Metabolomics-assisted proteomics identifies succinylation and SIRT5 as important regulators of cardiac function.

Cellular metabolites, such as acyl-CoA, can modify proteins, leading to protein posttranslational modifications (PTMs). One such PTM is lysine succinylation, which is regulated by sirtuin 5 (SIRT5). Although numerous proteins are modified by lysine succinylation, the physiological significance of lysine succinylation and SIRT5 remains elusive. Here, by profiling acyl-CoA molecules in various mouse tissues, we have discovered that different tissues have different acyl-CoA profiles and that succinyl-CoA is the most abundant acyl-CoA molecule in the heart. This interesting observation has prompted us to examine protein lysine succinylation in different mouse tissues in the presence and absence of SIRT5. Protein lysine succinylation predominantly accumulates in the heart whenSirt5is deleted. Using proteomic studies, we have identified many cardiac proteins regulated by SIRT5. Our data suggest that ECHA, a protein involved in fatty acid oxidation, is a major enzyme that is regulated by SIRT5 and affects heart function.Sirt5knockout (KO) mice have lower ECHA activity, increased long-chain acyl-CoAs, and decreased ATP in the heart under fasting conditions.Sirt5KO mice develop hypertrophic cardiomyopathy, as evident from the increased heart weight relative to body weight, as well as reduced shortening and ejection fractions. These findings establish that regulating heart metabolism and function is a major physiological function of lysine succinylation and SIRT5.

Delusional Disorder Arising From a CNS Neoplasm.

Erotomania arising from a central nervous system (CNS) neoplasm has not been previously described. Here, we present the first known case, to our knowledge, of erotomania with associated persecutory delusions arising following diagnosis and treatment of a left frontal lobe brain tumor.

Creatinine clearance predicts the goal enoxaparin dose in traumatic brain injury.

BACKGROUND: Patients with traumatic brain injury (TBI) are at high risk of venous thromboembolism (VTE). Recent guidelines recommend starting TBI patients on enoxaparin 30 mg twice daily and then considering weight-based dosing. Creatinine clearance may be better than weight for patients when considering high and low enoxaparin dose requirements. We hypothesize that creatinine clearance (CrCl) predicts goal enoxaparin dose better than weight-based dosing. METHODS: A retrospective review was conducted on patients admitted to an urban, academic Level I trauma center from August 2017 to February 2020. Patients were included if greater than 18 years, admitted longer than 48 hours, and head and neck AIS ≥ 3. Patients were excluded if they did not have TBI, if they received deep vein thrombosis prophylaxis other than enoxaparin 12-hour dosing, if no anti-Xa levels were drawn, or if the goal anti-Xa level was not reached. Patients were grouped into dosing cohorts based on dose of enoxaparin required to reach goal. Pearson's correlation was used to compare mean CrCl and mean weight across dosing cohorts. RESULTS: A total of 120 patients met inclusion and exclusion criteria, mean age was 47 years and 68% of patients were male. The mean hospital length of stay was 24 days. There were 5 (4.2%) deep vein thrombosis, no pulmonary embolism, and 5 (4.2%) patients died. Mean CrCl increased significantly with increased dosing of enoxaparin, Pearson's correlation coefficient of 0.484 ( p < 0.001). Weight on admission also increased with increasing enoxaparin dose requirements, with Pearson's correlation coefficient of 0.411 ( p < 0.001). CONCLUSION: Creatine clearance predicts goal enoxaparin dose in TBI better than a weight-based dosing strategy. Further research with a larger patient population is required to validate CrCl values to guide enoxaparin dosing. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level IV.

Creatinine Clearance May Predict Goal Enoxaparin Dose in Trauma.

BACKGROUND: Guidelines for enoxaparin dosing after trauma recommend an initial dose of 40 mg twice daily for most patients and then adjusting by anti-Xa levels. Previous studies indicated higher enoxaparin doses are necessary with higher levels of creatinine clearance (CrCl). We sought to determine if the goal enoxaparin dose correlates with the admission CrCl to reduce the reliance on measuring anti-Xa levels. STUDY DESIGN: A retrospective review was conducted of patients admitted to an urban, academic Level 1 trauma center from April 2017 to February 2020. Patients started on enoxaparin who reached goal anti-Xa trough levels were included, and patients were excluded if they did not reach goal anti-Xa levels. Data collection included patient demographics, injury characteristics, admission CrCl, and final enoxaparin dose. CrCl was then correlated with the final enoxaparin dose. RESULTS: Of 421 patients included, the mean age was 46.6 years and 73% were male. The median goal enoxaparin dose was 40 mg twice daily. The mean CrCl significantly increased with increasing twice-daily doses of enoxaparin (20 mg: 69.2 mL/min; 30 mg: 89 mL/min; 40 mg: 112.8 mL/min; 50 mg: 140.5mL/min; 60 mg: 147.4 mL/min; and 70 mg: 140 mL/min; p < 0.01). CONCLUSIONS: Admission CrCl may predict the enoxaparin dose required to achieve adequate anti-Xa levels. Our data indicate that CrCls of approximately 70, 90, 110, 140, and 150 mL/min may predict the twice-daily enoxaparin doses of 20, 30, 40, 50, and 60 mg, respectively. CrCl dosing guidance may reduce the time to goal anti-Xa levels and the frequency of anti-Xa measurements. Further research is necessary, and enoxaparin dosing should continue to be monitored by anti-Xa levels.

The futility of closed chest compressions after trauma: A multi-institutional study.

BACKGROUND: The desire to deliver appropriate care after trauma creates challenges when deciding to proceed if care appears futile. This study aimed to analyze survival rates for trauma patients who undergo closed chest compressions by decade of life. METHODS: A multicenter retrospective review of trauma patients with an Injury Severity Score ≥16 who underwent closed chest compressions from 2015 to 2020 at four large, urban, academic Level I trauma centers was conducted. Those with intraoperative arrest were excluded. The primary endpoint was survival to discharge. RESULTS: Of the 247 patients meeting inclusion criteria, 18% were 70 years or older, 78% were male, and 24% presented due to a penetrating mechanism of injury. Compressions occurred in the prehospital setting (56%), emergency department (21%), intensive care unit (19%), and on the floor (3%). On average, patients arrested on hospital day 2, and survived 1 day after arrest if return of spontaneous circulation was achieved. Overall mortality was 92%. Average hospital length of stay was lower in patients 70 years or older (3 days vs. 6 days, p < 0.01). Survival was highest in patients 60 years to 69 years (24%), and although patients 70 years or older presented with lower Injury Severity Scores (28 vs. 32, p = 0.04), no patient 70 years or older survived to hospital discharge (0% v 9%, p = 0.03). CONCLUSION: Closed chest compressions are associated with a high mortality rate after moderate to severe trauma with 100% mortality in patients older than 70 years. This information may assist with the decision to withhold chest compression, especially in older adults. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level IV.

Silencing nox4 in the paraventricular nucleus improves myocardial infarction-induced cardiac dysfunction by attenuating sympathoexcitation and periinfarct apoptosis.

RATIONALE: Myocardial infarction (MI)-induced heart failure is characterized by central nervous system-driven sympathoexcitation and deteriorating cardiac function. The paraventricular nucleus (PVN) of the hypothalamus is a key regulator of sympathetic nerve activity and is implicated in heart failure. Redox signaling in the PVN and other central nervous system sites is a primary mechanism of neuro-cardiovascular regulation, and excessive oxidant production by activation of NADPH oxidases (Noxs) is implicated in some neuro-cardiovascular diseases. OBJECTIVE: We tested the hypothesis that Nox-mediated redox signaling in the PVN contributes to MI-induced sympathoexcitation and cardiac dysfunction in mice. METHODS AND RESULTS: Real-time PCR revealed that Nox4 was the most abundantly expressed Nox in PVN under basal conditions. Coronary arterial ligation (MI) caused a selective upregulation of this homolog compared to Nox1 and Nox2. Adenoviral gene transfer of Nox4 (AdsiNox4) to PVN (bilateral) attenuated MI-induced superoxide formation in this brain region (day 14) to the same level as that produced by PVN-targeted gene transfer of cytoplasmic superoxide dismutase (AdCu/ZnSOD). MI mice treated with AdsiNox4 or AdCu/ZnSOD in the PVN showed marked improvement in cardiac function as assessed by echocardiography and left ventricular hemodynamic analysis. This was accompanied by significantly diminished sympathetic outflow and apoptosis in the periinfarct region of the heart. CONCLUSIONS: These results suggest that MI causes dysregulation of Nox4-mediated redox signaling in the PVN, which leads to sympathetic overactivation and a decline in cardiac function. Targeted inhibition of oxidant signaling in the PVN could provide a novel treatment for MI-induced heart failure.

Dual modality endomicroscope with optical zoom capability.

We present a miniature endomicroscope that combines large field-of-view (FOV) (1.15 mm) reflectance imaging with high-resolution (~0.5 µm) multiphoton intrinsic fluorescence imaging. We acquired in vivo and ex vivo images of unstained normal and tumor-laden tissues by using the large-FOV mode to navigate to the site of interest and then switching to the high-resolution modality to resolve cellular details.

Genetic silencing of Nox2 and Nox4 reveals differential roles of these NADPH oxidase homologues in the vasopressor and dipsogenic effects of brain angiotensin II.

The renin-angiotensin system exerts a tremendous influence over fluid balance and arterial pressure. Angiotensin II (Ang-II), the effector peptide of the renin-angiotensin system, acts in the central nervous system to regulate neurohumoral outflow and thirst. Dysregulation of Ang-II signaling in the central nervous system is implicated in cardiovascular diseases; however, the mechanisms remain poorly understood. Recently we established that NADPH oxidase (Nox)-derived superoxide acting in the forebrain subfornical organ is critical in the physiological responses to central Ang-II. In addition, we have found that Nox2 and Nox4 are the most abundantly expressed Nox homologues within Ang-II-sensitive sites in the forebrain. To dissect out the functional importance and unique roles of these Nox enzymes in the pressor and dipsogenic effects of central Ang-II, we developed adenoviral vectors expressing small interfering RNA to selectively silence Nox2 or Nox4 expression in the subfornical organ. Our results demonstrate that both Nox2 and Nox4 are required for the full vasopressor effects of brain Ang-II but that only Nox2 is coupled to the Ang-II-induced water intake response. These studies establish the importance of both Nox2- and Nox4-containing NADPH oxidases in the actions of Ang-II in the central nervous system and are the first to reveal differential involvement of these Nox enzymes in the various physiological effects of central Ang-II.