Regional fractional ventilation mapping in spontaneously breathing mice using hyperpolarized 129Xe MRI

The feasibility of ventilation imaging with hyperpolarized (HP) ¹²⁹Xe MRI has been investigated for quantitative and regional assessment of ventilation in spontaneously breathing mice. The multiple breath ventilation imaging technique was modified to the protocol of spontaneous inhalation of HP ¹²⁹Xe delivered continuously from a ¹²⁹Xe polarizer. A series of ¹²⁹Xe ventilation images was obtained by varying the number of breaths before the ¹²⁹Xe lung imaging. The fractional ventilation, r, was successfully evaluated for spontaneously breathing mice. An attempt was made to detect ventilation dysfunction in the emphysematous mouse lung induced by intratracheal administration of porcine pancreatic elastase (PPE). As a result, the distribution of fractional ventilation could be visualized by the r map. Significant dysfunction of ventilation was quantitatively identified in the PPE‐treated group. The whole‐lung r value of 0.34 ± 0.01 for control mice (N = 4) was significantly reduced, to 0.25 ± 0.07, in PPE‐treated mice (N = 4) (p = 0.038). This study is the first application of multiple breath ventilation imaging to spontaneously breathing mice, and shows that this methodology is sensitive to differences in the pulmonary ventilation. This methodology is expected to improve simplicity as well as noninvasiveness when assessing regional ventilation in small rodents. Copyright © 2014 John Wiley & Sons, Ltd.     

Olmesartan is an angiotensin II receptor blocker with an inhibitory effect on angiotensin-converting enzyme.

Angiotensin II receptor blockers (ARBs) are widely used for the treatment of hypertension. It is believed that treatment with an ARB increases the level of plasma angiotensin II (Ang II) because of a lack of negative feedback on renin activity. However, Ichikawa (Hypertens Res 2001; 24: 641-646) reported that long-term treatment of hypertensive patients with olmesartan resulted in a reduction in plasma Ang II level, though the mechanism was not determined. It has been reported that angiotensin 1-7 (Ang-(1-7)) potentiates the effect of bradykinin and acts as an angiotensin-converting enzyme (ACE) inhibitor. It is known that ACE2, which was discovered as a novel ACE-related carboxypeptidase in 2000, hydrolyzes Ang I to Ang-(1-9) and also Ang II to Ang-(1-7). It has recently been reported that olmesartan increases plasma Ang-(1-7) through an increase in ACE2 expression in rats with myocardial infarction. We hypothesized that over-expression of ACE2 may be related to a reduction in Ang II level and the cardioprotective effect of olmesartan. Administration of 0.5 mg/kg/day of olmesartan for 4 weeks to 12-week-old stroke-prone spontaneously hypertensive rats (SHRSP) significantly reduced blood pressure and left ventricular weight compared to those in SHRSP given a vehicle. Co-administration of olmesartan and (D-Ala7)-Ang-(1-7), a selective Ang-(1-7) antagonist, partially inhibited the effect of olmesartan on blood pressure and left ventricular weight. Interestingly, co-administration of (D-Ala7)-Ang-(1-7) with olmesartan significantly increased the plasma Ang II level (453.2+/-113.8 pg/ml) compared to olmesartan alone (144.9+/-27.0 pg/ml, p<0.05). Moreover, olmesartan significantly increased the cardiac ACE2 expression level compared to that in Wistar Kyoto rats and SHRSP treated with a vehicle. Olmesartan significantly improved cardiovascular remodeling and cardiac nitrite/ nitrate content, but co-administration of olmesartan and (D-Ala7)-Ang-(1-7) partially reversed this anti-remodeling effect and the increase in nitrite/nitrate. These findings suggest that olmesartan may exhibit an ACE inhibitory action in addition to an Ang II receptor blocking action, prevent an increase in Ang II level, and protect cardiovascular remodeling through an increase in cardiac nitric oxide production and endogenous Ang-(1-7) via over-expression of ACE2.     

Expression of vascular endothelial growth factor and angiogenesis in patellar tendon grafts in the early phase after anterior cruciate ligament reconstruction

The aim of this study was to clarify vascular endothelial growth factor (VEGF) expression and angiogenesis in the patellar tendon (PT) autograft in the early phase after anterior cruciate ligament (ACL) reconstruction using a rabbit model. The right knees of 30 Japanese white rabbits underwent ACL reconstruction using the medial third of the PT complex. We evaluated the grafted tendon at 1, 2, 3, 4, and 8 weeks after ACL reconstruction by immunohistology for proliferating cell nuclear antigen, VEGF, and CD31, which is a marker for vascular endothelial cells. At week 1 , few cells were observed at the midsubstance of the grafted tendon. A number of proliferating cells were observed at the surface area of the PT graft 2 weeks after graft transplantation, while no vessel formation was observed in the graft at the same time. VEGF was highly expressed 2-3 weeks postoperatively. Vessel formation in the PT graft increased with time from 3 to 8 weeks after ACL reconstruction. The rates of proliferating cells and VEGF-expressing cells decreased with time from 3 to 8 weeks. This study has suggested that VEGF is involved in the graft remodeling process particularly at the early phase after ACL reconstruction.     

Living domino liver transplantation in an adult with congenital absence of portal vein.

Congenital absence of the portal vein (CAPV) is a rare malformation of the splanchnic venous system. Although CAPV is usually detected in the pediatric age group, our patient was a 35-year-old woman. She had been diagnosed with CAPV in 1996 when she was 27 years old. In 1998, she was placed on hemodialysis due to chronic renal failure. After several episodes of encephalopathy in 2002, liver transplantation (LT) was recommended to her and her family. Since there was no suitable living donor candidate, she was put on the waiting list for a deceased donor liver transplant in Japan. In 2004, her ammonia level increased to around 300 microg/dl, and she went into a coma lasting for three days. After recovering from this event, she underwent a living domino transplantation using a whole liver donated by a familial amyloid polyneuropathy (FAP) patient. Her portal vein, which had drained directly into the inferior vena cava (IVC), was transected together with a cuff of the IVC wall and anastomosed to the graft liver portal vein in an end-to-end fashion. In conclusion, liver transplantation proved to be a safe and effective way to save this patient and improve her quality of life.     

Effects of a new dihydropyridine calcium antagonist on vascular smooth muscles, cardiac muscles and [3H]-nitrendipine binding

The effects of methyl 2,6-dimethyl-4-(2-nitrophenyl)-5-(2-oxo-1,3,2-dioxaphosphorinan-2- yl)-1,4- dihydropyridine 3-carboxylate (DHP-218), a new dihydropyridine calcium antagonist, on vascular smooth muscles, cardiac muscles and [3H]-nitrendipine binding to the cardiac muscle and brain membranes were investigated in vitro. Vascular smooth muscles: Calcium-induced contraction of the rat aorta in high K+ solution was inhibited by DHP-218 with the pA2 value of 9.11. The IC50 value for the inhibitory effects of this compound in high K+-induced and phenylephrine-induced contraction was 6.3 nmol/l and 66 nmol/l, respectively. Vasodilatory effects of this drug on various blood vessels of rabbits contracted by high K+ appeared to a similar extent. The onset of the vasodilatory effect was very slow and the recovery rate of vasodilatory response after washout with the bathing solution containing high K+ or phenylephrine was also very slow. Cardiac muscles: Negative chronotropic and inotropic actions were observed at concentrations more than 30 and 100 nmol/l, respectively. Duration of the plateau phase of normal action potential was shortened and the amplitude and duration of slow action potential were reduced at concentrations more than 1 mumol/l. Very high vasculoselectivity was observed. Displacement of [3H]-nitrendipine binding: The pattern of displacement of [3H]-nitrendipine binding by DHP-218 was very similar to that of other 1,4-dihydropyridines but this compound was about 70 times less potent than nifedipine in [3H]-nitrendipine displacement capacity. These results indicate that DHP-218 has specific vasodilatory action due to calcium antagonism, but association and dissociation rates with tissue and receptors were different from those of nifedipine.     

Anti-tumor activity of human recombinant TNF against human malignant glioma cell lines and combined effect with Hu INF-beta

Human TNF was detected fairly recently and at present the anti-tumor activity of human recombinant TNF is being examined against various malignant tumors of human origin. In the present study, we report the anti-tumor activity of recombinant human TNF against human malignant glioma cell lines in vitro and in vivo, in addition to its combined effects with HuIFN-beta. The in vitro study was conducted as follows. Thirteen human glioma cell lines were exposed to 100 U/ml TNF, 1,000 IU/ml HuIFN-beta, or both, and the suppression rate was calculated on days 3, 5 and 7. In the in vivo study, nude mice carrying a human glioma cell line, KMS II, in the subcutaneous tissues were divided into groups and drugs were administered intratumorally as described below. 1) control, 2) TNF 5,000 U single administration, 3) TNF 5,000 U, intermittently administered (once/week for two weeks), 4) TNF 5,000 U, continuously administered (3/week for two weeks), 5) HuIFN-beta 50 X 10(4) IU (3/week for two weeks), and 6) combination of 4) with 5). Results of the in vitro study revealed some suppressive effects on proliferation of tumor cells on day 7 in all 13 glioma cell lines examined with 100 U/ml TNF. And also, especially in 8 of 13 cell lines, the suppression rate was more than 30%. The suppressive effects of TNF were augmented by combined use of HuIFN-beta in all cell lines, giving a range of suppression of 67.8 to 99.3%. The in vivo study revealed that the mean tumor weight ratios (control = 100%) on day 19 (the end of the experiment) were as follows; single administration of TNF: 41.3%, intermittent: 46.7%, continuous: 26.7%, HuIFN-beta: 65.9%, combination: 18.5%. Statistical analysis disclosed significant suppressive effects on tumor proliferation between the control group and 3 TNF-administered groups (single, intermittent, and continuous) and that suppression in the continuously administered group was more severe in comparison with the group given single administration. Moreover, it was suggested that combination therapy with TNF and Hu IFN-beta was more effective than a single therapy with TNF only or HuIFN-beta only. From the results described above, it was found that human recombinant TNF had some cytotoxic effects against human malignant gliomas in vitro and in vivo, although the degree of cytotoxicity was not always higher in comparison with the effects of TNF.     

Clinical outcome of surgical management for patients with renal cell carcinoma involving the inferior vena cava

BACKGROUND: The objective of this study was to evaluate the clinical outcome after surgical management of renal cell carcinoma (RCC) extending to the inferior vena cava (IVC). METHODS: This study included a total of 55 patients (41 men and 14 women; mean age, 59.3 years) with RCC (39 right- and 16 left-sided tumors) involving the IVC, who underwent radical nephrectomy and tumor thrombectomy between 1983 and 2005 at a single institution in Japan. The level of thrombus was classified as follows: level I, infrahepatic; level II, intrahepatic; level III, suprahepatic; and level IV, extending to the atrium. Clinicopathological data from these patients were retrospectively reviewed to identify factors associated with survival. RESULTS: There were 11 and 18 patients who were diagnosed as having lymph node and distant metastases, respectively. Twenty-two patients had tumor thrombus in level I, 20 in level II, 10 in level III, and 3 in level IV. Pathological examinations demonstrated that 34 and 21 patients had clear cell carcinoma and non-clear cell carcinoma, respectively, 42, 9 and 4 were pT3b, pT3c and pT4, respectively, and 6, 35 and 14 were Grades 1, 2 and 3, respectively. Cancer-specific 1-, 3- and 5-year survival rates of these 55 patients were 74.5%, 51.4% and 30.3%, respectively. Among several factors examined, clinical stage (P = 0.047), lymph node metastasis (P = 0.016), histological subtype (P = 0.034) and tumor grade (P < 0.001) were significantly associated with cancer-specific survival by univariate analysis. Furthermore, multivariate analysis demonstrated clinical stage (P = 0.037) and tumor grade (P < 0.001) as independent predictors of cancer-specific survival irrespective of other significant factors identified by univariate analysis. CONCLUSIONS: In patients with RCC involving the IVC, biological aggressiveness characterized by tumor grade rather than tumor extension would have more potential prognostic importance; therefore, more intensive multimodal therapy should be considered in patients with high grade RCC with tumor thrombus extending into the IVC.