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.     

Spontaneous recovery of fear differs among early – late adolescent and adult male mice

Adolescence is a vulnerable period for developing anxiety-related mental disorders such as post-traumatic stress disorder (PTSD), which requires a long-term course of therapy when a traumatic event has been experienced during childhood. However, the biological mechanism underlying these age-dependent characteristics remains unclear. In the present study, we used early adolescent, late adolescent and adult (4-, 8-, and 15-week old) male mice to examine age differences in fear memory, fear extinction, and spontaneous recovery of fear. We also measured the activation of extracellular signal-regulated kinase (ERK) 2 in the dorsal hippocampus (dHip) and the basolateral amygdala (BLA) following a spontaneous recovery test. Our major findings were as follows: (1) early adolescent and adult mice did not recover the fear response; only late adolescent mice recovered the fear response. (2) The ERK2 in the dHip was more activated after the spontaneous recovery test in late adolescent mice than in adult mice, and the ERK2 in the BLA was more activated after the spontaneous recovery test in adult mice than in late adolescent mice. These results suggest that there exists a unique period in which spontaneous recovery occurs and that these late adolescent behavioral signatures may be related to alteration in the ERK2 phosphorylation in the dHip and BLA.     

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.     

Laparoscopic cholecystectomy and time-course changes in renal function

Background: Recently, the retraction method has been used to reduce intraabdominal pressure (IAP) during laparoscopic surgery. The purpose of this study was to determine the serial changes in renal function during laparoscopic cholecystectomy (LC) using the retraction method. Methods: Urine output, effective renal plasma flow (ERPF), and glomerular filtration rate (GFR) were measured serially in seven patients who underwent LC with 12 mmHg pneumoperitoneum (High-IAP group) and five who underwent LC using the retraction method with 4 mmHg pneumoperitoneum (Low-IAP group). Results: Urine output, ERPF, and GFR were decreased during pneumoperitoneum in the High-IAP group, whereas no significant changes in any of these parameters were observed in the Low-IAP group. Conclusions: Our findings demonstrate that reduction of IAP to 4 mmHg using the retraction method prevents the transient renal dysfunction caused by prolonged 12 mmHg pneumoperitoneum during LC, suggesting that the retraction method reduces the risk of perioperative renal dysfunction during laparoscopic surgery. Received: 26 March 1996/Accepted: 27 July 1996     

Clinical effect of LM-001, prostaglandin synthetic inhibitor, on pain from urinary tract stone and vesical urgency after operation of the bladder or prostate

Clinical effect of LM-001, a prostaglandin synthetic inhibitor developed from a drug delivery system, was evaluated in 54 patients with pain from urinary tract stones (stone pain) and 32 with vesical urgency after an operation on bladder or prostate. LM-001, felbinac ethyl incorporated in lipid microsphere, wes intravenously administered at the onset of stone pain or vesical urgency. Of 54 with stones and 32 with urgency, 53 and 29 were eligible for response, respectively. The symptoms improved or disappeared in some cases just after the administration and in the majority of patients within 15 minutes, in 49 of 53 patients with stone pain. Further, the effectiveness lasted over 24 hours in 26 of the 49 responding to this agent. On one hand, improvement or disappearance of vesical urgency was recognized in 25 of 29 patients, and the effectiveness was observed shortly after injection in 16 and lasted over 24 hours in 13 cases. Toxicities of this drug were investigated in 54 patients with stone pain and 32 with urinary urgency. Side effects consisted of pain at the injection site in 4, a slight fall of blood pressure in 1, slight visual disturbance in 1, body heat sensation in 1, leukocytosis in 3 and elevation of alkaline phosphatase in 1. These symptoms were transient and disappeared without use of any agent. LM-001 is concluded to be a useful drug for controlling stone pain and vesical urgency since an immediate effect, long durability and high response rates were obtained without severe side     

Carnitine status in Reye and Reye-like syndromes

Fourteen children with the following Reye and Reye-like syndromes were studied to determine each patient's carnitine status: valproate-induced Reye-like attack, ornithine transcarbamylase deficiency, systemic carnitine deficiency, methylmalonic acidemia, and propionic acidemia. Reduced free carnitine and increased serum and urine acylcarnitine levels were found in all patients except for 2 with Reye syndrome, in whom serum creatinine levels were mildly elevated and serum free carnitine levels were not reduced. The renal free carnitine reabsorption rate was reduced in all cases. The free carnitine content of autopsied liver samples were reduced in 2 Reye syndrome patients, 2 OTC deficiency patients, and in a single systemic carnitine deficiency patient. The observed secondary free carnitine deficiency may be a factor in the pathogenesis of Reye and Reye-like syndromes.     

Clinical significance of renal hemodynamics in severe congestive heart failure: responsiveness to ultrafiltration therapies

Isolated ultrafiltration, hemodialysis & peritoneal dialysis (Tx) were recently used in the treatment of intractable heart failure (HF). We examined the relation between the response of HF to Tx and the residual kidney functions. Tx was carried out in 17 patients (Pts) with HF who did not respond to aggressive medical treatment. Ten Pts (R) responded to Tx and 7 Pts (N) did not. Serum urea nitrogen (UN), creatinine (Cr), uric acid (UA), sodium (Na), potassium (K), and chloride (Cl) concentrations on admission and before Tx were not different between R and N. Urine UN, Cr, Na, K, and Cl on admission and before Tx were also not significantly different. Fractional sodium excretions (FENa), renal failure indices (RFI), and urine/plasma Cr ratios (U/P Cr) on admission were 2.0 +/- 1.6, 2.7 +/- 2.2, and 30.5 +/- 20.0 in R and 5.9 +/- 4.2, 8.2 +/- 6.0 and 11.5 +/- 3.8 in N. They were significantly different (p less than 0.05). However, these did not differ before and after Tx. These data show that FENa, RFI and U/P Cr might be useful indices in predicting the responsiveness of intractable HF to Tx.