The transient receptor potential vanilloid 1 receptor (TRPV1) is an important nociceptor involved in neurogenic inflammation. We aimed to examine the role of TRPV1 in experimental colitis and in the development of visceral hypersensitivity to mechanical and chemical stimulation. Male Sprague-Dawley rats received a single dose of trinitrobenzenesulfonic acid (TNBS) in the distal colon. In the preemptive group, rats received the TRPV1 receptor antagonist JYL1421 (10 mumol/kg, i.v.) or vehicle 15 min prior to TNBS followed by daily doses for 7 days. In the post-inflammation group, rats received JYL1421 daily for 7 days starting on day 7 following TNBS. The visceromotor response (VMR) to colorectal distension (CRD), intraluminal capsaicin, capsaicin vehicle (pH 6.7) or acidic saline (pH 5.0) was assessed in all groups and compared with controls and naïve rats. Colon inflammation was evaluated with H&E staining and myeloperoxidase (MPO) activity. TRPV1 immunoreactivity was assessed in the thoraco-lumbar (TL) and lumbo-sacral (LS) dorsal root ganglia (DRG) neurons. In the preemptive vehicle group, TNBS resulted in a significant increase in the VMR to CRD, intraluminal capsaicin and acidic saline compared the JYL1421-treated group (P<0.05). Absence of microscopic colitis and significantly reduced MPO activity was also evident compared with vehicle-treated rats (P<0.05). TRPV1 immunoreactivity in the TL (69.1+/-4.6%) and LS (66.4+/-4.2%) DRG in vehicle-treated rats was increased following TNBS but significantly lower in the preemptive JYL1421-treated group (28.6+/-3.9 and 32.3+/-2.3 respectively, P<0.05). JYL1421 in the post-inflammation group improved microscopic colitis and significantly decreased the VMR to CRD compared with vehicle (P<0.05, >/=30 mm Hg) but had no effect on the VMR to chemical stimulation. TRPV1 immunoreactivity in the TL and LS DRG was no different from vehicle or naïve controls. These results suggest an important role for TRPV1 channel in the development of inflammation and subsequent mechanical and chemical visceral hyperalgesia.

Gastric suctioning is common in neonatal intensive care units. Studies suggest that gastric suctioning in premature infants may play a role in the development of visceral hyperalgesia. We hypothesized that repeated orogastric suctioning during the neonatal period results in chronic alterations in visceral and somatic sensation through a corticotropin-releasing factor mediated mechanism. Neonatal male Long Evans rats (n = 13) received daily orogastric suctioning for 10 days starting at postnatal day two (P2). Control rats (n = 15) were handled similarly without orogastric suction. A second study group was subjected to a similar protocol, only with pre-emptive administration of a CRF1 receptor antagonist (antalarmin, 20 mg/kg, IP) (n = 8). The control group received vehicle only (n = 8). An additional group was given antalarmin without suctioning (n = 5). After these rats grew to adulthood (PN 60), a visceromotor response to graded colorectal distension was recorded (10-80 mmHg, 30s, 180s inter-stimulus intervals) to assess changes in visceral sensitivity. Paw withdrawal latency to noxious heat applied to the hind paws was measured to assess changes in cutaneous sensitivity. Orogastric suctioning during the neonatal period results in global chronic somatic and visceral hyperalgesia in adult rats. Visceral hyperalgesia is prevented by pre-emptive administration of the CRF1 receptor antagonist, antalarmin.

Liver transplantation can provide definitive cure for patients with cirrhosis and hepatocellular carcinoma (HCC) when used appropriately. Advances in the management of HCC have allowed improved control of HCC while waiting for liver transplantation and new approaches to candidate selection particularly with regard to tumor burden and downstaging protocols. Additionally, there have been recent changes in allocation policy related to HCC in the U.S. that cap the HCC MELD exception at 34 points and implement a 6-month delay in a HCC MELD exception. This review examines the U.S. liver transplant allocation policy related to HCC, comprehensively details locoregional therapy options in HCC patients awaiting liver transplantation, and considers the impact of an increasing burden of HCC on future liver graft allocation policy. Liver Transpl 21:1543-1552, 2015. V C 2015 AASLD.

An acceptable SVR rate is achievable in a safety net patient population. Addressing the barriers to care will be paramount when using direct-acting antivirals.

Risk of recurrent hepatocellular carcinoma (rHCC) after liver transplantation (LT) depends on the pre‐LT HCC burden, tumor behavior, and response to locoregional therapy (LRT). In December 2017, LT priority for HCC was expanded to select patients outside the Milan criteria who respond to LRT. Our aims were to develop a novel objective measure of pre‐LT HCC burden (model of recurrent hepatocellular carcinoma–initial, maximum, last [RH‐IML]), incorporating tumor behavior over time, and to apply RH‐IML to model post‐LT rHCC. Using United Network for Organ Sharing data from between 2002‐2014 (development) and 2015‐2017 (validation), we identified adult LT recipients with HCC and assessed pre‐LT HCC tumor behavior and post‐LT rHCC. For each patient, HCC burden was measured at 3 points on the waiting list: initial (I), maximum (M) total tumor diameter, and last (L) exception petition. HCC burden at these 3 points were classified as (A) Milan to University of California, San Francisco (UCSF), and (D) >UCSF, resulting in each patient having a 3‐letter RH‐IML designation. Of 16,558 recipients with HCC, 1233 (7%) had any post‐LT rHCC. rHCC rates were highest in RH‐IML group CCC (15%) and DDD (18%). When M and L tumor burdens did not exceed Milan (class B or A), rHCC was low (≤10%) as in AAA, ABA, ABB, BBA, BBB; rHCC was also low (≤10%) with successful downstaging when L was A (