15(S)-hydroxyeicosatetraenoic acid-induced angiogenesis requires Src-mediated Egr-1-dependent rapid induction of FGF-2 expression.

To understand the mechanisms underlying 15(S)-hydroxyeicosatetraenoic acid [15(S)-HETE]-induced angiogenesis, we studied the role of Egr-1. 15(S)-HETE induced Egr-1 expression in a time-dependent manner in human dermal microvascular endothelial cells (HDMVECs). Blockade of Egr-1 via forced expression of its dominant-negative mutant attenuated 15(S)-HETE-induced HDMVEC migration and tube formation as well as Matrigel plug angiogenesis. 15(S)-HETE-induced Egr-1 expression requires Src activation. In addition, adenovirus-mediated expression of dominant-negative mutant of Src blocked 15(S)-HETE's effects on migration and tube formation of HDMVECs and Matrigel plug angiogenesis. 15(S)-HETE induced fibroblast growth factor-2 (FGF-2) expression rapidly via Src-mediated production of Egr-1. Cloning and mutational analysis of FGF-2 promoter revealed that Egr-1 binding site proximal to transcription start site is required for 15(S)-HETE-induced FGF-2 expression. Neutralizing antibody-mediated suppression of FGF-2 function also attenuated the effects of 15(S)-HETE on HDMVEC migration and tube formation as well as Matrigel plug angiogenesis. Furthermore, in contrast to wild-type mice, 12/15-LOX(-/-) mice exhibited decreased Matrigel plug angiogenesis in response to AA, which was rescued by 15(S)-HETE. On the basis of these observations, we conclude that 15(S)-HETE-induced angiogenesis requires Src-mediated Egr-1-dependent rapid induction of FGF-2. These findings may suggest that 15(S)-HETE could be a potential endogenous regulator of pathologic angiogenesis associated with atherosclerosis and restenosis.

Severe Hemolysis in a COVID-19 Patient with Paroxysmal Nocturnal Hemoglobinuria.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), has been demonstrated to be able to activate complement, making patients with deficiency in negative complement regulation, such as paroxysmal nocturnal hemoglobinuria (PNH), particularly vulnerable to complement-mediated cell damage. We report a case of a patient who presented with fatigue, facial swelling, and upper respiratory infection (URI) symptoms and was found to have COVID-19 with laboratory tests showing severe hemolysis and pancytopenia secondary to PNH.

CIN or not: An approach to the evaluation and management of chronic idiopathic neutrophilia.

Neutrophilia refers to an increase in the number of circulating neutrophils in the peripheral blood. Some common etiologies include infection, inflammatory conditions, myeloproliferative disorders, malignancies, endocrinopathies, drugs, and anemia. Rare disorders such as leukocyte adhesion deficiency can also cause neutrophilia. In many cases, there is an elevation of neutrophil count that persists for months or even years with no clear underlying cause in an otherwise asymptomatic patient. This is referred to as chronic idiopathic neutrophilia (CIN). Despite being a condition encountered by many physicians, there is a paucity of literature addressing CIN. Certain conditions such as stress, exercise, smoking, obesity, and obstructive sleep apnea have been associated with CIN and may provide explanations for neutrophilia previously thought to be idiopathic. Herein, we present a review of the literature on CIN and propose a systematic approach to this commonly encountered clinical condition.

Outcomes of Liver Transplant Recipients With Acute-on-Chronic Liver Failure Based on EASL-CLIF Consortium Definition: A Single-center Study.

The impact of acute-on-chronic liver failure (ACLF) defined by European Association for the Study of the Liver-Chronic Liver Failure in liver transplant (LT) recipients has not been well characterized. The aim of the study was to assess early posttransplant morbidity and survival of ACLF patients. METHODS: Eight hundred twenty-five consecutive LT patients (04/2006-03/2013) were included in a retrospective analysis. Of the 690 evaluable patients, 589 had no ACLF, and the remaining 101 were grouped into ACLF Grades 1-3 (ACLF Grade 1: 50 [49.5%], ACLF Grade 2: 32 [31.7%], and ACLF Grade 3: 19 [18.8%]). RESULTS: LT recipients transplanted in the context of ACLF had significantly increased serum creatinine (2.27 ± 1.16 versus 0.98 ± 0.32; P < 0.0001), and inferior 1-year graft (90% versus 78%; P < 0.0001) and patient survival (92% versus 82%; P = 0.0004) by Kaplan-Meier survival analysis; graft and patient survival correlated negatively with increasing severity of ACLF. One-year graft and patient survival were lower in those with high ACLF (Grade 2 and 3) irrespective of Model for End-Stage Liver Disease compared with other groups. The ACLF group had longer intensive care unit stays (10.6 ± 19.5 versus 4.2 ± 9; P < 0.0001), hospital stays (20.9 ± 25.9 versus 11.7 ± 11.4; P < 0.0001), and increased surgical re-exploration (26.7 % versus 14.6%, P = 0.002). CONCLUSIONS: Patients with ACLF undergoing LT have significantly higher resource utilization, inferior graft survival and patient survival, and renal dysfunction at 1 year. The combination of ACLF and Model for End-Stage Liver Disease can be considered when determining the suitability for potential transplantation.

Longitudinal Renal Function in Liver Transplant Recipients With Acute-on-Chronic Liver Failure.

INTRODUCTION: To analyze the impact of acute-on-chronic liver failure (ACLF) immediately before liver transplantation (LT) on short-term kidney function. METHODS: In this retrospective study, we included 416 of 687 consecutive patients who had an estimated glomerular filtration rates (eGFRs) at 3-month post-LT. We compared the non-ACLF (N = 356), ACLF with eGFR ≥30 mL/min/1.73 m (A-HGFR, N = 32), and ACLF with eGFR <30 mL/min/1.73 m (A-LGFR, N = 28) groups at LT and for 2 kidney-related outcomes: (i) slope of eGFR by linear mixed model and (ii) time to development of composite kidney outcomes (eGFR < 15 mL/min/1.73 m or need for dialysis). RESULTS: The mean eGFRs at LT in non-ACLF, A-HGFR, and A-LGFR groups were significantly different as follows: 83.9 ± 29.5, 56.5 ± 31.2, and 21.6 ± 5.0 mL/min/1.73 m, respectively. The eGFR slope significantly increased in A-LGFR group (+7.26 mL/min/1.73 m/mo), whereas it remained stable in A-HGFR group (+1.05 mL/min/1.73 m/mo) and significantly declined in non-ACLF group (-7.61 mL/min/1.73 m/mo) by the first 3-month period. On the other hand, the eGFR slope in all groups stabilized after 3 months post-LT. A-LGFR group showed significantly increased risk of developing composite kidney outcomes in adjusted analysis (hazard ratio = 3.61, 95% confidence interval: 1.35-9.70) compared with the non-ACLF group. However, this significance disappeared after the further adjustment for eGFR at 3-month post-LT (hazard ratio = 1.91, 95% confidence interval: 0.70-5.23). DISCUSSION: The slopes of eGFR before 3-month post-LT were significantly different among non-ACLF, A-HGFR, and A-LGFR groups. The renal dysfunction in A-LGFR group stabilized after partial recovery by 3-month post-LT (eGFR reset point).

Cutaneous Mucormycosis Following a Bullous Pemphigoid Flare in a Chronic Lymphocytic Leukemia Patient on Ibrutinib.

While the recent development of novel therapeutics in oncology, such as small molecule kinase inhibitors (SMKIs), has enabled our ability to target disease-specific molecular pathways, the prolonged impact of these agents on the immune system and infectious risk remains to be seen. We present a 68-year-old male with refractory chronic lymphocytic leukemia (CLL) on ibrutinib monotherapy for 3 years who developed extensive cutaneous mucormycosis following a severe bullous pemphigoid (BP) flare. He received amphotericin B for 4 weeks and was continued on posaconazole with resolution of his mucormycosis infection. Consistent with a growing evidence of literature identifying opportunistic fungal infections in patients on ibrutinib therapy, providers should be cognizant of medical comorbidities that may predispose to such infections and explore methods of prevention before starting ibrutinib and other SMKIs.

Thermodynamic characterization of RNA duplexes containing naturally occurring 1 x 2 nucleotide internal loops.

Thermodynamic data for RNA 1 x 2 nucleotide internal loops are lacking. Thermodynamic data that are available for 1 x 2 loops, however, are for loops that rarely occur in nature. In order to identify the most frequently occurring 1 x 2 nucleotide internal loops, a database of 955 RNA secondary structures was compiled and searched. Twenty-four RNA duplexes containing the most common 1 x 2 nucleotide loops were optically melted, and the thermodynamic parameters DeltaH degrees , DeltaS degrees , DeltaG degrees 37, and TM for each duplex were determined. This data set more than doubles the number of 1 x 2 nucleotide loops previously studied. A table of experimental free energy contributions for frequently occurring 1 x 2 nucleotide loops (as opposed to a predictive model) is likely to result in better prediction of RNA secondary structure from sequence. In order to improve free energy calculations for duplexes containing 1 x 2 nucleotide loops that do not have experimental free energy contributions, the data collected here were combined with data from 21 previously studied 1 x 2 loops. Using linear regression, the entire dataset was used to derive nearest neighbor parameters that can be used to predict the thermodynamics of previously unmeasured 1 x 2 nucleotide loops. The DeltaG degrees 37,loop and DeltaH degrees loop nearest neighbor parameters derived here were compared to values that were published previously for 1 x 2 nucleotide loops but were derived from either a significantly smaller dataset of 1 x 2 nucleotide loops or from internal loops of various sizes [Lu, Z. J., Turner, D. H., and Mathews, D. H. (2006) Nucleic Acids Res. 34, 4912-4924]. Most of these values were found to be within experimental error, suggesting that previous approximations and assumptions associated with the derivation of those nearest neighbor parameters were valid. DeltaS degrees loop nearest neighbor parameters are also reported for 1 x 2 nucleotide loops. Both the experimental thermodynamics and the nearest neighbor parameters reported here can be used to improve secondary structure prediction from sequence.