Research Spotlight

Kennedy, L., L. Hargrove, J. Demieville, J. M. Bailey, W. Dar, K. Polireddy, Q. Chen, M. I. Nevah Rubin, A. Sybenga, S. DeMorrow, F. Meng, L. Stockton, G. Alpini and H. Francis (2018). “Knockout of l-Histidine Decarboxylase Prevents Cholangiocyte Damage and Hepatic Fibrosis in Mice Subjected to High-Fat Diet Feeding via Disrupted Histamine/Leptin Signaling.” Am J Pathol 188(3): 600-615.

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Feeding a high-fat diet (HFD) coupled with sugar, mimicking a Western diet, causes fatty liver disease in mice. Histamine induces biliary proliferation and fibrosis and regulates leptin signaling. Wild-type (WT) and l-histidine decarboxylase (Hdc(-/-)) mice were fed a control diet or an HFD coupled with a high fructose corn syrup equivalent. Hematoxylin and eosin and Oil Red O staining were performed to determine steatosis. Biliary mass and cholangiocyte proliferation were evaluated by immunohistochemistry. Senescence and fibrosis were measured by quantitative PCR and immunohistochemistry. Hepatic stellate cell activation was detected by immunofluorescence. Histamine and leptin levels were measured by enzyme immunoassay. Leptin receptor (Ob-R) was evaluated by quantitative PCR. The HDC/histamine/histamine receptor axis, ductular reaction, and biliary senescence were evaluated in patients with nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, or end-stage liver disease. Hdc(-/-) HFD mice had increased steatosis compared with WT HFD mice. WT HFD mice had increased biliary mass, biliary proliferation, senescence, fibrosis, and hepatic stellate cell activation, which were reduced in Hdc(-/-) HFD mice. In Hdc(-/-) HFD mice, serum leptin levels increased, whereas biliary Ob-R expression decreased. Nonalcoholic steatohepatitis patients had increased HDC/histamine/histamine receptor signaling. Hdc(-/-) HFD mice are susceptible to obesity via dysregulated leptin/Ob-R signaling, whereas the lack of HDC protects from HFD-induced fibrosis and cholangiocyte damage. HDC/histamine/leptin signaling may be important in managing obesity-induced biliary damage.

Keller, D. S., J. Qiu and A. J. Senagore (2018). “Predicting opportunities to increase utilization of laparoscopy for rectal cancer.” Surg Endosc 32(3): 1556-1563.

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BACKGROUND: Despite proven safety and efficacy, rates of laparoscopy for rectal cancer in the US are low. With reports of inferiority with laparoscopy compared to open surgery, and movements to develop accredited centers, investigating utilization and predictors of laparoscopy are warranted. Our goal was to evaluate current utilization and identify factors impacting use of laparoscopic surgery for rectal cancer. METHODS: The Premier Hospital Database was reviewed for elective inpatient rectal cancer resections (1/1/2010-6/30/2015). Patients were identified by ICD-9-CM diagnosis codes, and then stratified into open or laparoscopic approaches by ICD-9-CM procedure codes or billing charge. Logistic multivariable regression identified variables predictive of laparoscopy. The Cochran-Armitage test assessed trend analysis. The main outcome measures were trends in utilization and factors independently associated with use of laparoscopy. RESULTS: 3336 patients were included-43.8% laparoscopic (n = 1464) and 56.2% open (n = 1872). Use of laparoscopy increased from 37.6 to 55.3% during the study period (p < 0.0001). General surgeons performed the majority of all resections, but colorectal surgeons were more likely to approach rectal cancer laparoscopically (41.31 vs. 36.65%, OR 1.082, 95% CI [0.92, 1.27], p < 0.3363). Higher volume surgeons were more likely to use laparoscopy than low-volume surgeons (OR 3.72, 95% CI [2.64, 5.25], p < 0.0001). Younger patients (OR 1.49, 95% CI [1.03, 2.17], p = 0.036) with minor (OR 2.13, 95% CI [1.45, 3.12], p < 0.0001) or moderate illness severity (OR 1.582, 95% CI [1.08, 2.31], p < 0.0174) were more likely to receive a laparoscopic resection. Teaching hospitals (OR 0.842, 95% CI [0.710, 0.997], p = 0.0463) and hospitals in the Midwest (OR 0.69, 95% CI [0.54, 0.89], p = 0.0044) were less likely to use laparoscopy. Insurance status and hospital size did not impact use. CONCLUSIONS: Laparoscopy for rectal cancer steadily increased over the years examined. Patient, provider, and regional variables exist, with hospital status, geographic location, and colorectal specialization impacting the likelihood. However, surgeon volume had the greatest influence. These results emphasize training and surgeon-specific outcomes to increase utilization and quality in appropriate cases.

Grayburn, P. A. (2018). “Evaluating Patients With Low-Flow, Low-Gradient Aortic Stenosis by Dobutamine Echocardiography: It’s Complicated.” J Am Coll Cardiol 71(5): 486-488.

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The concept of low-flow, low-gradient aortic stenosis (LF-LG AS) was first introduced in 1980 by Carabello, who described 4 patients with low left ventricular ejection fraction (LVEF) and severe AS by calculated aortic valve area (AVA), but mean transvalvular gradient <25 mm Hg. Those patients either died (n = 3) after aortic valve replacement (AVR) or continued to have intractable heart failure (n = 1). Subsequent articles on the topic have highlighted the poor prognosis of such patients relative to high-gradient AS and the difficulty in evaluating whether such patients have truly severe AS or “pseudo-severe” AS, a condition in which the calculated AVA is artificially low because there is not enough flow to open a mild or moderately diseased valve. deFilippi et al. introduced the concept of using dobutamine stress echocardiography (DSE) to evaluate the response of peak velocity, mean gradient, and calculated AVA at baseline and after a graded infusion of dobutamine to increase forward flow across the valve. Three general responses were identified: true AS (increased peak velocity and gradient with no significant change in AVA), pseudo-severe AS (increased AVA with minimal change in peak velocity or gradient), and uncertain resulting from failure of forward flow to increase with dobutamine. Although numerous articles have now been written on this topic, it can still be difficult to accurately classify some patients based on their response to DSE. Recent American College of Cardiology/American Heart Association guidelines have proposed that AVR is indicated (Class IIa) if the mean gradient is ≥40 mm Hg or AVA ≤1.0 cm2 during dobutamine challenge. (Excerpt from text, p. 486; no abstract available.)

Florman, S., F. Vincenti, A. Durrbach, M. Abouljoud, B. Bresnahan, V. D. Garcia, L. Mulloy, K. Rice, L. Rostaing, C. Zayas, K. Calderon, U. Meier-Kriesche, M. Polinsky, L. Yang, J. M. Pestana and C. P. Larsen (2018). “Outcomes at 7 years post-transplant in black versus non-black kidney transplant recipients administered belatacept or cyclosporine in BENEFIT and BENEFIT-EXT.” Clin Transplant. Feb 20. [Epub ahead of print].

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Clinical outcomes are generally worse for black versus non-black renal allograft recipients. In BENEFIT and BENEFIT-EXT, recipients were randomized to belatacept more-intense-based, belatacept less-intense-based, or cyclosporine-based immunosuppression. At year 7, belatacept was associated with superior graft survival versus cyclosporine in BENEFIT (recipients of living or standard criteria deceased donor kidneys); belatacept was associated with similar graft survival versus cyclosporine in BENEFIT-EXT (recipients of extended criteria donor kidneys). In both studies, renal function was superior for belatacept-treated versus cyclosporine-treated patients. Seven-year outcomes were examined by race post hoc in each study. The effect of race and treatment on time to death or graft loss was compared using Cox regression. The interaction between treatment and race was also considered. Glomerular filtration rate (GFR) was estimated from months 1-84 using a repeated-measures model. In total, 8.3% (55/666) and 13.1% (71/543) of patients in BENEFIT and BENEFIT-EXT, respectively, were black. Time to death or graft loss was similar in blacks and non-blacks. For both subgroups, estimated mean GFR increased over 7 years for belatacept, but declined for cyclosporine. Outcomes were similar in belatacept-treated black and non-black patients. Due to the small number of black patients, these results must be interpreted with caution.

El-Dokla, A. M., R. Hasan and S. T. Ali (2018). “Unilateral faciobrachial weakness: An unusual neuromuscular presentation Of West Nile Virus infection.” Muscle Nerve 57(3): E110-e112.

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West Nile virus (WNV) first gained entry into North America in the New York City outbreak of 1999 and subsequently spread to other areas of the United States. (1) The clinical manifestations range from a mild febrile illness to West Nile neuroinvasive disease (WNND) characterized by meningitis, encephalitis and/or asymmetric flaccid paralysis (AFP). (2,3) However, patients with WNND may lack the classic clinical features of meningitis or encephalitis, which may confound the diagnosis. We describe 2 patients with WNND who presented with unilateral faciobrachial weakness without overt meningitis or encephalitis. Both were initially misdiagnosed with Bell’s palsy and treated with high dose corticosteroids with complete or near complete resolution of the facial nerve palsy. E