Research Spotlight

McCabe, J. M., P. H. Huang, D. J. Cohen, E. H. Blackstone, F. G. Welt, M. J. Davidson, T. Kaneko, M. H. Eng, K. B. Allen, K. Xu, A. M. Lowry, Y. Lei, J. Rajeswaran, D. L. Brown, M. J. Mack, J. G. Webb, C. R. Smith, M. B. Leon and A. C. Eisenhauer (2016). “Surgical versus percutaneous femoral access for delivery of large-bore cardiovascular devices (from the partner trial).” Am J Cardiol 117(10): 1643-1650.

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It is unclear if surgical exposure confers a risk advantage compared with a percutaneous approach for patients undergoing endovascular procedures requiring large-bore femoral artery access. From the randomized controlled Placement of Aortic Transcatheter Valve trials A and B and the continued access registries, a total of 1,416 patients received transfemoral transcatheter aortic valve replacement, of which 857 underwent surgical, and 559 underwent percutaneous access. Thirty-day rates of major vascular complications and quality of life scores were assessed. Propensity matching was used to adjust for unmeasured confounders. Overall, there were 116 major vascular complications (8.2%). Complication rates decreased dramatically during the study period. In unadjusted analysis, major vascular complications were significantly less common in the percutaneous access group (35 [6.3%] vs 81 [9.5%] p = 0.032). However, among 292 propensity-matched pairs, there was no difference in major vascular complications (22 [7.5%] vs 28 [9.6%], p = 0.37). Percutaneous access was associated with fewer total in-hospital vascular complications (46 [16%] vs 66 [23%], p = 0.036), shorter median procedural duration (97 interquartile range [IQR 68 to 166] vs 121 [IQR 78 to 194] minutes, p <0.0001), and median length of stay (4 [IQR 2 to 8] vs 6 [IQR 3 to 10] days, p <0.0001). There were no significant differences in quality of life scores at 30 days. Surgical access for large-bore femoral access does not appear to confer any advantages over percutaneous access and may be associated with more minor vascular complications.

Meng, X. L., T. S. Day, N. McNeill, P. Ashcraft, T. Frischmuth, S. H. Cheng, Z. P. Liu, J. S. Shen and R. Schiffmann (2016). “Molecular basis for globotriaosylceramide regulation and enzyme uptake in immortalized aortic endothelial cells from fabry mice.” J Inherit Metab Dis 39(3): 447-455.

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Fabry disease is caused by deficient activity of alpha-galactosidase A and subsequent intracellular accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3). Vascular endothelial cells may play important roles in disease pathogenesis, and are one of the main target cell types in therapeutic interventions. In this study, we generated immortalized aortic endothelial cell lines from a mouse model of Fabry disease. These cells retained endothelial cell-specific markers and functions. Gb3 expression level in one of these clones (referred to as FMEC2) was highly susceptible to culture media, and appeared to be regulated by glucosylceramide synthase. Results also showed that Gb3 could be upregulated by hydrocortisone. FMEC2 express the mannose 6-phosphate receptor and sortilin but not the mannose receptor. Uptake studies suggested that sortilin plays a role in the binding and internalization of mammalian cell-produced alpha-galactosidase A. Moss-aGal (a plant-made enzyme) was endocytosed by FMEC2 via a receptor other than the aforementioned receptors. In conclusion, this study suggests that glucosylceramide synthase and hydrocortisone may play important roles in modulating Gb3 levels in Fabry mouse aortic endothelial cells, and that endocytosis of recombinant alpha-galactosidase A involves a combination of multiple receptors depending on the properties of the enzyme.

Mochel, F., E. Hainque, D. Gras, I. M. Adanyeguh, S. Caillet, B. Heron, A. Roubertie, E. Kaphan, R. Valabregue, D. Rinaldi, S. Vuillaumier, R. Schiffmann, C. Ottolenghi, J. Y. Hogrel, L. Servais and E. Roze (2016). “Triheptanoin dramatically reduces paroxysmal motor disorder in patients with glut1 deficiency.” J Neurol Neurosurg Psychiatry 87(5): 550-553.

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OBJECTIVE: On the basis of our previous work with triheptanoin, which provides key substrates to the Krebs cycle in the brain, we wished to assess its therapeutic effect in patients with glucose transporter type 1 deficiency syndrome (GLUT1-DS) who objected to or did not tolerate ketogenic diets. METHODS: We performed an open-label pilot study with three phases of 2 months each (baseline, treatment and withdrawal) in eight patients with GLUT1-DS (7-47 years old) with non-epileptic paroxysmal manifestations. We used a comprehensive patient diary to record motor and non-motor paroxysmal events. Functional (31)P-NMR spectroscopy was performed to quantify phosphocreatine (PCr) and inorganic phosphate (Pi) within the occipital cortex during (activation) and after (recovery) a visual stimulus. RESULTS: Patients with GLUT1-DS experienced a mean of 30.8 (+/-27.7) paroxysmal manifestations (52% motor events) at baseline that dropped to 2.8 (+/-2.9, 76% motor events) during the treatment phase (p=0.028). After withdrawal, paroxysmal manifestations recurred with a mean of 24.2 (+/-21.9, 52% motor events; p=0.043). Furthermore, brain energy metabolism normalised with triheptanoin, that is, increased Pi/PCr ratio during brain activation compared to the recovery phase (p=0.021), and deteriorated when triheptanoin was withdrawn. CONCLUSIONS: Treatment with triheptanoin resulted in a 90% clinical improvement in non-epileptic paroxysmal manifestations and a normalised brain bioenergetics profile in patients with GLUT1-DS.

Nadalin, S., I. Capobianco, F. Panaro, F. Di Francesco, R. Troisi, M. Sainz-Barriga, P. Muiesan, A. Konigsrainer and G. Testa (2016). “Living donor liver transplantation in europe.” Hepatobiliary Surg Nutr 5(2): 159-175.

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Living donor liver transplantation (LDLT) sparked significant interest in Europe when the first reports of its success from USA and Asia were made public. Many transplant programs initiated LDLT and some of them especially in Germany and Belgium became a point of reference for many patients and important contributors to the advancement of the field. After the initial enthusiasm, most of the European programs stopped performing LDLT and today the overall European activity is concentrated in a few centers and the number of living donor liver transplants is only a single digit fraction of the overall number of liver transplants performed. In this paper we analyse the present European activities and highlight the European contribution to the advancement of the field of LDLT.

Ogola, G. O. and S. Shafi (2016). “Cost of specific emergency general surgery diseases and factors associated with high-cost patients.” J Trauma Acute Care Surg 80(2): 265-271.

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BACKGROUND: We have previously shown that overall cost of hospitalization for emergency general surgery (EGS) diseases is more than $28 billion annually and rising. The purposes of this study were to estimate the costs associated with specific EGS diseases and to identify factors associated with high-cost hospitalizations. METHODS: The American Association for the Surgery of Trauma definition was used to identify hospitalizations of adult EGS patients in the 2010 National Inpatient Sample data. Cost of each hospitalization was obtained using cost-to-charge ratio in National Inpatient Sample. Regression analysis was used to estimate the cost for each EGS disease adjusted for patient and hospital characteristics. Hospitalizations with cost exceeding 75th percentile for each EGS disease were compared with lower-cost hospitalizations to identify factors associated with high cost. RESULTS: Thirty-one EGS diseases resulted in 2,602,074 hospitalizations nationwide in 2010 at an average adjusted cost of $10,110 (95% confidence interval, $10,086-$10,134) per hospitalization. Of these, only nine diseases constituted 80% of the total volume and 74% of the total cost. Empyema chest, colorectal cancer, and small intestine cancer were the most expensive EGS diseases with adjusted mean cost per hospitalization exceeding $20,000, while breast infection, abdominal pain, and soft tissue infection were the least expensive, with mean adjusted costs of less than $7,000 per hospitalization. The most important factors associated with high-cost hospitalizations were the number and type of procedures performed (76.2% of variance), but a region in Western United States (11.3%), Medicare and Medicaid payors (2.6%), and hospital ownership by public or not-for-profit entities (5.6%) were also associated with high-cost hospitalizations. CONCLUSION: A small number of diseases constitute a vast majority of EGS hospitalizations and their cost. Attempts at reducing the cost of EGS hospitalization will require controlling the cost of procedures.