Catecholamine upregulation is a core pathophysiological feature in critical illness. Sustained catecholamine β-adrenergic induction produces adverse effects relevant to critical illness management. ...β-blockers (βB) have proposed roles in various critically ill disease states, including sepsis, trauma, burns, and cardiac arrest. Mounting evidence suggests βB improve hemodynamic and metabolic parameters culminating in decreased burn healing time, reduced mortality in traumatic brain injury, and improved neurologic outcomes following cardiac arrest. In sepsis, βB appear hemodynamically benign after acute resuscitation and may augment cardiac function. The emergence of ultra-rapid βB provides new territory for βB, and early data suggest significant improvements in mitigating atrial fibrillation in persistently tachycardic septic patients. This review summarizes the evidence regarding the pharmacotherapeutic role of βB on relevant pathophysiology and clinical outcomes in various types of critical illness.
The optimal dose and duration of tissue plasminogen activator (tPA) administered with ultrasound-facilitated catheter-directed thrombolysis (USCDT) to patients with acute PE remains to be determined. ...Our institution recently adopted a shorter duration (4 h) of USCDT and lower dosing strategy (tPA 1 mg/h) based on data from the OPTALYSE PE Trial. The purpose was to evaluate the implementation at our institution of shorter duration (4 h) of USCDT and lower dosing strategy (tPA 1 mg/h) as outlined by OPTALYSE PE Trial. This was a retrospective, single-center, observational study included patients from 01/01/2017 to 12/31/2018 in a large, academic medical center. Group 1 represented patients who underwent USCDT prior to 01/18/18. Group 2 represented patients who underwent USCDT after 01/18/18 and received 4 h of USCDT and tPA 1 mg/h/catheter. The primary outcome was intensive care unit (ICU) length of stay (LOS). Secondary outcomes were the proportion of patients experiencing a composite of major adverse events (death, recurrent PE, major bleeding, or stroke), change in right ventricle size/function and pulmonary artery pressures, need for mechanical respiratory or hemodynamic support, hospital LOS and drug cost. A total of 31 patients were included in the study: twenty patients in Group 1 and eleven patients in Group 2. Median ICU LOS was 3.5 days in Group 1 and 1 day in Group 2. Group 2 had reduced MACE, requirement for mechanical respiratory or hemodynamic support, hospital LOS, drug costs and adverse events. Implementation of a shorter duration of USCDT and lower dosing strategy for tPA in patients with acute PE may be one strategy to reduce the total ICU LOS and costs associated with care.
Populus deltoides (eastern cottonwood) is cultivated worldwide for lumber and biomass, but production of new cultivars is hindered by the lengthy breeding cycle and difficulties to phenotype yield ...and disease resistance traits. Genetic variation controlling these phenotypes can be used in genomics-assisted breeding programs for early selection of elite genotypes to accelerate improvement. However, the genetic control of these traits is not well understood. Previous efforts to use genome-wide association studies (GWAS) to identify loci that contribute to phenotypic variation in poplar have had limited statistical power, partly due to the large number of nonfunctional variants in the genome that were evaluated. This study used the Assay for Transposase-Accessible Chromatin combined with next-generation DNA sequencing (ATAC-seq) to uncover open chromatin regions in the genome and identify putative functional variants. Variants that contribute most to phenotype were identified by conducting a GWAS targeted to polymorphisms in open chromatin regions. The hypothesis is that integrating GWAS with ATAC-seq reveals causative polymorphisms within the functional genome of P. deltoides that underlie phenotypes of interest. This research is at the interface among breeding, quantitative genetics, and genomics/bioinformatics.
Generalized reciprocity is a widely recognized but little studied component of social capital in organizations. We develop a causal model of the multiple mechanisms that sustain generalized ...reciprocity in an organization, drawing together disparate literatures in the social, organizational, and biological sciences. We conduct the first-ever critical test of two key mechanisms: paying it forward and rewarding reputation. These are fundamentally different grammars of organizing, either of which could sustain a system of generalized reciprocity. In an organization, paying it forward is a type of organizational citizenship behavior (OCB) that occurs when members of an organization help third parties because they themselves were helped. Rewarding reputation is a type of OCB that occurs when peers monitor one another, helping those who help others and refusing to help those who do not. Using behavioral data collected from members of two organizational groups over a three-month period, we found that reputational effects were strongest in the short term but decayed thereafter. Paying it forward had stronger and more lasting effects. Dominant theories assume that rewarding reputation is the main cause of generalized reciprocity, but our analysis demonstrates that generalized reciprocity in an organization occurs for multiple reasons. We use the empirical findings to develop propositions about the mechanisms of generalized reciprocity in organizations and link these to management practices. Our study contributes to social exchange theory, macro-level prosocial behavior, OCB, positive organizational scholarship, and management.
Mormyrid electric fish are a model system for understanding how neural circuits predict the sensory consequences of motor acts. Medium ganglion cells in the electrosensory lobe create negative images ...that predict sensory input resulting from the fish's electric organ discharge (EOD). Previous studies have shown that negative images can be created through plasticity at granule cell-medium ganglion cell synapses, provided that granule cell responses to the brief EOD command are sufficiently varied and prolonged. Here we show that granule cells indeed provide such a temporal basis and that it is well-matched to the temporal structure of self-generated sensory inputs, allowing rapid and accurate sensory cancellation and explaining paradoxical features of negative images. We also demonstrate an unexpected and critical role of unipolar brush cells (UBCs) in generating the required delayed responses. These results provide a mechanistic account of how copies of motor commands are transformed into sensory predictions.
Approximately one-third of the world's population suffers from allergies
. Exposure to allergens crosslinks immunoglobulin E (IgE) antibodies that are bound to mast cells and basophils, triggering ...the release of inflammatory mediators, including histamine
. Although IgE is absolutely required for allergies, it is not understood why total and allergen-specific IgE concentrations do not reproducibly correlate with allergic disease
. It is well-established that glycosylation of IgG dictates its effector function and has disease-specific patterns. However, whether IgE glycans differ in disease states or affect biological activity is completely unknown
. Here we perform an unbiased examination of glycosylation patterns of total IgE from individuals with a peanut allergy and from non-atopic individuals without allergies. Our analysis reveals an increase in sialic acid content on total IgE from individuals with a peanut allergy compared with non-atopic individuals. Removal of sialic acid from IgE attenuates effector-cell degranulation and anaphylaxis in several functional models of allergic disease. Therapeutic interventions-including removing sialic acid from cell-bound IgE with a neuraminidase enzyme targeted towards the IgE receptor FcεRI, and administering asialylated IgE-markedly reduce anaphylaxis. Together, these results establish IgE glycosylation, and specifically sialylation, as an important regulator of allergic disease.
Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the ...latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-X(L)), which has shown clinical efficacy in some BCL-2-dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-X(L) inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers.
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