Citations

Abstract The lipid microenvironment of membrane proteins can affect their structure, function, and regulation. We recently described differential effects of acute modification of membrane cholesterol on the function of type 1 and 2 cholecystokinin (CCK) receptors. We now explore the regulatory impact of chronic cholesterol modification on these receptors using novel receptor‐bearing cell lines with elevated membrane cholesterol. Stable CCK1R and CCK2R expression was established in clonal lines of 25RA cells having gain‐of‐function in SCAP [sterol regulatory element binding protein (SREBP) cleavage‐activating protein] and SRD15 cells having deficiencies in Insig‐1 and Insig‐2 enzymes affecting HMG CoA reductase and SREBP. Increased cholesterol in the plasma membrane of these cells was directly demonstrated, and receptor binding and signaling characteristics were shown to reflect predicted effects on receptor function. In both environments, both types of CCK receptors were internalized and recycled normally in response to agonist occupation. No differences in receptor distribution within the membrane were appreciated at the light microscopic level in these CHO‐derived cell lines. Fluorescence anisotropy was studied for these receptors occupied by fluorescent agonist and antagonist, as well as when tagged with YFP. These studies demonstrated increased anisotropy of the agonist ligand occupying the active state of the CCK1R in a cholesterol‐enriched environment, mimicking fluorescence of the uncoupled, inactive state of this receptor, while there was no effect of increasing cholesterol on fluorescence at the CCK2R. These cell lines should be quite useful for examining the functional characteristics of potential drugs that might be used in an abnormal lipid environment.

Background: The optimal choice for intervention for recalcitrant lateral elbow tendinopathy remains unclear as various treatment modalities have documented comparable results in the literature. Purpose: To explore the safety, tolerability, and early efficacy of a new minimally invasive mode of treatment that delivers focused, calibrated ultrasonic energy, effectively microresecting the pathological tendon and removing only pathological tissue. Study Design: Case series; Level of evidence, 4. Methods: Seven male and 13 female patients aged 33 to 65 years averaging 12.5 months (range, 4-48) of failed nonoperative therapy underwent the ultrasonic microresection procedure in an outpatient clinic setting. The procedure involved a sterile, ultrasound-guided percutaneous microresection with a proprietary device (TX1) performed through a stab incision under local anesthesia. The duration of the procedure and complications of the device or procedure were assessed. Outcome parameters included patient satisfaction; visual analog scale (VAS) pain scores; Disabilities of the Arm, Shoulder and Hand (DASH) scores at 1, 3, 6, and 12 months; and ultrasound assessment at 3 and 6 months. Results: The median duration for the sterile confirmatory ultrasound examination (phase 1) was 88.5 seconds (range, 39-211; SD, ±47.6), the median duration of the procedure proper (phase 2) was 10.1 minutes (range, 4.1-19.4; SD, ±3.7), and the median energy time (duration the TX1 device was activated) was 32.5 seconds (range, 18-58; SD, ±11.0). No complications were encountered. A significant improvement in VAS score (from 5.5 to 3.3; P < .001) occurred by 1 week, and significant improvements in both DASH-Compulsory (from 21.7 to 11.3; P = .001) and DASH-Work (from 25.0 to 6.3; P = .012) scores occurred by 1 month. The VAS scores further improved at 3, 6, and 12 months (from 2.0 to 1.0 to 0.50; P = .003 and .023). The DASH-Compulsory score improved significantly from 3 to 6 months (from 8.6 to 4.6; P = .003), and both the DASH-Compulsory and DASH-Work scores were sustained by 12 months. Sonographically reduced tendon thickness (19 patients), resolved or reduced hypervascularity (17 patients), and reduced hypoechoic area (18 patients) occurred by 6 months. Nineteen of the 20 patients (95%) expressed satisfaction with the procedure, with 9 patients being very satisfied with their overall experience at 6 months after the procedure, 10 patients somewhat satisfied, and 1 patient neutral. Conclusion: Ultrasonic microresection of diseased tissue with the TX1 device provides a focally directed, safe, specific, minimally invasive, and well-tolerated treatment for recalcitrant lateral elbow tendinopathy in an office-based or ambulatory surgical setting with good evidence of some level of efficacy in 19 of 20 patients (95%) that is sustained for at least 1 year.

AbstractBackground and AimHepatocellular carcinoma (HCC) is a major complication of cirrhosis and has been increasing in incidence in recent years. Fatty liver disease is an increasingly common cause of chronic liver disease, and there have been several case reports of HCC in patients with non‐cirrhotic fatty liver disease. However, there is limited data from systematic studies with histological confirmation of the presence of both the HCC and the non‐cirrhotic fatty liver disease.MethodsWe studied the occurrence of fatty liver disease and the associated demographic, clinical, and pathological characteristics of a large cohort of patients with HCC in non‐cirrhotic livers. Patients with intrahepatic cholangiocarcinoma (CC) occurring in non‐cirrhotic livers and diagnosed during the same time period were used as the comparison group.ResultsSignificant steatosis in the nontumor liver had a statistically significant association with HCC, being present in 54% (85/157) of HCC compared with 27% (32/120) of CC (P < 0.0001). Steatohepatitis was present in 15% (24/157) of HCC and 1% (2/120) of CC (P = 0.0014). Furthermore, HCC was more prevalent in cases with higher grades of steatosis. In addition, the recently described intratumoral steatohepatitic morphology of HCC (SH‐HCC) was also associated with significant steatosis in nontumor liver, with significant steatosis being present in 89% with SH‐HCC compared with 50% without SH‐HCC (P = 0.0162). Finally, SH‐HCC was increasingly more prevalent in patients with higher grades of nontumor steatosis.ConclusionsTaken together, these findings suggest a strong association between fatty liver disease and HCC in non‐cirrhotic livers.