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BACKGROUND: There is growing evidence of the benefits of intravenous fluid therapy with balanced crystalloids over 0.9% 'normal' saline. This analysis evaluated the economic impact of increasing usage of a calcium-free balanced crystalloid solution (BAL) in patients with systemic inflammatory response syndrome (SIRS) on an annual hospital budget. METHODS: An Excel®-based economic model was developed to estimate costs associated with increased BAL usage (i.e., use in a greater proportion of patients), from the US hospital perspective, over a 5-year time horizon. Clinical inputs were based on the results of a retrospective Electronic Health Record (EHR) database analysis identifying significantly fewer complications among SIRS patients receiving predominantly BAL versus saline. Complication-associated costs, adjusted to 2015, were obtained from published reports. Scenario analyses examined cost impacts for hospitals of various sizes, with different BAL adoption levels and rates. RESULTS: Base-case scenario analysis (300-bed hospital, 80% occupancy, current and year 5 BAL usage in 5 and 75% of SIRS patients, respectively, exponential year-over-year adoption) showed year 1 hospital savings of US$29,232 and cumulative 5-year savings of US$1.16M. Cumulative 5-year pharmacy savings were US$172,641. Scenario analyses demonstrated increasing cumulative 5-year savings with increasing hospital size, year 5 BAL usage in greater proportions of patients, and rapid/early BAL adoption. CONCLUSIONS: Increased BAL usage represents an opportunity for hospitals and pharmacy departments to reduce complication-related costs associated with managing SIRS patients. The model suggests that savings could be expected across a range of scenarios, likely benefiting hospitals of various sizes and with different adoption capabilities.
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PURPOSE: Recent data suggest that both elevated serum chloride levels and volume overload may be harmful during fluid resuscitation. The purpose of this study was to examine the relationship between the intravenous chloride load and in-hospital mortality among patients with systemic inflammatory response syndrome (SIRS), with and without adjustment for the crystalloid volume administered. METHODS: We conducted a retrospective analysis of 109,836 patients ≥ 18 years old that met criteria for SIRS and received fluid resuscitation with crystalloids. We examined the association between changes in serum chloride concentration, the administered chloride load and fluid volume, and the 'volume-adjusted chloride load' and in-hospital mortality. RESULTS: In general, increases in the serum chloride concentration were associated with increased mortality. Mortality was lowest (3.7%) among patients with minimal increases in serum chloride concentration (0-10 mmol/L) and when the total administered chloride load was low (3.5% among patients receiving 100-200 mmol; P < 0.05 versus patients receiving ≥ 500 mmol). After controlling for crystalloid fluid volume, mortality was lowest (2.6%) when the volume-adjusted chloride load was 105-115 mmol/L. With adjustment for severity of illness, the odds of mortality increased (1.094, 95% CI 1.062, 1.127) with increasing volume-adjusted chloride load (≥ 105 mmol/L). CONCLUSIONS: Among patients with SIRS, a fluid resuscitation strategy employing lower chloride loads was associated with lower in-hospital mortality. This association was independent of the total fluid volume administered and remained significant after adjustment for severity of illness, supporting the hypothesis that crystalloids with lower chloride content may be preferable for managing patients with SIRS.
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Cloruros/administración & dosificación , Coloides/administración & dosificación , Fluidoterapia , Mortalidad Hospitalaria , Síndrome de Respuesta Inflamatoria Sistémica/tratamiento farmacológico , Síndrome de Respuesta Inflamatoria Sistémica/mortalidad , Administración Intravenosa , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Cloruros/efectos adversos , Cloruros/sangre , Enfermedad Crítica/mortalidad , Enfermedad Crítica/terapia , Femenino , Fluidoterapia/efectos adversos , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Resucitación , Estudios Retrospectivos , Desequilibrio Hidroelectrolítico/etiología , Desequilibrio Hidroelectrolítico/prevención & control , Adulto JovenRESUMEN
Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by intellectual disability, sensory hypersensitivity, and high incidences of autism spectrum disorders and epilepsy. These phenotypes are suggestive of defects in neural circuit development and imbalances in excitatory glutamatergic and inhibitory GABAergic neurotransmission. While alterations in excitatory synapse function and plasticity are well-established in Fmr1 knockout (KO) mouse models of FXS, a number of recent electrophysiological and molecular studies now identify prominent defects in inhibitory GABAergic transmission in behaviorally relevant forebrain regions such as the amygdala, cortex, and hippocampus. In this review, we summarize evidence for GABAergic system dysfunction in FXS patients and Fmr1 KO mouse models alike. We then discuss some of the known developmental roles of GABAergic signaling, as well as the development and refinement of GABAergic synapses as a framework for understanding potential causes of mature circuit dysfunction. Finally, we highlight the GABAergic system as a relevant target for the treatment of FXS.
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Síndrome del Cromosoma X Frágil/fisiopatología , Sinapsis/fisiología , Transmisión Sináptica/fisiología , Ácido gamma-Aminobutírico/metabolismo , Amígdala del Cerebelo/fisiopatología , Amígdala del Cerebelo/ultraestructura , Animales , Corteza Cerebral/fisiopatología , Corteza Cerebral/ultraestructura , Modelos Animales de Enfermedad , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Síndrome del Cromosoma X Frágil/terapia , Hipocampo/fisiopatología , Hipocampo/ultraestructura , Humanos , Plasticidad Neuronal/fisiologíaRESUMEN
Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by severe cognitive impairments, sensory hypersensitivity, and comorbidities with autism and epilepsy. Fmr1 knockout (KO) mouse models of FXS exhibit alterations in excitatory and inhibitory neurotransmission, but it is largely unknown how aberrant function of specific neuronal subtypes contributes to these deficits. In this study we show specific inhibitory circuit dysfunction in layer II/III of somatosensory cortex of Fmr1 KO mice. We demonstrate reduced activation of somatostatin-expressing low-threshold-spiking (LTS) interneurons in response to the group I metabotropic glutamate receptor (mGluR) agonist 3,5-dihydroxyphenylglycine (DHPG) in Fmr1 KO mice, resulting in impaired synaptic inhibition. Paired recordings from pyramidal neurons revealed reductions in synchronized synaptic inhibition and coordinated spike synchrony in response to DHPG, indicating a weakened LTS interneuron network in Fmr1 KO mice. Together, these findings reveal a functional defect in a single subtype of cortical interneuron in Fmr1 KO mice. This defect is linked to altered activity of the cortical network in line with the FXS phenotype.
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Sincronización Cortical/fisiología , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/fisiopatología , Inhibición Neural/fisiología , Corteza Somatosensorial/fisiopatología , Potenciales de Acción/fisiología , Animales , Síndrome del Cromosoma X Frágil/genética , Interneuronas/fisiología , Masculino , Metoxihidroxifenilglicol/análogos & derivados , Metoxihidroxifenilglicol/farmacología , Ratones , Ratones Endogámicos , Ratones Noqueados , Técnicas de Cultivo de Órganos , Fenotipo , Células Piramidales/fisiología , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/metabolismo , Corteza Somatosensorial/citología , Somatostatina/metabolismo , Transmisión Sináptica/fisiología , Ácido gamma-Aminobutírico/fisiologíaRESUMEN
Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by variable cognitive impairment and behavioral disturbances such as exaggerated fear, anxiety and gaze avoidance. Consistent with this, findings from human brain imaging studies suggest dysfunction of the amygdala. Underlying alterations in amygdala synaptic function in the Fmr1 knock-out (KO) mouse model of FXS, however, remain largely unexplored. Utilizing a combination of approaches, we uncover profound alterations in inhibitory neurotransmission in the amygdala of Fmr1 KO mice. We demonstrate a dramatic reduction in the frequency and amplitude of phasic IPSCs, tonic inhibitory currents, as well as in the number of inhibitory synapses in Fmr1 KO mice. Furthermore, we observe significant alterations in GABA availability, both intracellularly and at the synaptic cleft. Together, these findings identify abnormalities in basal and action potential-dependent inhibitory neurotransmission. Additionally, we reveal a significant neuronal hyperexcitability in principal neurons of the amygdala in Fmr1 KO mice, which is strikingly rescued by pharmacological augmentation of tonic inhibitory tone using the GABA agonist gaboxadol (THIP). Thus, our study reveals relevant inhibitory synaptic abnormalities in the amygdala in the Fmr1 KO brain and supports the notion that pharmacological approaches targeting the GABAergic system may be a viable therapeutic approach toward correcting amygdala-based symptoms in FXS.
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Amígdala del Cerebelo/efectos de los fármacos , Síndrome del Cromosoma X Frágil/tratamiento farmacológico , Síndrome del Cromosoma X Frágil/fisiopatología , Agonistas del GABA/farmacología , Isoxazoles/farmacología , Transmisión Sináptica/efectos de los fármacos , Amígdala del Cerebelo/metabolismo , Animales , Modelos Animales de Enfermedad , Potenciales Evocados , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Glutamato Descarboxilasa/metabolismo , Técnicas In Vitro , Interneuronas/metabolismo , Masculino , Ratones , Ratones Noqueados , Inhibición Neural/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Técnicas de Placa-Clamp , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Tonic inhibition mediated by extrasynaptic gamma-aminobutyric acid type A (GABA A) receptors is a powerful conductance that controls cell excitability. Throughout the CNS, tonic inhibition is expressed at varying degrees across different cell types. Despite a rich history of cortical interneuron diversity, little is known about tonic inhibition in the different classes of cells in the cerebral cortex. We therefore examined the cell-type specificity and functional significance of tonic inhibition in layer 4 of the mouse somatosensory barrel cortex. In situ hybridization and immunocytochemistry showed moderate delta-subunit expression across the barrel structures. Whole cell patch-clamp recordings additionally indicated that significant levels of tonic inhibition can be found across cell types, with differences in the magnitude of inhibition between cell types. To activate tonic currents, we used 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP, a superagonist at delta-subunit-containing GABA A receptors) at a concentration that did not affect synaptic decay kinetics. THIP produced greater shifts in baseline holding current in inhibitory cells (low-threshold spiking [LTS], 109 +/- 17 pA; fast spiking [FS], 111 +/- 15 pA) than in excitatory cells (39 +/- 10 pA; P < 0.001). In addition to these differences across cell types, there was also variability within inhibitory cells. FS cells with faster action potentials had larger baseline shifts. Because FS cells are known mediators of feedforward inhibition, we tested whether THIP-induced tonic conductance selectively controls feedforward circuits. THIP application resulted in the abolishment of the inhibitory postsynaptic potential in thalamic-evoked disynaptic responses in a subset of excitatory neurons. These data suggest multiple feedforward circuits can be differentiated by the inhibitory control of the presynaptic inhibitory neuron.