression. The SE and growth models were validated on separate data sets (N = 200 SE model, N = 63 growth model) including both dynamic and static conditions. The SE model predicted all occurrences of toxin formation in the validation data sets. The growth model is a fail-safe model and the prediction errors are comparable to laboratory reproducibility. In conclusion, the models are applicable for predicting the increase in S. aureus and for evaluating if SE formation is likely during processing of meat products. The models are available to producers and other interested parties at www.dmripredict.dk.

[Relevance of big data for molecular diagnostics]. / Bedeutung von Big Data für die molekulare Diagnostik.

Big data analysis raises the expectation that computerized algorithms may extract new knowledge from otherwise unmanageable vast data sets. What are the algorithms behind the big data discussion? In principle, high throughput technologies in molecular research already introduced big data and the development and application of analysis tools into the field of rheumatology some 15 years ago. This includes especially omics technologies, such as genomics, transcriptomics and cytomics. Some basic methods of data analysis are provided along with the technology, however, functional analysis and interpretation requires adaptation of existing or development of new software tools. For these steps, structuring and evaluating according to the biological context is extremely important and not only a mathematical problem. This aspect has to be considered much more for molecular big data than for those analyzed in health economy or epidemiology. Molecular data are structured in a first order determined by the applied technology and present quantitative characteristics that follow the principles of their biological nature. These biological dependencies have to be integrated into software solutions, which may require networks of molecular big data of the same or even different technologies in order to achieve cross-technology confirmation. More and more extensive recording of molecular processes also in individual patients are generating personal big data and require new strategies for management in order to develop data-driven individualized interpretation concepts. With this perspective in mind, translation of information derived from molecular big data will also require new specifications for education and professional competence.

Translational neurocardiology: preclinical models and cardioneural integrative aspects.

Neuronal elements distributed throughout the cardiac nervous system, from the level of the insular cortex to the intrinsic cardiac nervous system, are in constant communication with one another to ensure that cardiac output matches the dynamic process of regional blood flow demand. Neural elements in their various 'levels' become differentially recruited in the transduction of sensory inputs arising from the heart, major vessels, other visceral organs and somatic structures to optimize neuronal coordination of regional cardiac function. This White Paper will review the relevant aspects of the structural and functional organization for autonomic control of the heart in normal conditions, how these systems remodel/adapt during cardiac disease, and finally how such knowledge can be leveraged in the evolving realm of autonomic regulation therapy for cardiac therapeutics.

Postural influence on intracranial and cerebral perfusion pressure in ambulatory neurosurgical patients.

We evaluated postural effects on intracranial pressure (ICP) and cerebral perfusion pressure [CPP: mean arterial pressure (MAP) - ICP] in neurosurgical patients undergoing 24-h ICP monitoring as part of their diagnostic workup. We identified nine patients (5 women, age 44 ± 20 yr; means ± SD), who were "as normal as possible," i.e., without indication for neurosurgical intervention (e.g., focal lesions, global edema, abnormalities in ICP-profile, or cerebrospinal fluid dynamics). ICP (tip-transducer probe; Raumedic) in the brain parenchyma (n = 7) or in the lateral ventricles (n = 2) and cardiovascular variables (Nexfin) were determined from 20° head-down tilt to standing up. Compared with the supine position, ICP increased during 10° and 20° of head-down tilt (from 9.4 ± 3.8 to 14.3 ± 4.7 and 19 ± 4.7 mmHg; P < 0.001). Conversely, 10° and 20° head-up tilt reduced ICP to 4.8 ± 3.6 and 1.3 ± 3.6 mmHg and ICP reached -2.4 ± 4.2 mmHg in the standing position (P < 0.05). Concordant changes in MAP maintained CPP at 77 ± 7 mmHg regardless of body position (P = 0.95). During head-down tilt, the increase in ICP corresponded to a hydrostatic pressure gradient with reference just below the heart, likely reflecting the venous hydrostatic indifference point. When upright, the decrease in ICP was attenuated, corresponding to formation of a separate hydrostatic gradient with reference to the base of the skull, likely reflecting the site of venous collapse. ICP therefore seems to be governed by pressure in the draining veins and collapse of neck veins may protect the brain from being exposed to a large negative pressure when upright. Despite positional changes in ICP, MAP keeps CPP tightly regulated.

Opioids inhibit visceral afferent activation of catecholamine neurons in the solitary tract nucleus.

Brainstem A2/C2 catecholamine (CA) neurons within the solitary tract nucleus (NTS) influence many homeostatic functions, including food intake, stress, respiratory and cardiovascular reflexes. They also play a role in both opioid reward and withdrawal. Injections of opioids into the NTS modulate many autonomic functions influenced by catecholamine neurons including food intake and cardiac function. We recently showed that NTS-CA neurons are directly activated by incoming visceral afferent inputs. Here we determined whether opioid agonists modulate afferent activation of NTS-CA neurons using transgenic mice with EGFP expressed under the control of the tyrosine hydroxylase promoter (TH-EGFP) to identify catecholamine neurons. The opioid agonist Met-enkephalin (Met-Enk) significantly attenuated solitary tract-evoked excitatory postsynaptic currents (ST-EPSCs) in NTS TH-EGFP neurons by 80%, an effect reversed by wash or the mu opioid receptor-specific antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (CTOP). Met-Enk had a significantly greater effect to inhibit afferent inputs onto TH-EGFP-positive neurons than EGFP-negative neurons, which were only inhibited by 50%. The mu agonist, DAMGO, also inhibited the ST-EPSC in TH-EGFP neurons in a dose-dependent manner. In contrast, neither the delta agonist DPDPE, nor the kappa agonist, U69,593, consistently inhibited the ST-EPSC amplitude. Met-Enk and DAMGO increased the paired pulse ratio, decreased the frequency, but not amplitude, of mini-EPSCs and had no effect on holding current, input resistance or current-voltage relationships in TH-EGFP neurons, suggesting a presynaptic mechanism of action on afferent terminals. Met-Enk significantly reduced both the basal firing rate of NTS TH-EGFP neurons and the ability of afferent stimulation to evoke an action potential. These results suggest that opioids inhibit NTS-CA neurons by reducing an excitatory afferent drive onto these neurons through presynaptic inhibition of glutamate release and elucidate one potential mechanism by which opioids could control autonomic functions and modulate reward and opioid withdrawal symptoms at the level of the NTS.

Intracranial Pressure Monitoring: Invasive versus Non-Invasive Methods-A Review.

Monitoring of intracranial pressure (ICP) has been used for decades in the fields of neurosurgery and neurology. There are multiple techniques: invasive as well as noninvasive. This paper aims to provide an overview of the advantages and disadvantages of the most common and well-known methods as well as assess whether noninvasive techniques (transcranial Doppler, tympanic membrane displacement, optic nerve sheath diameter, CT scan/MRI and fundoscopy) can be used as reliable alternatives to the invasive techniques (ventriculostomy and microtransducers). Ventriculostomy is considered the gold standard in terms of accurate measurement of pressure, although microtransducers generally are just as accurate. Both invasive techniques are associated with a minor risk of complications such as hemorrhage and infection. Furthermore, zero drift is a problem with selected microtransducers. The non-invasive techniques are without the invasive methods' risk of complication, but fail to measure ICP accurately enough to be used as routine alternatives to invasive measurement. We conclude that invasive measurement is currently the only option for accurate measurement of ICP.

Fisiopatología de la insuficiencia renal aguda durante la sepsis / Physiopathology of acute renal failure during sepsis

La insuficiencia renal aguda (IRA) es un factor de riesgo independiente asociado a mayor mortalidad durante la sepsis. Definiciones de con senso recientes han permitido estandarizarlos trabajos de investigación en el tema. La comprensión de la fisiopatología de la IRA durante la sepsis está limitada por la escasez de estudios histológicos y por la imposibilidad de medir los flujos microcirculatorios renales. Históricamente se ha considerado a la IRA séptica como una patología dependiente de la caída del flujo sanguíneo renal (FSR). Efectivamente, en las etapas precoces de la sepsis o en la sepsis acompañada de shock cardiogénico existe compromiso del FSR; sin embargo, estudios recientes han demostrado que en la sepsis reanimada, aquella en que característicamente se observa un gasto cardiaco normal o alto y vasodilatación sistémica, el FSR es normal o incluso aumentado y no existe evidencia histológica significativa denecrosis tubular. Otros factores, distintos al puramente hemodinámico, participan en la génesis de la IRA en la sepsis. Entre éstos están la apoptosis celular, los trastornos microcirculatorios glomerulares y medulares, los cambios celulares en respuestas a la cascada proinflamatoria propia de la sepsis, el estrés oxidativo, la disfunción mitocondrial y el daño a distancia inducido por ventilación mecánica, entre otros. En la actualidad, el tratamiento de la IRA en la sepsis es de soporte. En general, las terapias de reemplazo renal pueden ser clasificadas como intermitentes o continuas, y en las que buscan primariamente el reemplazo de la función renal deteriorada, frente a aquellas cuyo objetivo principal es lograr la estabilidad hemodinámica de los pacientes mediante la remoción de mediadores proinflamatorios (AU)

Acute renal failure (ARF) is an independent risk factor associated with increased mortality during sepsis. Recent consensus definitions have allowed the standardization of researchon the subject. The understanding of the physiopathology of ARF during sepsis is limited by the scarcity of histological studies and the inability to measure renal microcirculatory flows. Historically, ARF during sepsis has been considered to be a consequence of diminished renal bloodflow (RBF). Indeed, in early stages of sepsis or in sepsis associated to cardiogenic shock, RBF may decrease. However, recent studies have shown that in resuscitated sepsis, in which cardiacout put is characteristically normal or even elevated and there is systemic vasodilatation, RBF is normal or even increased, with no associated histological evidence of significant tubularnecrosis. Thus, other factors may participate in the genesis of ARF in sepsis. These includeapoptosis, glomerular and medullary microcirculatory disorders, cell changes in response to thepro-inflammatory cascade characteristic of sepsis, oxidative stress, mitochondrial dysfunction and damage induced by mechanical ventilation, among others. Sepsis associated ARF treatmentis supportive. In general, renal replacement therapies can be grouped as intermittent or continuous, and as those whose primary objective is the replacement of impaired renal function,versus those whose main objective is to secure hemodynamic stability through the clearing ofpro-inflammatory mediators (AU)

GABA(B) restrains release from singly-evoked GABA terminals.

Neurotransmitter release regulation is highly heterogeneous across the brain. The fundamental units of release, individual boutons, are difficult to access and poorly understood. Here we directly activated single boutons on mechanically isolated nucleus tractus solitarius (NTS) neurons to record unitary synaptic events under voltage clamp. By scanning the cell surface with a stimulating pipette, we located unique sites that generated evoked excitatory postsynaptic currents (eEPSCs) or evoked inhibitory postsynaptic currents (eIPSCs) events. Stimulus-response relations had abrupt thresholds for all-or-none synaptic events consistent with unitary responses. Thus, irrespective of shock intensity, focal stimulation selectively evoked either eEPSCs or eIPSCs from single retained synaptic boutons and never recruited other synapses. Evoked EPSCs were rarely encountered. Our studies, thus, focused primarily on the more common GABA release. At most locations, shocks often failed to release GABA even at low frequencies (0.075 Hz), and eIPSCs succeeded only on average 2.7±0.7 successful IPSCs per 10 shocks. Activation of eIPSCs decreased spontaneous IPSCs in the same neurons. The GABA(A) receptor antagonist gabazine (3 µM) reversibly blocked eIPSCs as did tetrodotoxin (TTX) (300 nM). The initial low rate of successful eIPSCs decreased further in a use-dependent manner at 0.5 Hz stimulation-depressing 70% in 2 min. The selective GABA(B) receptor antagonist 3-[[(3,4-Dichlorophenyl)methyl]amino]propyl] diethoxymethyl)phosphinic acid (CGP 52432) (5 µM) had three actions: tripling the initial release rate, slowing the use-dependent decline without changing amplitudes, and blocking the shock-related decrease in spontaneous IPSCs. The results suggest strong, surprisingly long-lasting, negative feedback by GABA(B) receptors within single GABA terminals that determine release probability even in isolated terminals.

[Physiopathology of acute renal failure during sepsis]. / Fisiopatología de la insuficiencia renal aguda durante la sepsis.

Acute renal failure (ARF) is an independent risk factor associated with increased mortality during sepsis. Recent consensus definitions have allowed the standardization of research on the subject. The understanding of the physiopathology of ARF during sepsis is limited by the scarcity of histological studies and the inability to measure renal microcirculatory flows. Historically, ARF during sepsis has been considered to be a consequence of diminished renal blood flow (RBF). Indeed, in early stages of sepsis or in sepsis associated to cardiogenic shock, RBF may decrease. However, recent studies have shown that in resuscitated sepsis, in which cardiac output is characteristically normal or even elevated and there is systemic vasodilatation, RBF is normal or even increased, with no associated histological evidence of significant tubular necrosis. Thus, other factors may participate in the genesis of ARF in sepsis. These include apoptosis, glomerular and medullary microcirculatory disorders, cell changes in response to the pro-inflammatory cascade characteristic of sepsis, oxidative stress, mitochondrial dysfunction and damage induced by mechanical ventilation, among others. Sepsis associated ARF treatment is supportive. In general, renal replacement therapies can be grouped as intermittent or continuous, and as those whose primary objective is the replacement of impaired renal function, versus those whose main objective is to secure hemodynamic stability through the clearing of pro-inflammatory mediators.

Heterosynaptic crosstalk: GABA-glutamate metabotropic receptors interactively control glutamate release in solitary tract nucleus.

Synaptic terminals often contain metabotropic receptors that act as autoreceptors to control neurotransmitter release. Less appreciated is the heterosynaptic crossover of glutamate receptors to control GABA release and vice versa GABA receptors which control glutamate release. In the brainstem, activation of solitary tract (ST) afferents releases glutamate onto second-order neurons within the solitary tract nucleus (NTS). Multiple metabotropic receptors are expressed in NTS for glutamate (mGluRs) and for GABA (GABA(B)). The present report identifies mGluR regulation of glutamate release at second and higher order sensory neurons in NTS slices. We found strong inhibition of glutamate release to group II and III mGluR activation on mechanically isolated NTS neurons. However, the same mGluR-selective antagonists paradoxically decreased glutamate release (miniature, mEPSCs) at identified second-order NTS neurons. Unaltered amplitudes were consistent with selective presynaptic mGluR actions. GABA(B) blockade in slices resolved the paradoxical differences and revealed a group II/III mGluR negative feedback of mEPSC frequency similar to isolated neurons. Thus, the balance of glutamate control is tipped by mGluR receptors on GABA terminals resulting in predominating heterosynaptic GABA(B) inhibition of glutamate release. Regulation by mGluR or GABA(B) was not consistently evident in excitatory postsynaptic currents (EPSCs) in higher-order NTS neurons demonstrating metabotropic receptor distinctions in processing at different NTS pathway stages. These cellular localizations may figure importantly in understanding interventions such as brain-penetrant compounds or microinjections. We conclude that afferent glutamate release in NTS produces a coordinate presynaptic activation of co-localized mGluR and GABA(B) feedback on cranial afferent terminals to regulate glutamate release.

Optical tracking of phenotypically diverse individual synapses on solitary tract nucleus neurons.

The solitary tract nucleus (NTS) is the termination site for cranial visceral afferents-peripheral primary afferent neurons which differ by phenotype (e.g. myelinated and unmyelinated). These afferents have very uniform glutamate release properties calculated by variance mean analysis. In the present study, we optical measured the inter-terminal release properties across individual boutons by assessing vesicle membrane turnover with the dye FM1-43. Single neurons were mechanically micro-harvested from medial NTS without enzyme treatment. The TRPV1 agonist capsaicin (CAP, 100 nM) was used to identify afferent, CAP-sensitive terminals arising from unmyelinated afferents. Isolated NTS neurons retained both glutamatergic and inhibitory terminals that generated EPSCs and IPSCs, respectively. Visible puncta on the neurons were stained positively with monoclonal antibody for synaptophysin, a presynaptic marker. Elevating extracellular K(+) concentration to 10 mM increased synaptic release measured at individual terminals by FM1-43. Within single neurons, CAP destained some but not other individual terminals. FM1-43 positive terminals that were resistant to CAP could be destained with K(+) solution. Individual terminals responded to depolarization with similar vesicle turnover kinetics. Thus, vesicular release was relatively homogenous across individual release sites. Surprisingly, conventionally high K(+) concentrations (>50 mM) produced erratic synaptic responses and at 90 mM K(+) overt neuron swelling--results that suggest precautions about assuming consistent K(+) responses in all neurons. The present work demonstrates remarkably uniform glutamate release between individual unmyelinated terminals and suggests that the homogeneous EPSC release properties of solitary tract afferents result from highly uniform release properties across multiple contacts on NTS neurons.

[Mitochondrial dysfunction during sepsis, impact and possible regulating role of hypoxia-inducible factor-1alpha]. / Disfunción mitocondrial en sepsis, impacto y posible papel regulador del factor inducible por hipoxia (HIF-1alpha).

There is a direct correlation between the development of the multiple organ dysfunction syndrome (MODS) and the elevated mortality associated with sepsis. The mechanisms responsible for MODS development are being studied, however, the main efforts regarding MODS evaluation have focused on oxygen delivery optimization and on the modulation of the characteristic inflammatory cascade of sepsis, all with negative results. Recent studies have shown that there is development of tissue acidosis, even when there are normal oxygen conditions and limited presence of tissue cellular necrosis or apoptosis, which would indicate that cellular energetic dysfunction may be a central element in MODS pathogenesis. Mitochondrias are the main source of cellular energy, central regulators of cell death and the main source for reactive oxygen species. Several mechanisms contribute to mitochondrial dysfunction during sepsis, that is blockage of pyruvate entry into the Krebs cycle, oxidative phosphorylation substrate use in other enzymatic complexes, enzymatic complex inhibition and membrane damage mediated by oxidative stress, and reduction in mitochondrial content. Hypoxia-inducible factor-1alpha (HIF-1alpha) is a nuclear transcription factor with a central role in the regulation of cellular oxygen homeostasis. Its induction under hypoxic conditions is associated to the expression of hundreds of genes that coordinate the optimization of cellular oxygen delivery and the cellular energy metabolism. HIF-1alpha can also be stabilized under normoxic condition during inflammation and this activation seems to be associated with a prominent pro-inflammatory profile, with lymphocytes dysfunction, and to a reduction in cellular oxygen consumption. Further studies should establish a role for HIF-1alpha as a therapeutic target.

Disfunción mitocondrial en sepsis, impacto y posible papel regulador del factor inducible por hipoxia (HIF-1alfa) / Mitochondrial dysfunction during sepsis, impact and possible regulating role of hypoxia-inducible factor -1alfa

Existe una relación directa entre el desarrollo del síndrome de disfunción de órganos (SDOM) y la alta mortalidad asociada a sepsis. Los mecanismos causantes del desarrollo de SDOM permanecen en estudio, pero los mayores esfuerzos en su evaluación se han centrado en la optimización de la oxigenación tisular y en la modulación de la cascada inflamatoria característica de la sepsis, con resultados negativos. Estudios recientes muestran desarrollo de acidosis tisular aun con niveles de oxigenación tisular adecuados y escasa presencia de necrosis o apoptosis celular en los tejidos afectados, lo que indica una disfunción celular energética como un elemento central en el desarrollo del SDOM. Las mitocondrias son la principal fuente energética celular, reguladores clave de la muerte celular y principal fuente de especies reactivas de oxígeno. Varios mecanismos contribuyen al desarrollo de disfunción mitocondrial durante la sepsis: el bloqueo en la entrada de piruvato al ciclo de Krebs, el consumo de sustratos de la fosforilación oxidativa por parte de otros complejos enzimáticos, la inhibición enzimática y el daño de membrana secundarios a estrés oxidativo, y la disminución en el contenido mitocondrial celular. El hypoxia inducible factor (HIF)-1alfa es un factor de trascripción que actúa como un regulador clave en la homeostasis del oxígeno celular. Su inducción en condiciones de hipoxia se asocia a la expresión de cientos de genes que coordinan la optimización de la entrega de oxígeno celular y el metabolismo energético celular. El HIF-1alfa puede estabilizarse en normoxia en presencia de inflamación; esta activación parece asociarse a un patrón de respuesta inmunitaria proinflamatorio, a una disfunción de linfocitos y a una disminución de consumo de oxígeno celular. Nuevos estudios deberán establecer un papel terapeútico en la modulación del HIF-1alfa (AU)

There is a direct correlation between the development of the multiple organ dysfunction syndrome (MODS) and the elevated mortality associated with sepsis. The mechanisms responsible for MODS development are being studied, however, the main efforts regarding MODS evaluation have focused on oxygen delivery optimization and on the modulation of the characteristic inflammatory cascade of sepsis, all with negative results. Recent studies have shown that there is development of tissue acidosis, even when there are normal oxygen conditions and limited presence of tissue cellular necrosis or apoptosis, which would indicate that cellular energetic dysfunction may be a central element in MODS pathogenesis. Mitochondrias are the main source of cellular energy, central regulators of cell death and the main source for reactive oxygen species. Several mechanisms contribute to mitochondrial dysfunction during sepsis, that is blockage of pyruvate entry into the Krebs cycle, oxidative phosphorylation substrate use in other enzymatic complexes, enzymatic complex inhibition and membrane damage mediated by oxidative stress, and reduction in mitochondrial content. Hypoxia-inducible factor-1alfa (HIF-1alfa) is a nuclear transcription factor with a central role in the regulation of cellular oxygen homeostasis. Its induction under hypoxic conditions is associated to the expression of hundreds of genes that coordinate the optimization of cellular oxygen delivery and the cellular energy metabolism. HIF-1alfa can also be stabilized under normoxic condition during inflammation and this activation seems to be associated with a prominent pro-inflammatory profile, with lymphocytes dysfunction, and to a reduction in cellular oxygen consumption. Further studies should establish a role for HIF-1alfa as a therapeutic target (AU)

[Characteristics and impact of sedation, analgesia, and neuromuscular blockage in critical patients undergoing prolonged mechanical ventilation]. / Características e impacto de la sedación, la analgesia y el bloqueo neuromuscular en los pacientes críticos que recibieron ventilación mecánica prolongada.

AIM: To describe use of sedatives, analgesics, and neuromuscular blockers (NMB) in patients undergoing long-term mechanical ventilation and to assess factors associated with their use and their association with mortality at 28 days. DESIGN: Prospective observational multicenter cohort study. SETTING: Thirteen intensive care units (ICU) in Chile. PATIENTS: Patients undergoing mechanical ventilation for more than 48h. We excluded patients with neurological disorders, cirrhosis of the liver, chronic renal failure, suspected drug addiction, and early no resuscitation orders. INTERVENTION: None. MAIN MEASUREMENTS: Proportion of use and dosage of sedatives, analgesics, and NMB. Level of sedation observed (SAS). Variables associated with the Sedation Agitation Scale (SAS), use of sedatives, analgesics, and NMB. Multivariate logistic regression of variables associated to mortality at 28 days. RESULTS: A total of 155 patients participated (60+/-18 years, 57% male, SOFA 7 [6-10], APACHE II 18 [15-22], 63% with sepsis, and 47% with acute lung injury/adult respiratory distress syndrome. The drugs most frequently used were midazolam (85%, 4 [1.9-6.8]mg/hr) and fentanyl (81%, 76 [39-140]microg/hr). NMB were administered at least 1 day in 30% of patients. SAS score was 1 or 2 in 55% of patients. There was an association between NMB use and mortality at 28 days, but it was not consistent in all the models of NMB evaluated. CONCLUSIONS: Sedatives were frequently employed and deep sedation was common. Midazolam and fentanyl were the most frequently administered drugs. The use of NMB might be independently associated to greater mortality.

Características e impacto de la sedación, la analgesia y el bloqueo neuromuscular en los pacientes críticos que recibieron ventilación mecánica prolongada / Characteristics and impact of sedation, analgesia, and neuromuscular blockage in critical patients under going prolonged mechanical ventilation

Objetivo: Describir el uso de sedantes, analgésicos y bloqueantes neuromusculares (BNM) en los pacientes con ventilación mecánica (VM) prolongada y evaluar los factores asociados a su empleo y asociación con la mortalidad a los 28 días. Diseño: Estudio multicéntrico, prospectivo y observacional de cohorte. Ámbito: Trece unidades de cuidados intensivos (UCI) en Chile. Pacientes: Pacientes con VM superior a 48h. Excluimos los pacientes con enfermedad neurológica, cirrosis hepática, insuficiencia renal crónica, sospecha de adicción a drogas y limitación precoz del esfuerzo terapéutico. Intervención: Ninguna Variables de interés principales Proporción de uso y dosis de sedantes, analgésicos y BNM. Nivel de sedación observado (SAS [sedation-agitation scale 'escala de sedación-agitación']). Variables asociadas al nivel de la SAS, y el uso de sedantes, analgésicos y BNM. Regresión logística multivariada de variables asociadas a la mortalidad a los 28 días. Resultados: Participaron 155 pacientes (60±18 años, el 57% eran varones, SOFA 7 [6-10], APACHE II 18 [15-22], el 63% con sepsis y el 47% con lesión pulmonar aguda/síndrome de distrés respiratorio agudo. Los fármacos empleados fueron midazolam (85%; 4 mg/h [1,9-6,8]) y fentanilo (81%; 76 μg/h [39-140]). Un 30% de los pacientes usó BNM al menos un día. El 55% de la SAS fue 1-2. Existe una asociación entre el uso de BNM y la mortalidad a los 28 días, pero ésta no fue consistente en todos los modelos de uso de BNM evaluados. Conclusiones: En el grupo estudiado fue frecuente el uso de sedantes y la presencia de sedación profunda, el midazolam y el fentanilo fueron los fármacos más usados. El uso de BNM podría asociarse de forma independiente a una mayor mortalidad (AU)

Aim: To describe use of sedatives, analgesics, and neuromuscular blockers (NMB) in patients undergoing long-term mechanical ventilation and to assess factors associated with their use and their association with mortality at 28 days. Design: Prospective observational multicenter cohort study. Setting: Thirteen intensive care units (ICU) in Chile. Patients: Patients undergoing mechanical ventilation for more than 48h. We excluded patients with neurological disorders, cirrhosis of the liver, chronic renal failure, suspected drug addiction, and early no resuscitation orders. Intervention None. Main measurements: Proportion of use and dosage of sedatives, analgesics, and NMB. Level of sedation observed (SAS). Variables associated with the Sedation Agitation Scale (SAS), use of sedatives, analgesics, and NMB. Multivariate logistic regression of variables associated to mortality at 28 days. Results: A total of 155 patients participated (60±18 years, 57% male, SOFA 7 [6-10], APACHE II 18 [15-22], 63% with sepsis, and 47% with acute lung injury/adult respiratory distress syndrome. The drugs most frequently used were midazolam (85%, 4 [1.9-6.8]mg/hr) and fentanyl (81%, 76 [39-140]μg/hr). NMB were administered at least 1 day in 30% of patients. SAS score was 1 or 2 in 55% of patients. There was an association between NMB use and mortality at 28 days, but it was not consistent in all the models of NMB evaluated. Conclusions: Sedatives were frequently employed and deep sedation was common. Midazolam and fentanyl were the most frequently administered drugs. The use of NMB might be independently associated to greater mortality (AU)

An evidence-based resuscitation algorithm applied from the emergency room to the ICU improves survival of severe septic shock.

BACKGROUND: Septic shock is highly lethal. We recently implemented an algorithm (advanced resuscitation algorithm for septic shock, ARAS 1) with a global survival of 67%, but with a very high mortality (72%) in severe cases [norepinephrine (NE) requirements >0.3 microg/kg/min for mean arterial pressure > or =70 mmHg]. As new therapies with different levels of evidence were proposed [steroids, drotrecogin alpha, high-volume hemofiltration (HVHF)], we incorporated them according to severity (NE requirements; algorithm ARAS-2), and constructed a multidisciplinary team to manage these patients from the emergency room (ER) to the ICU. The aim of this study was to compare the outcome of severe septic shock patients under both protocols. METHODS: Adult patients with severe septic shock were enrolled consecutively and managed prospectively with ARAS-1 (1999-2001), and ARAS-2 (2002-05). ARAS-2 incorporates HVHF for intractable shock. RESULTS: Thirty-three patients were managed with each protocol, without statistical differences in baseline demographics, APACHE II (22.2 vs 23.8), SOFA (11.4 vs 12.7) and NE peak levels (0.62 vs 0.8 microg/kg/min). The 28-day mortality and epinephrine use were higher with ARAS-1 (72.7% vs 48.5%; 87.9% vs 18.2 %); and low-dose steroids (35.9% vs 72.7%), drotrecogin (0 vs 15 %) and HVHF use (3.0% vs 39.4%) were higher for ARAS-2 (P<0.05 for all). CONCLUSION: Management of severe septic shock with a multidisciplinary team and an updated protocol (according to the best current evidence), with precise entry criteria for every intervention at different stages of severity, may improve survival in these patients. Multidisciplinary management, rationalization of the use of vasoactives and rescue therapy based on HVHF instead of epinephrine may have contributed to these RESULTS: Management of severe septic shock with these kinds of algorithms is feasible and should be encouraged.

Reversible photoswitching enables single-molecule fluorescence fluctuation spectroscopy at high molecular concentration.

We demonstrate that photoswitchable markers enable fluorescence fluctuation spectroscopy at high molecular concentration. Reversible photoswitching allows precise control of the density of fluorescing entities, because the equilibrium between the fluorescent ON- and the dark OFF-state can be shifted through optical irradiation at a specific wavelength. Depending on the irradiation intensity, the concentration of the ON-state markers can be up to 1,000 times lower than the actual concentration of the labeled molecular entity. Photoswitching expands the range of single-molecule detection based experiments such as fluorescence fluctuation spectroscopy to large entity concentrations in the micromolar range.

A-type potassium channels differentially tune afferent pathways from rat solitary tract nucleus to caudal ventrolateral medulla or paraventricular hypothalamus.

The solitary tract nucleus (NTS) conveys visceral information to diverse central networks involved in homeostatic regulation. Although afferent information content arriving at various CNS sites varies substantially, little is known about the contribution of processing within the NTS to these differences. Using retrograde dyes to identify specific NTS projection neurons, we recently reported that solitary tract (ST) afferents directly contact NTS neurons projecting to caudal ventrolateral medulla (CVLM) but largely only indirectly contact neurons projecting to the hypothalamic paraventricular nucleus (PVN). Since intrinsic properties impact information transmission, here we evaluated potassium channel expression and somatodendritic morphology of projection neurons and their relation to afferent information output directed to PVN or CVLM pathways. In slices, tracer-identified projection neurons were classified as directly or indirectly (polysynaptically) coupled to ST afferents by EPSC latency characteristics (directly coupled, jitter < 200 micros). In each neuron, voltage-dependent potassium currents (IK) were evaluated and, in representative neurons, biocytin-filled structures were quantified. Both CVLM- and PVN-projecting neurons had similar, tetraethylammonium-sensitive IK. However, only PVN-projecting NTS neurons displayed large transient, 4-aminopyridine-sensitive, A-type currents (IKA). PVN-projecting neurons had larger cell bodies with more elaborate dendritic morphology than CVLM-projecting neurons. ST shocks faithfully (> 75%) triggered action potentials in CVLM-projecting neurons but spike output was uniformly low (< 20%) in PVN-projecting neurons. Pre-conditioning hyperpolarization removed IKA inactivation and attenuated ST-evoked spike generation along PVN but not CVLM pathways. Thus, multiple differences in structure, organization, synaptic transmission and ion channel expression tune the overall fidelity of afferent signals that reach these destinations.

Revisión clínica: depresión miocárdica en sepsis y shock séptico / Clinical revision: myocardial depression in sepsis and septic shock

La sepsis y el shock séptico son patologías de gran mortalidad, cuyo evento final es la hipotensión refractaria, colapso cardiocirculatorio y falla multiorgánica. En los últimos años se han realizado importantes esfuerzos para entender la disfunción cardiaca asociada a este cuadro, que puede objetivarse hasta en el 50 por ciento de los pacientes con sepsis severa y shock séptico. A pesar de que hoy se acepta que la disfunción miocárdica juega un importante rol en la sepsis, aún no existe consenso respecto a la manera de evaluar la función cardiaca en este contexto, surgiendo nuevas propuestas como el uso de marcadores séricos. Por otra parte, el tratamiento más utilizado hasta hoy han sido los inótropos como la dobutamina, sin embargo con los nuevos estudios sobre la etiología de la disfunción miocárdica, se ha logrado el desarrollo de nuevas líneas experimentales de tratamiento.

The sepsis and the septic shock are pathologies of the great mortality, whose final event is the refractory hypotension, circulatory collapse and multiorganic failure. In the last years important efforts have been made to understand the associate cardiac dysfunction to this picture, which can appear until in 50 percent of the patients with severe sepsis and septic shock. Although today it is accepted that the myocardial dysfunction plays an important role in the sepsis. It does not yet exist consensus with respect to the way to evaluate the function cardiac. New proposals arising as the use from seric markers. On the other hand, the more used treatment until today has been the inotropic agent like the dobutamine. But with the new studies on the etiology of the myocardial dysfunction, has been obtained the development of experimental new line of treatment.