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Articles by E Hirsch
Total Records ( 3 ) for E Hirsch
  G. C Velmahos , M Tabbara , R Gross , P Willette , E Hirsch , P Burke , T Emhoff , R Gupta , R. J Winchell , L. A Patterson , Y Manon Matos , H. B Alam , M Rosenblatt , J Hurst , S Brotman , B Crookes , K Sartorelli and Y. Chang

Objectives  To evaluate the safety of nonoperative management (NOM), to examine the diagnostic sensitivity of computed tomography (CT), and to identify missed diagnoses and related outcomes in patients with blunt pancreatoduodenal injury (BPDI).

Design  Retrospective multicenter study.

Setting  Eleven New England trauma centers (7 academic and 4 nonacademic).

Patients  Two hundred thirty patients (>15 years old) with BPDI admitted to the hospital during 11 years. Each BPDI was graded from 1 (lowest) to 5 (highest) according to the American Association for the Surgery of Trauma grading system.

Main Outcome Measures  Success of NOM, sensitivity of CT, BPDI-related complications, length of hospital stay, and mortality.

Results  Ninety-seven patients (42.2%) with mostly grades 1 and 2 BPDI were selected for NOM: NOM failed in 10 (10.3%), 10 (10.3%) developed BPDI-related complications (3 in patients in whom NOM failed), and 7 (7.2%) died (none related to failure of NOM). The remaining 133 patients were operated on urgently: 34 (25.6%) developed BPDI-related complications and 20 (15.0%) died. The initial CT missed BPDI in 30 patients (13.0%); 4 of them (13.3%) died but not because of the BPDI. The mortality rate in patients without a missed diagnosis was 8.8% (P = .50). There was no correlation between time to diagnosis and length of hospital stay (Spearman r = 0.06; P = .43). The sensitivity of CT for BPDI was 75.7% (76% for pancreatic and 70% for duodenal injuries).

Conclusions  The NOM of low-grade BPDI is safe despite occasional failures. Missed diagnosis of BPDI continues to occur despite advances in CT but does not seem to cause adverse outcomes in most patients.

  M Siragusa , R Katare , M Meloni , F Damilano , E Hirsch , C Emanueli and P. Madeddu

Rationale: Phosphoinositide 3-kinase (PI3K) is expressed in hematopoietic cells, endothelial cells (ECs), and cardiomyocytes and regulates different cellular functions relevant to inflammation, tissue remodeling and cicatrization. Recently, PI3K inhibitors have been indicated for the treatment of chronic inflammatory/autoimmune diseases and atherosclerosis.

Objective: We aimed to determine PI3K contribution to the angiogenic capacity of ECs and the effect of PI3K inhibition on healing of myocardial infarction (MI).

Methods and Results: Human umbilical ECs were treated with a selective PI3K inhibitor, AS605240, or a pan-phosphoinositide 3-kinases inhibitor, LY294002. Both inhibitory treatments and small interfering RNA–mediated PI3K knockdown strongly impaired ECs angiogenic capacity, because of suppression of the PI3K/Akt and mitogen-activated protein kinase pathways. Constitutive activation of Akt rescued the angiogenic defect. Reparative angiogenesis was studied in vivo in a model of MI. AS605240 did not affect MI-induced PI3K upregulation, whereas it suppressed Akt activation and downstream signaling. AS605240 strongly reduced inflammation, enhanced cardiomyocyte apoptosis, and impaired survival and proliferation of ECs in peri-infarct zone, which resulted in defective reparative neovascularization. As a consequence, AS605240-treated MI hearts showed increased infarct size and impaired recovery of left ventricular function. Similarly, PI3K-deficient mice showed impaired reparative neovascularization, enhanced cardiomyocyte apoptosis and marked deterioration of cardiac function following MI. Mice expressing catalytically inactive PI3K also failed to mount a proper neovascularization, although cardiac dysfunction was similar to wild-type controls.

Conclusions: PI3K expression and catalytic activity are involved at different levels in reparative neovascularization and healing of MI.

  D Guo , Z Kassiri , R Basu , F. L Chow , V Kandalam , F Damilano , W Liang , S Izumo , E Hirsch , J. M Penninger , P. H Backx and G. Y. Oudit

Mechanotransduction and the response to biomechanical stress is a fundamental response in heart disease. Loss of phosphoinositide 3-kinase (PI3K), the isoform linked to G protein–coupled receptor signaling, results in increased myocardial contractility, but the response to pressure overload is controversial.


To characterize molecular and cellular responses of the PI3K knockout (KO) mice to biomechanical stress.

Methods and Results:

In response to pressure overload, PI3KKO mice deteriorated at an accelerated rate compared with wild-type mice despite increased basal myocardial contractility. These functional responses were associated with compromised phosphorylation of Akt and GSK-3. In contrast, isolated single cardiomyocytes from banded PI3KKO mice maintained their hypercontractility, suggesting compromised interaction with the extracellular matrix as the primary defect in the banded PI3KKO mice. β-Adrenergic stimulation increased cAMP levels with increased phosphorylation of CREB, leading to increased expression of cAMP-responsive matrix metalloproteinases (MMPs), MMP2, MT1-MMP, and MMP13 in cardiomyocytes and cardiofibroblasts. Loss of PI3K resulted in increased cAMP levels with increased expression of MMP2, MT1-MMP, and MMP13 and increased MMP2 activation and collagenase activity in response to biomechanical stress. Selective loss of N-cadherin from the adhesion complexes in the PI3KKO mice resulted in reduced cell adhesion. The β-blocker propranolol prevented the upregulation of MMPs, whereas MMP inhibition prevented the adverse remodeling with both therapies, preventing the functional deterioration in banded PI3KKO mice. In banded wild-type mice, long-term propranolol prevented the adverse remodeling and systolic dysfunction with preservation of the N-cadherin levels.


The enhanced propensity to develop heart failure in the PI3KKO mice is attributable to a cAMP-dependent upregulation of MMP expression and activity and disorganization of the N-cadherin/β-catenin cell adhesion complex. β-Blocker therapy prevents these changes thereby providing a novel mechanism of action for these drugs.

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