Neuronal nitric oxide synthase modulation of intracellular Ca2+ handling overrides fatty acid potentiation of cardiac inotropy in hypertensive rats.

Cardiac neuronal nitric oxide synthase (nNOS) is an important molecule that regulates intracellular Ca2+ homeostasis and contractility of healthy and diseased hearts. Here, we examined the effects of nNOS on fatty acid (FA) regulation of left ventricular (LV) myocyte contraction in sham and angiotensin II (Ang II)-induced hypertensive (HTN) rats. Our results showed that palmitic acid (PA, 100 µM) increased the amplitudes of sarcomere shortening and intracellular ATP in sham but not in HTN despite oxygen consumption rate (OCR) was increased by PA in both groups. Carnitine palmitoyltransferase-1 inhibitor, etomoxir (ETO), reduced OCR and ATP with PA in sham and HTN but prevented PA potentiation of sarcomere shortening only in sham. PA increased nNOS-derived NO only in HTN. Inhibition of nNOS with S-methyl-L-thiocitrulline (SMTC) prevented PA-induced OCR and restored PA potentiation of myocyte contraction in HTN. Mechanistically, PA increased intracellular Ca2+ transient ([Ca2+]i) without changing Ca2+ influx via L-type Ca2+ channel (I-LTCC) and reduced myofilament Ca2+ sensitivity in sham. nNOS inhibition increased [Ca2+]i, I-LTCC and reduced myofilament Ca2+ sensitivity prior to PA supplementation; as such, normalized PA increment of [Ca2+]i. In HTN, PA reduced I-LTCC without affecting [Ca2+]i or myofilament Ca2+ sensitivity. However, PA increased I-LTCC, [Ca2+]i and reduced myofilament Ca2+ sensitivity following nNOS inhibition. Myocardial FA oxidation (18F-fluoro-6-thia-heptadecanoic acid, 18F-FTHA) was comparable between groups, but nNOS inhibition increased it only in HTN. Collectively, PA increases myocyte contraction through stimulating [Ca2+]i and mitochondrial activity in healthy hearts. PA-dependent cardiac inotropy was limited by nNOS in HTN, predominantly due to its modulatory effect on [Ca2+]i handling.

Surgical completeness of bilateral axillo-breast approach robotic thyroidectomy: comparison with conventional open thyroidectomy after propensity score matching.

BACKGROUND: Bilateral axillo-breast approach (BABA) robotic thyroidectomy (RoT) has good postoperative and excellent cosmetic outcomes. To assess the surgical completeness of BABA RoT, it was compared to open thyroidectomy (OT) after propensity score matching of the cohorts. METHODS: Between 2008 and 2010, 760 patients who underwent total thyroidectomy with central node dissection (CND) caused by papillary thyroid carcinoma (PTC) in Seoul National University Hospital were enrolled; 327 BABA robotic and 423 open method operations were performed. We selected 174 robotic and 237 open thyroidectomy patients who received radioactive iodine (RAI) ablation. Propensity score matching using 3 demographic and 5 pathologic factors was used to generate 2 matched cohorts, each composed of 108 patients. RESULTS: The matched BABA RoT and OT cohorts were not different with regard to the RAI uptake ratio, stimulated thyroglobulin (Tg) levels, or proportion of patients with stimulated Tg levels <1.0 ng/mL on the first ablation. The number of RAI ablation sessions and RAI doses needed to achieve a complete ablation also did not differ significantly. CONCLUSION: The surgical completeness of BABA RoT did not differ from OT. BABA RoT may be suitable for patients with PTC who prefer scarless neck surgery.

Transcatheter arterial embolization with 188Rhenium-HDD-labeled iodized oil in rabbit VX2 liver tumor.

PURPOSE: To evaluate the antitumor effect of transcatheter arterial embolization (TAE) with use of rhenium 188 HDD (4-hexadecyl 2,2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol)-labeled iodized oil and to compare it with that of transcatheter arterial chemoembolization (TACE) with use of an established chemotherapeutic agent and iodized oil in experimentally induced liver tumor. MATERIALS AND METHODS: VX2 carcinoma was grown in the livers of 57 rabbits. TAE was performed with (188)Re-HDD-labeled iodized oil (Re-Lp group; n = 21), doxorubicin/iodized oil emulsion (Dx-Lp group; n = 21), and iodized oil alone (n = 15). Sequential conjugated planar imaging was performed for dosimetry of the radioisotope in the Re-Lp group (n = 15). Growth ratio and percentage of viable tumor were estimated by computed tomography and histopathologic examination. Hepatic and hematologic toxicities were evaluated by biochemical analysis. RESULTS: On conjugated planar imaging, radioactivity was concentrated on the tumor (effective half-life, 16.2 hours), and mean radiation dose to the tumor was 147.7 Gy. The mean growth ratios 1, 2, and 3 weeks after TAE and the percentage of viable tumor in the Re-Lp group (-3.4, -7.6, -11.1, and 0.3%) and the Dx-Lp group (-3.2, -5.3, 29.0, and 2.6%) were significantly lower than the respective values in the iodized oil group (45.5, 145.4, 283.0, and 30.1%; P < .001). However, the differences between the values in the Re-Lp group and those in the Dx-Lp group were not significant (P values of .165-0.497 for growth ratios; P = .134 for percentage of viable tumor). There was similar transient hepatotoxicity in all three groups. CONCLUSIONS: TAE with (188)Re-HDD-labeled iodized oil has potent antitumor effect in VX2 liver tumor that is comparable with that of TACE with an established chemotherapeutic agent.

Lipiodol solution of 188Re-HDD as a new therapeutic agent for transhepatic arterial embolization in liver cancer: preclinical study in a rabbit liver cancer model.

UNLABELLED: It has been reported that lipiodol solution of (188)Re-labeled 2,2,9,9-tetramethyl-4,7-diaza-1,10-decanedithiol (TDD), an N(2)S(2) derivative, shows excellent targeting of liver cancer after transhepatic arterial embolization (TAE). However, its tumor retention is not high enough to treat liver cancer. Therefore, a new form of TDD, 4-hexadecyl-TDD (HDD), was developed to improve tumor retention by introducing a long alkyl chain. In this study, we compared the tumor retention properties of (188)Re-HDD/lipiodol and (188)Re-TDD/lipiodol, using a rabbit liver cancer model, and performed dosimetry using the results. METHODS: The VX2 cancer cell line was implanted into the livers of 7 rabbits. TAE was performed on 3 rabbits with (188)Re-TDD/lipiodol and on 4 rabbits with (188)Re-HDD/lipiodol, and conjugated anterior and posterior planar scans were obtained at 1, 2, 6, 24, and 48 h after TAE. From these images, tumor retention was calculated and compared between (188)Re-TDD and (188)Re-HDD. Afterward, the required dose of radioactivity and the radiation dosimetry for exposure of major organs were calculated using MIRDOSE3.1 software. RESULTS: The residence times of radioactivity in the liver were 10.2 +/- 1.0 h in the (188)Re-TDD group and 17.6 +/- 0.8 h in the (188)Re-HDD group (P = 0.034). The required radioactivity for 100 Gy of irradiation to 2.64- to 5.27-cm tumors was 142-1,070 MBq of (188)Re-HDD in the rabbit model. The radiation exposures for the major organs were within the tolerable range, and the S-value for the whole body (effective dose equivalent) was calculated to be 0.209 mSv/MBq. CONCLUSION: Introduction of a long alkyl chain significantly improved the tumor retention of (188)Re-HDD/lipiodol, compared with that of (188)Re-TDD/lipiodol. Moreover, the required radioactivity for humans and the radiation exposure were within the feasible range for clinical application.