Liver trauma: hepatic vascular injury on computed tomography as a predictor of patient outcome.

OBJECTIVES: To evaluate hepatic vascular injury (HVI) on CT in blunt and penetrating trauma and assess its relationship to patient management and outcome. METHOD AND MATERIALS: This retrospective study was IRB approved and HIPAA compliant. Informed consent was waived. Included were patients ≥ 16 years old who sustained blunt or penetrating trauma with liver laceration seen on a CT performed at our institution within 24 h of presentation over the course of 10 years and 6 months (August 2007-February 2018). During this interval, 171 patients met inclusion criteria (123 males, 48 females; mean age 34; age range 17-80 years old). Presence of HVI was evaluated and liver injury was graded in a blinded fashion by two radiologists using the 1994 and 2018 American Association for the Surgery of Trauma (AAST) liver injury scales. Hospital length of stay and treatment (angioembolization or operative) were recorded from the electronic medical record. Multivariate linear regressions were used to determine our variables' impact on the length of stay, and logistic regressions were used for categorical outcomes. RESULTS: Of the included liver trauma patients, 25% had HVI. Patients with HVI had a 3.2-day longer length of hospital stay on average and had a 40.3-fold greater odds of getting angioembolization compared to those without. Patients with high-grade liver injury (AAST grades IV-V, 2018 criteria) had a 3.2-fold greater odds of failing non-operative management and a 14.3-fold greater odds of angioembolization compared to those without. CONCLUSION: HVI in liver trauma is common and is predictive of patient outcome and management. KEY POINTS: • Hepatic vascular injury occurs commonly (25%) with liver trauma. • Hepatic vascular injury is associated with increased length of hospital stay and angioembolization. • High-grade liver injury is associated with failure of non-operative management and with angioembolization.

Time to conventional angiography in gastrointestinal bleeding: CT angiography compared to tagged RBC scan.

PURPOSE: To compare CT angiography (CTA) and tagged red blood cell (RBC) scan as a function of time from these initial imaging studies to subsequent conventional angiography and catheter-directed embolization in patients with gastrointestinal (GI) bleeding. METHODS: An IRB-approved retrospective study was conducted of 35 consecutive patients diagnosed with GI bleeding that received angiography for planned catheter-directed embolization. Of these patients, 20 were diagnosed with bleeding using a tagged RBC scan, whereas 15 were diagnosed using CTA. The lengths of time between diagnostic study order to study completion, diagnostic study completion to angiography, and total time from diagnostic study order to angiography were calculated. The results of both groups were compared using a t test with p value of < 0.05 considered statistically significant. RESULTS: The mean time from diagnostic study order to study completion was 3 h and 4 min for the CTA group and 5 h and 1 min for the tagged RBC scan group (p value = 0.0001). There was no statistically significant difference between the time to angiography after completion of the preceding diagnostic study. The total mean time from diagnostic study order to intervention was 6 h and 8 min for the CTA group and 9 h and 29 min for the tagged RBC scan group, a statistically significant difference (p value = 0.028). CONCLUSIONS: In patients requiring conventional angiography for GI bleeding, CT angiography results in a faster time to angiography than tagged RBC scan, which appears to be due to the longer duration required to complete the tagged RBC scan. Decreasing time to angiography is vital, as GI bleeding can be fatal and earlier diagnosis and intervention has the potential to reduce morbidity and mortality, while also increasing sensitivity of angiography. These findings may assist ordering clinicians in deciding on the appropriate diagnostic study.

Scribble co-operatively binds multiple α1D-adrenergic receptor C-terminal PDZ ligands.

Many G protein-coupled receptors (GPCRs) are organized as dynamic macromolecular complexes in human cells. Unraveling the structural determinants of unique GPCR complexes may identify unique protein:protein interfaces to be exploited for drug development. We previously reported α1D-adrenergic receptors (α1D-ARs) - key regulators of cardiovascular and central nervous system function - form homodimeric, modular PDZ protein complexes with cell-type specificity. Towards mapping α1D-AR complex architecture, biolayer interferometry (BLI) revealed the α1D-AR C-terminal PDZ ligand selectively binds the PDZ protein scribble (SCRIB) with >8x higher affinity than known interactors syntrophin, CASK and DLG1. Complementary in situ and in vitro assays revealed SCRIB PDZ domains 1 and 4 to be high affinity α1D-AR PDZ ligand interaction sites. SNAP-GST pull-down assays demonstrate SCRIB binds multiple α1D-AR PDZ ligands via a co-operative mechanism. Structure-function analyses pinpoint R1110PDZ4 as a unique, critical residue dictating SCRIB:α1D-AR binding specificity. The crystal structure of SCRIB PDZ4 R1110G predicts spatial shifts in the SCRIB PDZ4 carboxylate binding loop dictate α1D-AR binding specificity. Thus, the findings herein identify SCRIB PDZ domains 1 and 4 as high affinity α1D-AR interaction sites, and potential drug targets to treat diseases associated with aberrant α1D-AR signaling.

Social Cognition Impairments in Mice Overexpressing Alpha-Synuclein Under the Thy1 Promoter, a Model of Pre-manifest Parkinson's Disease.

BACKGROUND: Patients with Parkinson's disease (PD) may exhibit deficits in "Theory of Mind", the ability to read others' mental states and react appropriately, a prerequisite for successful social interaction. Alpha-synuclein overexpression is widely distributed in the brain of patients with sporadic PD, suggesting that it may contribute to the non-motor deficits observed in PD patients. Mice over-expressing human wild-type alpha-synuclein under the Thy1 promoter (Thy1-aSyn mice) have synaptic deficits in the frontostriatal pathway, low cortical acetylcholine, and high level of expression of mGluR5 receptors, which have all been implicated in social recognition deficits. OBJECTIVE: To determine whether Thy1-aSyn mice present alterations in their response to social stimuli. METHODS: We have submitted Thy1-aSyn mice to tests adapted from autism models. RESULTS: At 7-8 month of age Thy1-aSyn mice explored their conspecifics significantly less than did wild-type littermates, without differences in exploration of inanimate objects, and pairs of Thy1-aSyn mice were involved in reciprocal interactions for a shorter duration than wild-type mice at this age. These deficits persisted when the test animal was enclosed in a beaker and were not present at 3-4 months of age despite the presence of olfactory deficits at that age, indicating that they were not solely caused by impairment in olfaction. CONCLUSION: Thy1-aSyn mice present progressive deficits in social recognition, supporting an association between alpha-synuclein overexpression and Theory of Mind deficits in PD and providing a useful model for identifying mechanisms and testing novel treatments for these deficits which impact patients and caretakers quality of life.

Cognitive deficits in a mouse model of pre-manifest Parkinson's disease.

Early cognitive deficits are increasingly recognized in patients with Parkinson's disease (PD), and represent an unmet need for the treatment of PD. These early deficits have been difficult to model in mice, and their mechanisms are poorly understood. α-Synuclein is linked to both familial and sporadic forms of PD, and is believed to accumulate in brains of patients with PD before cell loss. Mice expressing human wild-type α-synuclein under the Thy1 promoter (Thy1-aSyn mice) exhibit broad overexpression of α-synuclein throughout the brain and dynamic alterations in dopamine release several months before striatal dopamine loss. We now show that these mice exhibit deficits in cholinergic systems involved in cognition, and cognitive deficits in domains affected in early PD. Together with an increase in extracellular dopamine and a decrease in cortical acetylcholine at 4-6 months of age, Thy1-aSyn mice made fewer spontaneous alternations in the Y-maze and showed deficits in tests of novel object recognition (NOR), object-place recognition, and operant reversal learning, as compared with age-matched wild-type littermates. These data indicate that cognitive impairments that resemble early PD manifestations are reproduced by α-synuclein overexpression in a murine genetic model of PD. With high power to detect drug effects, these anomalies provide a novel platform for testing improved treatments for these pervasive cognitive deficits.

Tricuspid valve repair in hypoplastic left heart syndrome.

Tricuspid valve regurgitation (TR) remains an obstacle for staged palliation of hypoplastic left heart syndrome (HLHS). Because previous results from our institution suggested that posterior leaflet obliteration (PLO) is effective in tricuspid valve repair (TVR), we preferentially used this method. This report analyzes the effect of this preference on repair success and patient survival. All HLHS patients with 3-4+ preoperative TR undergoing TVR between 2002 and 2007 were retrospectively analyzed. Clinical and echocardiographic data were used to determine outcomes. Seventy-one percent (17 of 24) of patients had success at early outcome; the remaining 29% experienced early failure. Sixty-three percent (15 of 24) of patients demonstrated success at late outcome. Early outcome status was found to be a predictor of late outcome status (OR 22.9, P = 0.0037). Overall survival was 71% (17 of 24). Survival could not be shown to be associated with early or late outcome status (odds ratio = 0.96). A preference for PLO was found to give improved, long-lasting results for HLHS patients. Success at immediate outcome was predictive of success with time. PLO has the advantage of being simple and reproducible and produces good outcomes in this challenging group. Continued follow-up will be necessary to confirm long-term outcomes.

Coated carbon hemoperfusion provides limited clearance of protein-bound solutes.

This study assessed the capacity of a cartridge containing coated granular carbon to clear protein-bound solutes. Clearances for test solutes were measured while an albumin solution representing plasma was pumped from a 10 L reservoir through the cartridge at a rate of 200 mL/min for 5 h. Clearance values for phenol red, phenytoin, and indican were well below the limit imposed by the plasma flow and declined with time. The clearance of phenol red, which was the most tightly bound solute, fell from 38 +/- 12 to 17 +/- 2 mL/min. Additional studies revealed that the cartridge contained enough carbon to absorb all the protein-bound test solutes, but that the rate of their clearance was limited by the inability of granular carbon to take up solutes rapidly at a low concentration. The rate of solute uptake at low concentration was shown to be much greater when carbon was in powdered rather than granular form. A device in which approximately 50 g of powdered carbon was recirculated in the dialysate compartment of hollow fiber kidneys cleared phenol red and phenytoin more rapidly than the hemoperfusion cartridge containing 300 g of coated granular carbon. These results indicate that hemoperfusion over coated granular carbon provides limited clearance of protein-bound solutes.

Increasing the clearance of protein-bound solutes by addition of a sorbent to the dialysate.

The capacity of sorbent systems to increase solute clearances above the levels that are provided by hemodialysis has not been well defined. This study assessed the extent to which solute clearances can be increased by addition of a sorbent to the dialysate. Attention was focused on the clearance of protein-bound solutes, which are cleared poorly by conventional hemodialysis. A reservoir that contained test solutes and artificial plasma was dialyzed first with the plasma flow set at 46 +/- 3 ml/min and the dialysate flow (Q(d)) set at 42 +/- 3 ml/min using a hollow fiber kidney with mass transfer area coefficients greater than Q(d) for each of the solutes. Under these conditions, the clearance of urea (Cl(urea)) was 34 +/- 1 ml/min, whereas the clearances of the protein-bound solutes indican (Cl(ind)), p-cresol sulfate (Cl(pcs)), and p-cresol (Cl(pc)) averaged only 5 +/- 1, 4 +/- 1, and 14 +/- 1 ml/min, respectively The effect of addition of activated charcoal to the dialysate then was compared with the effect of increasing Q(d) without addition of any sorbent. Addition of charcoal increased Cl(ind), Cl(pcs), and Cl(pc) to 12 +/- 1, 9 +/- 2, and 35 +/- 4 ml/min without changing Cl(urea). Increasing Q(d) without the addition of sorbent had a similar effect on the clearance of the protein-bound solutes. Mathematical modeling predicted these changes and showed that the maximal effect of addition of a sorbent to the dialysate is equivalent to that of an unlimited increase in Q(d). These results suggest that as an adjunct to conventional hemodialysis, addition of sorbents to the dialysate could increase the clearance of protein-bound solutes without greatly altering the clearance of unbound solutes.

Dynamic kinetic asymmetric allylic alkylations of allenes.

The dynamic kinetic asymmetric allylic alkylations of racemic allene acetates has been developed with the DACH-phenyl Trost ligand 2 to give general access to allenes with high enantiomeric excess (84-95%) for both malonate and amine nucleophiles. Further, a most unusual dependence of enantioselectivity on base has been uncovered. The magnitude of the enantioselectivity is heavily dependent on the base for the malonate nucleophiles, but the sense and magnitude of the asymmetric induction is dependent on the base for the amine nucleophiles. A Rh(I)-catalyzed intramolecular [4 + 2] cycloaddition of the DYKAT products was accomplished to afford formal Diels-Alder adducts, wherein the axial chirality is faithfully transferred into multiple stereogenic centers as well as olefin geometry.